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Phan P, Hoang J, Kumar TKS. Overexpression and biophysical and functional characterization of a recombinant FGF21. BIOPHYSICAL REPORTS 2025; 5:100198. [PMID: 39884432 PMCID: PMC11869967 DOI: 10.1016/j.bpr.2025.100198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/17/2025] [Accepted: 01/24/2025] [Indexed: 02/01/2025]
Abstract
Fibroblast growth factor 21 (FGF21) is an endocrine FGF that plays a vital role in regulating essential metabolic pathways. FGF21 increases glucose uptake by cells, promotes fatty acid oxidation, reduces blood glucose levels, and alleviates metabolic diseases. However, detailed studies on its stability and biophysical characteristics have not been reported. Herein, we present the overexpression, biophysical characterization, and metabolic activity of a soluble recombinant FGF21 (rFGF21). The far-UV circular dichroism spectra of rFGF21 show a negative trough at 215 nm, indicating that the protein's backbone predominantly adopts a β sheet conformation. rFGF21 shows intrinsic tyrosine fluorescence at 305 nm. Thermal denaturation using differential scanning calorimetry reveals that rFGF21 is relatively thermally unstable, with a melting temperature of 46.8°C (±0.1°C). The urea-induced unfolding of rFGF21 is rapid, with a chemical transition midpoint of 0.4 M. rFGF21 is readily cleaved by trypsin in limited trypsin digestion assays. Isothermal titration calorimetry experiments show that rFGF21 does not bind to heparin. Interestingly, rFGF21 demonstrates proliferative activity in NIH/3T3 fibroblasts and enhances mitochondrial oxidative phosphorylation and fatty acid oxidation in 3T3-L1 adipocytes. These findings provide a crucial framework for the engineering of novel structure-based variants of FGF21 with improved stability and biological activity to treat metabolic disorders.
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Affiliation(s)
- Phuc Phan
- Department of Chemistry and Biochemistry, Fulbright College of Art and Sciences, University of Arkansas, Fayetteville, Arkansas
| | - Jason Hoang
- Department of Chemistry and Biochemistry, Fulbright College of Art and Sciences, University of Arkansas, Fayetteville, Arkansas
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Sammut MJ, Thorne BR, Melling CWJ. Skeletal muscle growth to combat diabetes and obesity: the potential role of muscle-secreted factors. Obesity (Silver Spring) 2025; 33:435-451. [PMID: 39948829 PMCID: PMC11897867 DOI: 10.1002/oby.24223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 11/21/2024] [Accepted: 11/22/2024] [Indexed: 03/14/2025]
Abstract
As the prevalence of obesity and metabolic disease continues to climb, the need for effective therapeutic interventions remains high. The growth of skeletal muscle (SkM) greatly influences systemic metabolism across the whole body, making this tissue an important therapeutic target to combat the rise of metabolic dysfunction. Transgenic rodent models of targeted SkM growth exhibit profound improvements in various remote tissues, including adipose tissue and the liver. It is currently unclear how selective stimulation of SkM growth alters the metabolism of distant tissues; however, evidence suggests that muscle-secreted factors may be involved. Here, we aim to provide basic biomedical researchers with a summary of the current knowledge regarding various muscle-secreted factors regulated by anabolic pathways and proteins in SkM, as well as their systemic metabolic effects, to implicate them in the whole-body metabolic effects of SkM growth. In this review, we also identify several knowledge gaps in this field, future directions of investigation, and implications for therapeutic interventions such as resistance exercise and pharmacology.
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Affiliation(s)
- Mitchell J. Sammut
- School of Kinesiology, Faculty of Health SciencesWestern UniversityLondonOntarioCanada
| | - Benjamin R. Thorne
- School of Kinesiology, Faculty of Health SciencesWestern UniversityLondonOntarioCanada
| | - C. W. James Melling
- School of Kinesiology, Faculty of Health SciencesWestern UniversityLondonOntarioCanada
- Department of Physiology & Pharmacology, Schulich School of Medicine & DentistryWestern UniversityLondonOntarioCanada
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Yoshida Y, Shinomiya A, Oikawa M, Shimada T, Hanaki KI, Watanabe Y. [Neonatal Malnutrition Impacts Fibroblast Growth Factor 21-induced Neurite Outgrowth and Growth Hormone-releasing Hormone Secretion in Neonatal Mouse Brain]. YAKUGAKU ZASSHI 2025; 145:183-188. [PMID: 40024730 DOI: 10.1248/yakushi.24-00177-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2025]
Abstract
Neonatal malnutrition has been suggested as a factor contributing to neurological and other disorders. However, the details of this mechanism remain unclear. We focused on fibroblast growth factor 21 (FGF21), an endocrine factor produced in the liver during lactation-the main source of nutrition during the neonatal period- and analyzed its role in the brain. From the RNA-seq analysis of mouse brains, we analyzed the genes whose expression was regulated by FGF21 and their respective functions. We found that FGF21 has two functions in the neonatal brain; FGF21 induces the production of growth hormone-releasing hormone (GHRH) in the hypothalamus and is involved in isoform determination of Kalirin, a Ras homologous guanine nucleotide exchange factor, and promotes neurite outgrowth in the brain. Furthermore, the above mechanism is regulated by SH2-containing tyrosine phosphatase (SHP2) activity downstream of the FGF receptor. Additionally, the conserved intron of the SHP2 gene, Ptpn11, shows altered activity in malnourished mouse brains. In summary, FGF21 functions in neurite outgrowth and GHRH production in the neonatal mouse brain, with the mechanism being regulated by SHP2. However, SHP2 activity depends on nutritional status. Our goal was to elucidate the mechanisms by which FGF21 is involved in the maintenance of the central nervous system during the neonatal period. This study provides new insights into the role of FGF21 in diseases caused by dysfunction due to malnutrition.
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Affiliation(s)
- Yuko Yoshida
- Laboratory of Biosecurity Management, Research Center for Biosafety, Laboratory Animal and Pathogen Bank, NIID
| | | | | | | | - Ken-Ichi Hanaki
- Laboratory of Biosecurity Management, Research Center for Biosafety, Laboratory Animal and Pathogen Bank, NIID
| | - Yoshifumi Watanabe
- Faculty of Pharmacy, Musashino University
- Research Institute of Pharmaceutical Sciences, Musashino University
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Streeter J, Persaud L, Gao J, Manika D, Fairman W, García-Peña LM, Marti A, Manika C, Gaddi S, Schickling B, Pereira RO, Abel ED. ATF4-dependent and independent mitokine secretion from OPA1 deficient skeletal muscle in mice is sexually dimorphic. Front Endocrinol (Lausanne) 2024; 15:1325286. [PMID: 39381436 PMCID: PMC11458430 DOI: 10.3389/fendo.2024.1325286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 08/30/2024] [Indexed: 10/10/2024] Open
Abstract
Introduction Reducing Optic Atrophy 1 (OPA1) expression in skeletal muscle in male mice induces Activation Transcription Factor 4 (ATF4) and the integrated stress response (ISR). Additionally, skeletal muscle secretion of Fibroblast Growth Factor 21 (FGF21) is increased, which mediates metabolic adaptations including resistance to diet-induced obesity (DIO) and glucose intolerance in these mice. Although FGF21 induction in this model can be reversed with pharmacological attenuation of ER stress, it remains to be determined if ATF4 is responsible for FGF21 induction and its metabolic benefits in this model. Methods We generated mice with homozygous floxed Opa1 and Atf4 alleles and a tamoxifen-inducible Cre transgene controlled by the human skeletal actin promoter to enable simultaneous depletion of OPA1 and ATF4 in skeletal muscle (mAO DKO). Mice were fed high fat (HFD) or control diet and evaluated for ISR activation, body mass, fat mass, glucose tolerance, insulin tolerance and circulating concentrations of FGF21 and growth differentiation factor 15 (GDF15). Results In mAO DKO mice, ATF4 induction is absent. Other indices of ISR activation, including XBP1s, ATF6, and CHOP were induced in mAO DKO males, but not in mOPA1 or mAO DKO females. Resistance to diet-induced obesity was not reversed in mAO DKO mice of both sexes. Circulating FGF21 and GDF15 illustrated sexually dimorphic patterns. Loss of OPA1 in skeletal muscle increases circulating FGF21 in mOPA1 males, but not in mOPA1 females. Additional loss of ATF4 decreased circulating FGF21 in mAO DKO male mice, but increased circulating FGF21 in female mAO DKO mice. Conversely, circulating GDF15 was increased in mAO DKO males and mOPA1 females, but not in mAO DKO females. Conclusion Sex differences exist in the transcriptional outputs of the ISR following OPA deletion in skeletal muscle. Deletion of ATF4 in male and female OPA1 KO mice does not reverse the resistance to DIO. Induction of circulating FGF21 is ATF4 dependent in males, whereas induction of circulating GDF15 is ATF4 dependent in females. Elevated GDF15 in males and FGF21 in females could reflect activation by other transcriptional outputs of the ISR, that maintain mitokine-dependent metabolic protection in an ATF4-independent manner.
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Affiliation(s)
- Jennifer Streeter
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
| | - Luis Persaud
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
| | - Jason Gao
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
| | - Deeraj Manika
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
| | - Will Fairman
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
| | - Luis Miguel García-Peña
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
| | - Alex Marti
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
| | - Chethan Manika
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
| | - Shreya Gaddi
- Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
| | - Brandon Schickling
- Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
| | - Renata O. Pereira
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
| | - E. Dale Abel
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States
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Liu X, Tang Y, Luo Y, Gao Y, He L. Role and mechanism of specialized pro-resolving mediators in obesity-associated insulin resistance. Lipids Health Dis 2024; 23:234. [PMID: 39080624 PMCID: PMC11290132 DOI: 10.1186/s12944-024-02207-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 07/07/2024] [Indexed: 08/02/2024] Open
Abstract
With the changing times, obesity has become a characteristic epidemic in the context of the current era. Insulin resistance (IR) is most commonly caused by obesity, and IR is a common basis of the pathogenesis of many diseases such as cardiovascular disease, nonalcoholic fatty liver disease, and type 2 diabetes, which seriously threaten human life, as well as health. A major pathogenetic mechanism of obesity-associated IR has been found to be chronic low-grade inflammation in adipose tissue. Specialized pro-resolving mediators (SPMs) are novel lipid mediators that both function as "stop signals" for inflammatory reaction and promote inflammation to subside. In this article, we summarize the pathogenesis of obesity-associated IR and its treatments and outline the classification and biosynthesis of SPMs and their mechanisms and roles in the treatment of obesity-associated IR in order to explore the potential of SPMs for treating metabolic diseases linked with obesity-associated IR.
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Affiliation(s)
- Xinru Liu
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yu Tang
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuanyuan Luo
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yongxiang Gao
- College of International Education, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Lisha He
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
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Abudigin WI, Bajaber A, Subash-Babu P. Impact of various dietary lipids on amelioration of biomarkers linked to metabolic syndrome in both healthy and diabetic Wistar rats. BMC Nutr 2024; 10:75. [PMID: 38755663 PMCID: PMC11097575 DOI: 10.1186/s40795-024-00881-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 05/07/2024] [Indexed: 05/18/2024] Open
Abstract
BACKGROUND The present study was designed to investigate the influence of different dietary lipids (sheep's fat, olive oil, coconut oil, and corn oil) on specific biomarkers associated with metabolic syndrome in both healthy and diabetic rats. METHODS The study designed for 45 days, utilized a male diabetic wistar rat (body weight, 180-220 g) model induced by streptozotocin (45 mg/kg bw). The rats were divided into two sections: five non-diabetic and five diabetic groups, each containing six rats. The first group in each section serving as the control, received a standard diet. Both non-diabetic or diabetic groups, were provided with a standard diet enriched with 15% sheep fat, 15% coconut oil, 15% olive oil, and 15% corn oil, respectively for a duration of 45 days. RESULTS Post-supplementation, both healthy and diabetic control rats exhibited a higher food intake compared to rats supplemented with lipid diet; notably food intake was higher in diabetic control than healthy control. However, rats fed with coconut oil, olive oil and sheep fat showed weight gain at the end of the experiment, in both healthy and diabetic groups. Coconut oil supplementation significantly (p ≤ 0.05) increased HDL-C and total cholesterol level in diabetic groups compared to healthy group, it was confirmed by an increased PPAR-α and ABCA-1 protein level. Olive oil significantly decreased triglyceride, total cholesterol, and LDL-C levels in diabetic rats when compared to sheep fat or coconut oil. Corn oil significantly decreased fasting glucose, total cholesterol and LDL-C levels compared to all other groups. Corn and olive oil supplemented normal groups, found with significant increase in hepatic glucose-lipid oxidative metabolism associated protein, like FGF-21, MSH, ABCA-1, PPAR-γ and decreased lipogenesis proteins like, SREBP and PPAR-α levels. In contrast, sheep grease and coconut oil increased SREBP and PPAR-α expression in both normal and diabetic groups. Most notably, normal and diabetic groups pretreated with sheep grease resulted in increased inflammatory (MCP-1, IL-1β, TLR-4, TNF-α), and oxidative stress markers (LPO, GSH, GPx, SOD and CAT) linked with metabolic complications. CONCLUSION The combination or alternative use of olive oil and corn oil in daily diet may play a significant role in preventing proinflammatory condition associated with insulin resistance and cardiovascular diseases.
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Affiliation(s)
- Weaam I Abudigin
- Department of Food Science and Nutrition, College of Food & Agriculture Sciences, King Saud University, P.O. Box 22452, Riyadh, 11459, Saudi Arabia.
| | - Adnan Bajaber
- Department of Food Science and Nutrition, College of Food & Agriculture Sciences, King Saud University, P.O. Box 22452, Riyadh, 11459, Saudi Arabia
| | - Pandurangan Subash-Babu
- Department of Food Science and Nutrition, College of Food & Agriculture Sciences, King Saud University, P.O. Box 22452, Riyadh, 11459, Saudi Arabia
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Santos JDM, Silva JFT, Alves EDS, Cruz AG, Santos ARM, Camargo FN, Talarico CHZ, Silva CAA, Camporez JP. Strength Training Protects High-Fat-Fed Ovariectomized Mice against Insulin Resistance and Hepatic Steatosis. Int J Mol Sci 2024; 25:5066. [PMID: 38791103 PMCID: PMC11120807 DOI: 10.3390/ijms25105066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/02/2024] [Accepted: 05/03/2024] [Indexed: 05/26/2024] Open
Abstract
Menopause is characterized by a reduction in sex hormones in women and is associated with metabolic changes, including fatty liver and insulin resistance. Lifestyle changes, including a balanced diet and physical exercise, are necessary to prevent these undesirable changes. Strength training (ST) has been widely used because of the muscle and metabolic benefits it provides. Our study aims to evaluate the effects of ST on hepatic steatosis and insulin resistance in ovariectomized mice fed a high-fat diet (HFD) divided into four groups as follows: simulated sedentary surgery (SHAM-SED), trained simulated surgery (SHAM-EXE), sedentary ovariectomy (OVX-SED), and trained ovariectomy (OVX-EXE). They were fed an HFD for 9 weeks. ST was performed thrice a week. ST efficiently reduced body weight and fat percentage and increased lean mass in OVX mice. Furthermore, ST reduced the accumulation of ectopic hepatic lipids, increased AMPK phosphorylation, and inhibited the de novo lipogenesis pathway. OVX-EXE mice also showed a better glycemic profile, associated with greater insulin sensitivity identified by the euglycemic-hyperinsulinemic clamp, and reduced markers of hepatic oxidative stress compared with sedentary animals. Our data support the idea that ST can be indicated as a non-pharmacological treatment approach to mitigate metabolic changes resulting from menopause.
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Affiliation(s)
| | | | | | | | | | | | | | | | - João Paulo Camporez
- Department of Physiology, Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil (J.F.T.S.); (E.d.S.A.); (A.G.C.); (A.R.M.S.); (F.N.C.); (C.H.Z.T.); (C.A.A.S.)
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Chen M, Tan J, Jin Z, Jiang T, Wu J, Yu X. Research progress on Sirtuins (SIRTs) family modulators. Biomed Pharmacother 2024; 174:116481. [PMID: 38522239 DOI: 10.1016/j.biopha.2024.116481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 03/15/2024] [Accepted: 03/19/2024] [Indexed: 03/26/2024] Open
Abstract
Sirtuins (SIRTs) represent a class of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that exert a crucial role in cellular signal transduction and various biological processes. The mammalian sirtuins family encompasses SIRT1 to SIRT7, exhibiting therapeutic potential in counteracting cellular aging, modulating metabolism, responding to oxidative stress, inhibiting tumors, and improving cellular microenvironment. These enzymes are intricately linked to the occurrence and treatment of diverse pathological conditions, including cancer, autoimmune diseases, and cardiovascular disorders. Given the significance of histone modification in gene expression and chromatin structure, maintaining the equilibrium of the sirtuins family is imperative for disease prevention and health restoration. Mounting evidence suggests that modulators of SIRTs play a crucial role in treating various diseases and maintaining physiological balance. This review delves into the molecular structure and regulatory functions of the sirtuins family, reviews the classification and historical evolution of SIRTs modulators, offers a systematic overview of existing SIRTs modulation strategies, and elucidates the regulatory mechanisms of SIRTs modulators (agonists and inhibitors) and their clinical applications. The article concludes by summarizing the challenges encountered in SIRTs modulator research and offering insights into future research directions.
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Affiliation(s)
- Mingkai Chen
- Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China; School of Medicine Jiangsu University, Zhenjiang, Jiangsu, China
| | - Junfei Tan
- School of Medicine Jiangsu University, Zhenjiang, Jiangsu, China
| | - Zihan Jin
- Changzhou Second People's Hospital Affiliated to Nanjing Medical University, Changzhou City, China
| | - Tingting Jiang
- Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
| | - Jiabiao Wu
- Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
| | - Xiaolong Yu
- Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China; The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China.
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Garneau L, Mulvihill EE, Smith SR, Sparks LM, Aguer C. Myokine Secretion following an Aerobic Exercise Intervention in Individuals with Type 2 Diabetes with or without Exercise Resistance. Int J Mol Sci 2024; 25:4889. [PMID: 38732106 PMCID: PMC11084395 DOI: 10.3390/ijms25094889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 04/19/2024] [Accepted: 04/25/2024] [Indexed: 05/13/2024] Open
Abstract
Type 2 diabetes (T2D) is characterized by muscle metabolic dysfunction that exercise can minimize, but some patients do not respond to an exercise intervention. Myokine secretion is intrinsically altered in patients with T2D, but the role of myokines in exercise resistance in this patient population has never been studied. We sought to determine if changes in myokine secretion were linked to the response to an exercise intervention in patients with T2D. The participants followed a 10-week aerobic exercise training intervention, and patients with T2D were grouped based on muscle mitochondrial function improvement (responders versus non-responders). We measured myokines in serum and cell-culture medium of myotubes derived from participants pre- and post-intervention and in response to an in vitro model of muscle contraction. We also quantified the expression of genes related to inflammation in the myotubes pre- and post-intervention. No significant differences were detected depending on T2D status or response to exercise in the biological markers measured, with the exception of modest differences in expression patterns for certain myokines (IL-1β, IL-8, IL-10, and IL-15). Further investigation into the molecular mechanisms involving myokines may explain exercise resistance with T2D; however, the role in metabolic adaptations to exercise in T2D requires further investigation.
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Affiliation(s)
- Léa Garneau
- Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (L.G.); (E.E.M.)
- Institut du Savoir Montfort, Ottawa, ON K1K 0T2, Canada
| | - Erin E. Mulvihill
- Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (L.G.); (E.E.M.)
- University of Ottawa Heart Institute, Ottawa, ON K1Y 4W7, Canada
| | - Steven R. Smith
- Translational Research Institute for Metabolism and Diabetes, AdventHealth Orlando, Orlando, FL 32804, USA; (S.R.S.); (L.M.S.)
| | - Lauren M. Sparks
- Translational Research Institute for Metabolism and Diabetes, AdventHealth Orlando, Orlando, FL 32804, USA; (S.R.S.); (L.M.S.)
| | - Céline Aguer
- Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (L.G.); (E.E.M.)
- Institut du Savoir Montfort, Ottawa, ON K1K 0T2, Canada
- Faculty of Medicine and Health Sciences, Department of Physiology, McGill University–Campus Outaouais, Gatineau, QC J8V 3T4, Canada
- Faculty of Health Sciences, School of Human Kinetics, University of Ottawa, Ottawa, ON K1N 6N5, Canada
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Greeny A, Nair A, Sadanandan P, Satarker S, Famurewa AC, Nampoothiri M. Epigenetic Alterations in Alzheimer's Disease: Impact on Insulin Signaling and Advanced Drug Delivery Systems. BIOLOGY 2024; 13:157. [PMID: 38534427 DOI: 10.3390/biology13030157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 02/25/2024] [Accepted: 02/26/2024] [Indexed: 03/28/2024]
Abstract
Alzheimer's disease (AD) is a neurodegenerative condition that predominantly affects the hippocampus and the entorhinal complex, leading to memory lapse and cognitive impairment. This can have a negative impact on an individual's behavior, speech, and ability to navigate their surroundings. AD is one of the principal causes of dementia. One of the most accepted theories in AD, the amyloid β (Aβ) hypothesis, assumes that the buildup of the peptide Aβ is the root cause of AD. Impaired insulin signaling in the periphery and central nervous system has been considered to have an effect on the pathophysiology of AD. Further, researchers have shifted their focus to epigenetic mechanisms that are responsible for dysregulating major biochemical pathways and intracellular signaling processes responsible for directly or indirectly causing AD. The prime epigenetic mechanisms encompass DNA methylation, histone modifications, and non-coding RNA, and are majorly responsible for impairing insulin signaling both centrally and peripherally, thus leading to AD. In this review, we provide insights into the major epigenetic mechanisms involved in causing AD, such as DNA methylation and histone deacetylation. We decipher how the mechanisms alter peripheral insulin signaling and brain insulin signaling, leading to AD pathophysiology. In addition, this review also discusses the need for newer drug delivery systems for the targeted delivery of epigenetic drugs and explores targeted drug delivery systems such as nanoparticles, vesicular systems, networks, and other nano formulations in AD. Further, this review also sheds light on the future approaches used for epigenetic drug delivery.
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Affiliation(s)
- Alosh Greeny
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, India
| | - Ayushi Nair
- Department of Pharmaceutics, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Amrita Health Science Campus, Kochi 682041, India
| | - Prashant Sadanandan
- Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Amrita Health Science Campus, Kochi 682041, India
| | - Sairaj Satarker
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, India
| | - Ademola C Famurewa
- Department of Medical Biochemistry, Faculty of Basic Medical Sciences, College of Medical Sciences, Alex Ekwueme Federal University, Ndufu-Alike, Ikwo 482123, Nigeria
| | - Madhavan Nampoothiri
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, India
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Feger M, Meier L, Strotmann J, Hoene M, Vogt J, Wisser A, Hirschle S, Kheim MJ, Hocher B, Weigert C, Föller M. Endothelin receptor B-deficient mice are protected from high-fat diet-induced metabolic syndrome. Mol Metab 2024; 80:101868. [PMID: 38159882 PMCID: PMC10825011 DOI: 10.1016/j.molmet.2023.101868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 12/20/2023] [Accepted: 12/27/2023] [Indexed: 01/03/2024] Open
Abstract
OBJECTIVE Endothelin receptor B (ETB) together with ETA mediates cellular effects of endothelin 1 (ET-1), an autocrine and endocrine peptide produced by the endothelium and other cells. It regulates vascular tone and controls kidney function. Metabolic syndrome is due to high caloric intake and is characterized by insulin resistance, dyslipidemia, and white adipose tissue (WAT) accumulation. ETA/ETB antagonism has been demonstrated to favorably influence insulin resistance. Our study explored the role of ETB in metabolic syndrome. METHODS Wild type (etb+/+) and rescued ETB-deficient (etb-/-) mice were fed a high-fat diet, and energy, glucose, and insulin metabolism were analyzed, and hormones and lipids measured in serum and tissues. Cell culture experiments were performed in HepG2 cells. RESULTS Compared to etb+/+ mice, etb-/- mice exhibited better glucose tolerance and insulin sensitivity, less WAT accumulation, lower serum triglycerides, and higher energy expenditure. Protection from metabolic syndrome was paralleled by higher hepatic production of fibroblast growth factor 21 (FGF21) and higher serum levels of free thyroxine (fT4), stimulators of energy expenditure. CONCLUSIONS ETB deficiency confers protection from metabolic syndrome by counteracting glucose intolerance, dyslipidemia, and WAT accumulation due to enhanced energy expenditure, effects at least in part dependent on enhanced production of thyroid hormone/FGF21. ETB antagonism may therefore be a novel therapeutic approach in metabolic syndrome.
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Affiliation(s)
- Martina Feger
- University of Hohenheim, Department of Physiology, Stuttgart, Germany
| | - Leonie Meier
- University of Hohenheim, Department of Physiology, Stuttgart, Germany
| | - Jörg Strotmann
- University of Hohenheim, Department of Physiology, Stuttgart, Germany
| | - Miriam Hoene
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Julia Vogt
- University of Hohenheim, Department of Physiology, Stuttgart, Germany
| | - Alexandra Wisser
- University of Hohenheim, Department of Physiology, Stuttgart, Germany
| | - Susanna Hirschle
- University of Hohenheim, Department of Physiology, Stuttgart, Germany
| | - Marie-Jo Kheim
- University of Hohenheim, Department of Physiology, Stuttgart, Germany
| | - Berthold Hocher
- University of Heidelberg, Department of Nephrology, Mannheim, Germany; Institute of Medical Diagnostics, IMD, Berlin, Germany; Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, Hunan, China
| | - Cora Weigert
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München, University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD), 85784 Neuherberg, Germany
| | - Michael Föller
- University of Hohenheim, Department of Physiology, Stuttgart, Germany.
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12
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Kataoka H, Nirengi S, Matsui Y, Taniguchi H. Fructose-induced FGF21 secretion does not activate brown adipose tissue in Japanese young men: randomized cross-over and randomized controlled trials. J Physiol Anthropol 2024; 43:5. [PMID: 38178259 PMCID: PMC10765626 DOI: 10.1186/s40101-023-00353-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 12/22/2023] [Indexed: 01/06/2024] Open
Abstract
BACKGROUND Human brown adipose tissue (BAT) activity is associated with lower body fatness and favorable glucose metabolism. Previous studies reported that oral fructose loading induces postprandial fibroblast growth factor 21 (FGF21) secretion. FGF21 is a known inducer of adipose tissue thermogenesis; however, the effects of diet-induced FGF21 secretion on BAT thermogenesis remain to be elucidated. METHODS The effects of both single load and daily consumption of fructose on BAT activity were examined using a randomized cross-over trial and a 2-week randomized controlled trial (RCT), respectively. In the cross-over trial, 15 young men consumed a single dose of fructose solution or water and then consumed the other on a subsequent day. The RCT enrolled 22 young men, and the participants were allocated to a group that consumed fructose and a group that consumed water daily for 2 weeks. BAT activity was analyzed using thermography with cold exposure. Plasma FGF21 level was determined by enzyme-linked immunosorbent assay. RESULTS In the cross-over single-load trial, plasma FGF21 levels were significantly increased at 2 h after oral fructose load (p < 0.01); however, there was no significant difference in BAT activity between the fructose load and drinking water. The 2-week RCT revealed that both plasma FGF21 levels and BAT activity were not significantly increased by daily fructose consumption compared to water. Correlation analyses revealed that BAT activity at the baseline and the final measurements were strongly and positively associated with the RCT (r = 0.869, p < 0.001). Changes in BAT activity were significantly and negatively correlated with changes in plasma glucose levels during the 2-week intervention (r = - 0.497, p = 0.022). CONCLUSIONS Oral fructose load induces a temporary increase in circulating FGF21 levels; however, this does not activate BAT thermogenesis in healthy young men. Further studies are needed to elucidate the effect of endogenous FGF21 on physiological function. TRIAL REGISTRATION This study is registered with the University Hospital Medical Information Network in Japan (number 000051761, registered 1 August 2023, retrospectively registered, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000052680 ).
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Affiliation(s)
- Haruki Kataoka
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto, Japan
| | - Shinsuke Nirengi
- Clinical Research Institute, Division of Preventive Medicine, National Hospital Organization Kyoto Medical Center, Kyoto, Japan
- Dorothy M. Davis Heart and Lung Research Institute, Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Yuka Matsui
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto, Japan
| | - Hirokazu Taniguchi
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto, Japan.
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13
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Yuan L, Verhoeven A, Blomberg N, van Eyk HJ, Bizino MB, Rensen PCN, Jazet IM, Lamb HJ, Rabelink TJ, Giera M, van den Berg BM. Ethnic Disparities in Lipid Metabolism and Clinical Outcomes between Dutch South Asians and Dutch White Caucasians with Type 2 Diabetes Mellitus. Metabolites 2024; 14:33. [PMID: 38248836 PMCID: PMC10819672 DOI: 10.3390/metabo14010033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 12/26/2023] [Accepted: 12/30/2023] [Indexed: 01/23/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM) poses a higher risk for complications in South Asian individuals compared to other ethnic groups. To shed light on potential mediating factors, we investigated lipidomic changes in plasma of Dutch South Asians (DSA) and Dutch white Caucasians (DwC) with and without T2DM and explore their associations with clinical features. Using a targeted quantitative lipidomics platform, monitoring over 1000 lipids across 17 classes, along with 1H NMR based lipoprotein analysis, we studied 51 healthy participants (21 DSA, 30 DwC) and 92 T2DM patients (47 DSA, 45 DwC) from the MAGNetic resonance Assessment of VICTOza efficacy in the Regression of cardiovascular dysfunction in type 2 dIAbetes mellitus (MAGNA VICTORIA) study. This comprehensive mapping of the circulating lipidome allowed us to identify relevant lipid modules through unbiased weighted correlation network analysis, as well as disease and ethnicity related key mediatory lipids. Significant differences in lipidomic profiles, encompassing various lipid classes and species, were observed between T2DM patients and healthy controls in both the DSA and DwC populations. Our analyses revealed that healthy DSA, but not DwC, controls already exhibited a lipid profile prone to develop T2DM. Particularly, in DSA-T2DM patients, specific lipid changes correlated with clinical features, particularly diacylglycerols (DGs), showing significant associations with glycemic control and renal function. Our findings highlight an ethnic distinction in lipid modules influencing clinical outcomes in renal health. We discover distinctive ethnic disparities of the circulating lipidome and identify ethnicity-specific lipid markers. Jointly, our discoveries show great potential as personalized biomarkers for the assessment of glycemic control and renal function in DSA-T2DM individuals.
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Affiliation(s)
- Lushun Yuan
- Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (L.Y.); (P.C.N.R.); (T.J.R.)
- Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Aswin Verhoeven
- Center for Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (A.V.); (N.B.); (M.G.)
| | - Niek Blomberg
- Center for Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (A.V.); (N.B.); (M.G.)
| | - Huub J. van Eyk
- Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (H.J.v.E.); (I.M.J.)
| | - Maurice B. Bizino
- Department of Radiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (M.B.B.); (H.J.L.)
| | - Patrick C. N. Rensen
- Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (L.Y.); (P.C.N.R.); (T.J.R.)
- Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (H.J.v.E.); (I.M.J.)
| | - Ingrid M. Jazet
- Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (H.J.v.E.); (I.M.J.)
| | - Hildo J. Lamb
- Department of Radiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (M.B.B.); (H.J.L.)
| | - Ton J. Rabelink
- Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (L.Y.); (P.C.N.R.); (T.J.R.)
- Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Martin Giera
- Center for Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (A.V.); (N.B.); (M.G.)
| | - Bernard M. van den Berg
- Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (L.Y.); (P.C.N.R.); (T.J.R.)
- Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
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14
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Peng J, Yu L, Huang L, Paschoal VA, Chu H, de Souza CO, Varre JV, Oh DY, Kohler JJ, Xiao X, Xu L, Holland WL, Shaul PW, Mineo C. Hepatic sialic acid synthesis modulates glucose homeostasis in both liver and skeletal muscle. Mol Metab 2023; 78:101812. [PMID: 37777009 PMCID: PMC10583174 DOI: 10.1016/j.molmet.2023.101812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 09/22/2023] [Accepted: 09/26/2023] [Indexed: 10/02/2023] Open
Abstract
OBJECTIVE Sialic acid is a terminal monosaccharide of glycans in glycoproteins and glycolipids, and its derivation from glucose is regulated by the rate-limiting enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE). Although the glycans on key endogenous hepatic proteins governing glucose metabolism are sialylated, how sialic acid synthesis and sialylation in the liver influence glucose homeostasis is unknown. Studies were designed to fill this knowledge gap. METHODS To decrease the production of sialic acid and sialylation in hepatocytes, a hepatocyte-specific GNE knockdown mouse model was generated, and systemic glucose metabolism, hepatic insulin signaling and glucagon signaling were evaluated in vivo or in primary hepatocytes. Peripheral insulin sensitivity was also assessed. Furthermore, the mechanisms by which sialylation in the liver influences hepatic insulin signaling and glucagon signaling and peripheral insulin sensitivity were identified. RESULTS Liver GNE deletion in mice caused an impairment of insulin suppression of hepatic glucose production. This was due to a decrease in the sialylation of hepatic insulin receptors (IR) and a decline in IR abundance due to exaggerated degradation through the Eph receptor B4. Hepatic GNE deficiency also caused a blunting of hepatic glucagon receptor (GCGR) function which was related to a decline in its sialylation and affinity for glucagon. An accompanying upregulation of hepatic FGF21 production caused an enhancement of skeletal muscle glucose disposal that led to an overall increase in glucose tolerance and insulin sensitivity. CONCLUSION These collective observations reveal that hepatic sialic acid synthesis and sialylation modulate glucose homeostasis in both the liver and skeletal muscle. By interrogating how hepatic sialic acid synthesis influences glucose control mechanisms in the liver, a new metabolic cycle has been identified in which a key constituent of glycans generated from glucose modulates the systemic control of its precursor.
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Affiliation(s)
- Jun Peng
- Center for Pulmonary and Vascular Biology, Dept. of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA.
| | - Liming Yu
- Center for Pulmonary and Vascular Biology, Dept. of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA
| | - Linzhang Huang
- Center for Pulmonary and Vascular Biology, Dept. of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA
| | - Vivian A Paschoal
- Dept. of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA
| | - Haiyan Chu
- Center for Pulmonary and Vascular Biology, Dept. of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA
| | - Camila O de Souza
- Dept. of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA
| | - Joseph V Varre
- Dept. of Nutrition & Integrative Physiology, University of Utah College of Health, 250 1850 E, Salt Lake City, UT, 84112, USA
| | - Da Young Oh
- Dept. of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA
| | - Jennifer J Kohler
- Dept. of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA
| | - Xue Xiao
- Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA
| | - Lin Xu
- Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA
| | - William L Holland
- Dept. of Nutrition & Integrative Physiology, University of Utah College of Health, 250 1850 E, Salt Lake City, UT, 84112, USA
| | - Philip W Shaul
- Center for Pulmonary and Vascular Biology, Dept. of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA.
| | - Chieko Mineo
- Center for Pulmonary and Vascular Biology, Dept. of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA; Dept. of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA.
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15
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Kim J, Oh CM, Kim H. The Interplay of Adipokines and Pancreatic Beta Cells in Metabolic Regulation and Diabetes. Biomedicines 2023; 11:2589. [PMID: 37761031 PMCID: PMC10526203 DOI: 10.3390/biomedicines11092589] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 09/19/2023] [Accepted: 09/20/2023] [Indexed: 09/29/2023] Open
Abstract
The interplay between adipokines and pancreatic beta cells, often referred to as the adipo-insular axis, plays a crucial role in regulating metabolic homeostasis. Adipokines are signaling molecules secreted by adipocytes that have profound effects on several physiological processes. Adipokines such as adiponectin, leptin, resistin, and visfatin influence the function of pancreatic beta cells. The reciprocal communication between adipocytes and beta cells is remarkable. Insulin secreted by beta cells affects adipose tissue metabolism, influencing lipid storage and lipolysis. Conversely, adipokines released from adipocytes can influence beta cell function and survival. Chronic obesity and insulin resistance can lead to the release of excess fatty acids and inflammatory molecules from the adipose tissue, contributing to beta cell dysfunction and apoptosis, which are key factors in developing type 2 diabetes. Understanding the complex interplay of the adipo-insular axis provides insights into the mechanisms underlying metabolic regulation and pathogenesis of metabolic disorders. By elucidating the molecular mediators involved in this interaction, new therapeutic targets and strategies may emerge to reduce the risk and progression of diseases, such as type 2 diabetes and its associated complications. This review summarizes the interactions between adipokines and pancreatic beta cells, and their roles in the pathogenesis of diabetes and metabolic diseases.
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Affiliation(s)
- Joon Kim
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea;
| | - Chang-Myung Oh
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea;
| | - Hyeongseok Kim
- Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon 35105, Republic of Korea
- Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35105, Republic of Korea
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Badmus OO, Hinds TD, Stec DE. Mechanisms Linking Metabolic-Associated Fatty Liver Disease (MAFLD) to Cardiovascular Disease. Curr Hypertens Rep 2023; 25:151-162. [PMID: 37191842 PMCID: PMC10839567 DOI: 10.1007/s11906-023-01242-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/17/2023] [Indexed: 05/17/2023]
Abstract
PURPOSE OF REVIEW Metabolic-associated fatty liver disease (MAFLD) is a condition of fat accumulation in the liver that occurs in the majority of patients in combination with metabolic dysfunction in the form of overweight or obesity. In this review, we highlight the cardiovascular complications in MAFLD patients as well as some potential mechanisms linking MAFLD to the development of cardiovascular disease and highlight potential therapeutic approaches to treating cardiovascular diseases in patients with MAFLD. RECENT FINDINGS MAFLD is associated with an increased risk of cardiovascular diseases (CVD), including hypertension, atherosclerosis, cardiomyopathies, and chronic kidney disease. While clinical data have demonstrated the link between MAFLD and the increased risk of CVD development, the mechanisms responsible for this increased risk remain unknown. MAFLD can contribute to CVD through several mechanisms including its association with obesity and diabetes, increased levels of inflammation, and oxidative stress, as well as alterations in hepatic metabolites and hepatokines. Therapies to potentially treat MAFLD-induced include statins and lipid-lowering drugs, glucose-lowering agents, antihypertensive drugs, and antioxidant therapy.
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Affiliation(s)
- Olufunto O Badmus
- Department of Physiology & Biophysics, Cardiorenal, and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Terry D Hinds
- Department of Pharmacology and Nutritional Sciences, Barnstable Brown Diabetes Center, Markey Cancer Center, University of Kentucky, Lexington, KY, 40508, USA
| | - David E Stec
- Department of Physiology & Biophysics, Cardiorenal, and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
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17
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Hu Y, Li J, Li X, Wang D, Xiang R, Liu W, Hou S, Zhao Q, Yu X, Xu M, Zhao D, Li T, Chi Y, Yang J. Hepatocyte-secreted FAM3D ameliorates hepatic steatosis by activating FPR1-hnRNP U-GR-SCAD pathway to enhance lipid oxidation. Metabolism 2023:155661. [PMID: 37454871 DOI: 10.1016/j.metabol.2023.155661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 07/10/2023] [Accepted: 07/11/2023] [Indexed: 07/18/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide; however, the underlying mechanisms remain poorly understood. FAM3D is a member of the FAM3 family; however, its role in hepatic glycolipid metabolism remains unknown. Serum FAM3D levels are positively correlated with fasting blood glucose levels in patients with diabetes. Hepatocytes express and secrete FAM3D, and its expression is increased in steatotic human and mouse livers. Hepatic FAM3D overexpression ameliorated hyperglycemia and steatosis in obese mice, whereas FAM3D-deficient mice exhibited exaggerated hyperglycemia and steatosis after high-fat diet (HFD)-feeding. In cultured hepatocytes, FAM3D overexpression or recombinant FAM3D protein (rFAM3D) treatment reduced gluconeogenesis and lipid deposition, which were blocked by anti-FAM3D antibodies or inhibition of its receptor, formyl peptide receptor 1 (FPR1). FPR1 overexpression suppressed gluconeogenesis and reduced lipid deposition in wild hepatocytes but not in FAM3D-deficient hepatocytes. The addition of rFAM3D restored FPR1's inhibitory effects on gluconeogenesis and lipid deposition in FAM3D-deficient hepatocytes. Hepatic FPR1 overexpression ameliorated hyperglycemia and steatosis in obese mice. RNA sequencing and DNA pull-down revealed that the FAM3D-FPR1 axis upregulated the expression of heterogeneous nuclear ribonucleoprotein U (hnRNP U), which recruits the glucocorticoid receptor (GR) to the promoter region of the short-chain acyl-CoA dehydrogenase (SCAD) gene, promoting its transcription to enhance lipid oxidation. Moreover, FAM3D-FPR1 axis also activates calmodulin-Akt pathway to suppress gluconeogenesis in hepatocytes. In conclusion, hepatocyte-secreted FAM3D activated the FPR1-hnRNP U-GR-SCAD pathway to enhance lipid oxidation in hepatocytes. Under obesity conditions, increased hepatic FAM3D expression is a compensatory mechanism against dysregulated glucose and lipid metabolism.
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Affiliation(s)
- Yuntao Hu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
| | - Jing Li
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100027, China
| | - Xin Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
| | - Di Wang
- Department of Central Laboratory and Institute of Clinical Molecular Biology, Peking University People's Hospital, Beijing 100044, China
| | - Rui Xiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
| | - Wenjun Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
| | - Song Hou
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
| | - Qinghe Zhao
- Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, China
| | - Xiaoxing Yu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
| | - Ming Xu
- Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Beijing 100191, China
| | - Dong Zhao
- Department of Endocrinology, Beijing Luhe Hospital, Capital Medical University, Beijing 101100, China
| | - Tao Li
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Yujing Chi
- Department of Central Laboratory and Institute of Clinical Molecular Biology, Peking University People's Hospital, Beijing 100044, China; Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, China.
| | - Jichun Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China; Department of Cardiology, Peking University Third Hospital, Beijing 100191, China.
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18
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Araujo LCC, Cruz AG, Camargo FN, Sucupira FG, Moreira GV, Matos SL, Amaral AG, Murata GM, Carvalho CRO, Camporez JP. Estradiol Protects Female ApoE KO Mice against Western-Diet-Induced Non-Alcoholic Steatohepatitis. Int J Mol Sci 2023; 24:9845. [PMID: 37372993 DOI: 10.3390/ijms24129845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 05/15/2023] [Accepted: 06/03/2023] [Indexed: 06/29/2023] Open
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) and its severe form, non-alcoholic steatohepatitis (NASH), is higher in men than in women of reproductive age, and postmenopausal women are especially susceptible to developing the disease. AIM we evaluated if female apolipoprotein E (ApoE) KO mice were protected against Western-diet (WD)-induced NASH. METHODS Female ovariectomized (OVX) ApoE KO mice or sham-operated (SHAM) mice were fed either a WD or a regular chow (RC) for 7 weeks. Additionally, OVX mice fed a WD were treated with either estradiol (OVX + E2) or vehicle (OVX). RESULTS Whole-body fat, plasma glucose, and plasma insulin were increased and associated with increased glucose intolerance in OVX mice fed a WD (OVX + WD). Plasma and hepatic triglycerides, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) hepatic enzymes were also increased in the plasma of OVX + WD group, which was associated with hepatic fibrosis and inflammation. Estradiol replacement in OVX mice reduced body weight, body fat, glycemia, and plasma insulin associated with reduced glucose intolerance. Treatment also reduced hepatic triglycerides, ALT, AST, hepatic fibrosis, and inflammation in OVX mice. CONCLUSIONS These data support the hypothesis that estradiol protects OVX ApoE KO mice from NASH and glucose intolerance.
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Affiliation(s)
- Layanne C C Araujo
- Department of Physiology, Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil
| | - Alessandra G Cruz
- Department of Physiology, Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil
| | - Felipe N Camargo
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil
| | - Felipe G Sucupira
- Department of Physiology, Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil
| | - Gabriela V Moreira
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil
| | - Sandro L Matos
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil
| | - Andressa G Amaral
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil
| | - Gilson Masahiro Murata
- Department of Medicine, School of Medicine, University of Sao Paulo, Sao Paulo 01246-903, Brazil
| | - Carla R O Carvalho
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil
| | - Joao Paulo Camporez
- Department of Physiology, Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil
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19
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Tian Y, Mehta K, Jellinek MJ, Sun H, Lu W, Shi R, Ingram K, Friedline RH, Kim JK, Kemper JK, Ford DA, Zhang K, Wang B. Hepatic Phospholipid Remodeling Modulates Insulin Sensitivity and Systemic Metabolism. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2300416. [PMID: 37088778 PMCID: PMC10288282 DOI: 10.1002/advs.202300416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 04/13/2023] [Indexed: 05/03/2023]
Abstract
The liver plays a central role in regulating glucose and lipid metabolism. Aberrant insulin action in the liver is a major driver of selective insulin resistance, in which insulin fails to suppress glucose production but continues to activate lipogenesis in the liver, resulting in hyperglycemia and hypertriglyceridemia. The underlying mechanisms of selective insulin resistance are not fully understood. Here It is shown that hepatic membrane phospholipid composition controlled by lysophosphatidylcholine acyltransferase 3 (LPCAT3) regulates insulin signaling and systemic glucose and lipid metabolism. Hyperinsulinemia induced by high-fat diet (HFD) feeding augments hepatic Lpcat3 expression and membrane unsaturation. Loss of Lpcat3 in the liver improves insulin resistance and blunts lipogenesis in both HFD-fed and genetic ob/ob mouse models. Mechanistically, Lpcat3 deficiency directly facilitates insulin receptor endocytosis, signal transduction, and hepatic glucose production suppression and indirectly enhances fibroblast growth factor 21 (FGF21) secretion, energy expenditure, and glucose uptake in adipose tissue. These findings identify hepatic LPCAT3 and membrane phospholipid composition as a novel regulator of insulin sensitivity and provide insights into the pathogenesis of selective insulin resistance.
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Affiliation(s)
- Ye Tian
- Department of Comparative BiosciencesCollege of Veterinary MedicineUniversity of Illinois at Urbana‐ChampaignUrbanaIL61802USA
| | - Kritika Mehta
- Department of BiochemistrySchool of Molecular and Cellular BiologyUniversity of Illinois at Urbana‐ChampaignUrbanaIL61801USA
| | - Matthew J. Jellinek
- Department of Biochemistry and Molecular Biologyand Center for Cardiovascular ResearchSaint Louis UniversitySt. LouisMO63104USA
| | - Hao Sun
- Department of Molecular and Integrative PhysiologySchool of Molecular and Cellular BiologyUniversity of Illinois at Urbana‐ChampaignUrbanaIL61801USA
| | - Wei Lu
- Department of Comparative BiosciencesCollege of Veterinary MedicineUniversity of Illinois at Urbana‐ChampaignUrbanaIL61802USA
| | - Ruicheng Shi
- Department of Comparative BiosciencesCollege of Veterinary MedicineUniversity of Illinois at Urbana‐ChampaignUrbanaIL61802USA
| | - Kevin Ingram
- Department of BiochemistrySchool of Molecular and Cellular BiologyUniversity of Illinois at Urbana‐ChampaignUrbanaIL61801USA
| | - Randall H. Friedline
- Program in Molecular Medicine and Division of EndocrinologyMetabolism and DiabetesDepartment of MedicineUniversity of Massachusetts Medical SchoolWorcesterMA01655USA
| | - Jason K. Kim
- Program in Molecular Medicine and Division of EndocrinologyMetabolism and DiabetesDepartment of MedicineUniversity of Massachusetts Medical SchoolWorcesterMA01655USA
| | - Jongsook Kim Kemper
- Department of Molecular and Integrative PhysiologySchool of Molecular and Cellular BiologyUniversity of Illinois at Urbana‐ChampaignUrbanaIL61801USA
- Cancer Center at IllinoisUniversity of Illinois at Urbana‐ChampaignUrbanaIL61801USA
| | - David A. Ford
- Department of Biochemistry and Molecular Biologyand Center for Cardiovascular ResearchSaint Louis UniversitySt. LouisMO63104USA
| | - Kai Zhang
- Department of BiochemistrySchool of Molecular and Cellular BiologyUniversity of Illinois at Urbana‐ChampaignUrbanaIL61801USA
| | - Bo Wang
- Department of Comparative BiosciencesCollege of Veterinary MedicineUniversity of Illinois at Urbana‐ChampaignUrbanaIL61802USA
- Cancer Center at IllinoisUniversity of Illinois at Urbana‐ChampaignUrbanaIL61801USA
- Division of Nutritional SciencesCollege of AgriculturalConsumer and Environmental SciencesUniversity of Illinois at Urbana‐ChampaignUrbanaIL61801USA
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20
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Akingbesote ND, Leitner BP, Jovin DG, Desrouleaux R, Owusu D, Zhu W, Li Z, Pollak MN, Perry RJ. Gene and protein expression and metabolic flux analysis reveals metabolic scaling in liver ex vivo and in vivo. eLife 2023; 12:e78335. [PMID: 37219930 PMCID: PMC10205083 DOI: 10.7554/elife.78335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 05/08/2023] [Indexed: 05/24/2023] Open
Abstract
Metabolic scaling, the inverse correlation of metabolic rates to body mass, has been appreciated for more than 80 years. Studies of metabolic scaling have largely been restricted to mathematical modeling of caloric intake and oxygen consumption, and mostly rely on computational modeling. The possibility that other metabolic processes scale with body size has not been comprehensively studied. To address this gap in knowledge, we employed a systems approach including transcriptomics, proteomics, and measurement of in vitro and in vivo metabolic fluxes. Gene expression in livers of five species spanning a 30,000-fold range in mass revealed differential expression according to body mass of genes related to cytosolic and mitochondrial metabolic processes, and to detoxication of oxidative damage. To determine whether flux through key metabolic pathways is ordered inversely to body size, we applied stable isotope tracer methodology to study multiple cellular compartments, tissues, and species. Comparing C57BL/6 J mice with Sprague-Dawley rats, we demonstrate that while ordering of metabolic fluxes is not observed in in vitro cell-autonomous settings, it is present in liver slices and in vivo. Together, these data reveal that metabolic scaling extends beyond oxygen consumption to other aspects of metabolism, and is regulated at the level of gene and protein expression, enzyme activity, and substrate supply.
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Affiliation(s)
- Ngozi D Akingbesote
- Department of Cellular & Molecular Physiology, Yale UniversityNew HavenUnited States
- Department of Internal Medicine – Endocrinology, Yale UniversityNew HavenUnited States
| | - Brooks P Leitner
- Department of Cellular & Molecular Physiology, Yale UniversityNew HavenUnited States
- Department of Internal Medicine – Endocrinology, Yale UniversityNew HavenUnited States
| | - Daniel G Jovin
- Department of Cellular & Molecular Physiology, Yale UniversityNew HavenUnited States
- Department of Internal Medicine – Endocrinology, Yale UniversityNew HavenUnited States
| | - Reina Desrouleaux
- Department of Cellular & Molecular Physiology, Yale UniversityNew HavenUnited States
- Department of Comparative Medicine, Yale UniversityNew HavenUnited States
| | - Dennis Owusu
- Department of Cellular & Molecular Physiology, Yale UniversityNew HavenUnited States
- Department of Internal Medicine – Endocrinology, Yale UniversityNew HavenUnited States
| | - Wanling Zhu
- Department of Cellular & Molecular Physiology, Yale UniversityNew HavenUnited States
- Department of Internal Medicine – Endocrinology, Yale UniversityNew HavenUnited States
| | - Zongyu Li
- Department of Cellular & Molecular Physiology, Yale UniversityNew HavenUnited States
- Department of Internal Medicine – Endocrinology, Yale UniversityNew HavenUnited States
| | - Michael N Pollak
- Lady Davis Institute for Medical Research, Jewish General HospitalMontrealCanada
- Department of Oncology, McGill UniversityMontrealCanada
| | - Rachel J Perry
- Department of Cellular & Molecular Physiology, Yale UniversityNew HavenUnited States
- Department of Internal Medicine – Endocrinology, Yale UniversityNew HavenUnited States
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21
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Lee HJ, Shon J, Park YJ. Association of NAFLD with FGF21 Polygenic Hazard Score, and Its Interaction with Protein Intake Level in Korean Adults. Nutrients 2023; 15:2385. [PMID: 37242268 PMCID: PMC10220598 DOI: 10.3390/nu15102385] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/15/2023] [Accepted: 05/18/2023] [Indexed: 05/28/2023] Open
Abstract
Fibroblast growth factor 21 (FGF21) is a hormone that participates in the regulation of energy homeostasis and is induced by dietary protein restriction. Preclinical studies have suggested that FGF21 induction exerts a protective effect against non-alcoholic fatty liver disease (NAFLD), while human studies have revealed elevated levels of and potential resistance to FGF21 in patients with NAFLD. However, whether the FGF21 pathway also contributes to NAFLD risk at the genetic level remains uncertain. A few attempts to investigate the impact of individual genetic variants at the loci encoding FGF21 and its receptors on NAFLD risk have failed to establish a clear association due to a limited effect size. Therefore, this study aimed to (1) develop a polygenic hazard score (PHS) for FGF21-related loci that are associated with NAFLD risk and (2) investigate the effect of its interaction with protein intake level on NAFLD risk. Data on 3501 participants of the Korean Genome Epidemiology Study (Ansan-Ansung) were analyzed. Eight single-nucleotide polymorphisms of fibroblast growth factor receptors and beta-klotho were selected for PHS determination using forward stepwise analysis. The association between the PHS and NAFLD was validated (p-trend: 0.0171 for men and <0.0001 for women). Moreover, the association was significantly modulated by the protein intake level in all participants as well as women (p-interaction = 0.0189 and 0.0131, respectively) but not in men. In particular, the women with the lowest PHS values and a protein intake lower than the recommended nutrient intake (RNI) exhibited a greater NAFLD risk (HR = 2.021, p-trend = 0.0016) than those with an intake equal to or greater than the RNI; however, those with higher PHS values had a high risk, regardless of protein intake level. These findings demonstrate the contribution of FGF21-related genetic variants and restricted protein intake to NAFLD incidence.
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Affiliation(s)
- Hae Jin Lee
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 03760, Republic of Korea
- Graduate Program in System Health Science & Engineering, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Jinyoung Shon
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 03760, Republic of Korea
- Graduate Program in System Health Science & Engineering, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Yoon Jung Park
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 03760, Republic of Korea
- Graduate Program in System Health Science & Engineering, Ewha Womans University, Seoul 03760, Republic of Korea
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22
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Talarico CHZ, Alves ES, Dos Santos JDM, Sucupira FGS, Araujo LCC, Camporez JP. Progesterone Has No Impact on the Beneficial Effects of Estradiol Treatment in High-Fat-Fed Ovariectomized Mice. Curr Issues Mol Biol 2023; 45:3965-3976. [PMID: 37232722 DOI: 10.3390/cimb45050253] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 04/20/2023] [Accepted: 04/25/2023] [Indexed: 05/27/2023] Open
Abstract
In recent decades, clinical and experimental studies have revealed that estradiol contributes enormously to glycemic homeostasis. However, the same consensus does not exist in women during menopause who undergo replacement with progesterone or conjugated estradiol and progesterone. Since most hormone replacement treatments in menopausal women are performed with estradiol (E2) and progesterone (P4) combined, this work aimed to investigate the effects of progesterone on energy metabolism and insulin resistance in an experimental model of menopause (ovariectomized female mice-OVX mice) fed a high-fat diet (HFD). OVX mice were treated with E2 or P4 (or both combined). OVX mice treated with E2 alone or combined with P4 displayed reduced body weight after six weeks of HFD feeding compared to OVX mice and OVX mice treated with P4 alone. These data were associated with improved glucose tolerance and insulin sensitivity in OVX mice treated with E2 (alone or combined with P4) compared to OVX and P4-treated mice. Additionally, E2 treatment (alone or combined with P4) reduced both hepatic and muscle triglyceride content compared with OVX control mice and OVX + P4 mice. There were no differences between groups regarding hepatic enzymes in plasma and inflammatory markers. Therefore, our results revealed that progesterone replacement alone does not seem to influence glucose homeostasis and ectopic lipid accumulation in OVX mice. These results will help expand knowledge about hormone replacement in postmenopausal women associated with metabolic syndrome and non-alcoholic fatty liver disease.
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Affiliation(s)
- Carlos H Z Talarico
- Department of Physiology, Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirão Preto 14049-900, Brazil
| | - Ester S Alves
- Department of Physiology, Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirão Preto 14049-900, Brazil
| | - Jessica D M Dos Santos
- Department of Physiology, Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirão Preto 14049-900, Brazil
| | - Felipe G S Sucupira
- Department of Physiology, Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirão Preto 14049-900, Brazil
| | - Layanne C C Araujo
- Department of Physiology, Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirão Preto 14049-900, Brazil
| | - João Paulo Camporez
- Department of Physiology, Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirão Preto 14049-900, Brazil
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23
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Kocaman Kalkan K, Şen S, Narlı B, Seymen CM, Yılmaz C. Effects of quercetin on hepatic fibroblast growth factor-21 (FGF-21) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) levels in rats fed with high fructose. Mol Biol Rep 2023; 50:4983-4997. [PMID: 37086297 DOI: 10.1007/s11033-023-08444-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 04/11/2023] [Indexed: 04/23/2023]
Abstract
BACKGROUND Available studies show that quercetin reduces Metabolic Syndrome (MetS) and its complications, increases insulin sensitivity and improves glucose levels. It has been reported that the increase in hepatic gene expressions of fibroblast growth factor-21 (FGF-21), an important metabolic regulator of insulin sensitivity, glucose and energy homeostasis, and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), which plays a central role in the regulation of cellular energy metabolism, eliminate the negative effects of fructose in fructose-fed rats. The main purpose of our study is to examine the effects of quercetin on hepatic FGF-21 and PGC-1α expressions and levels, as well as its protective and therapeutic role on MetS components in rats fed with fructose. METHODS AND RESULTS In our study, 24 Sprague Dawley male rats were divided into 4 groups: control, fructose, quercetin, fructose+quercetin (n = 6). During the 10-week experiment, quercetin was administered at a daily dose of 15 mg/kg body weight and fructose at a rate of 20%. Blood pressure and weights of all groups were measured and recorded. At the end of week 10, blood and liver tissue samples were taken. Serum insulin, glucose and triglyceride, total, HDL and VLDL cholesterol levels were determined from the samples. Insulin resistance was calculated using the HOMA-IR formula. Hepatic PGC-1α and FGF-21 protein levels and their mRNA expressions were determined. Criteria for metabolic syndrome were successfully established with fructose. It was observed that the administration of quercetin alone and in combination with fructose exerted positive effects and improved MetS criteria. It was determined that the administration of quercetin increased hepatic FGF-21 and PGC-1α protein levels and Messenger RNA (mRNA) expressions of them, which were decreased by fructose application. CONCLUSIONS The results of our study showed that 10-week administration of quercetin at 15 mg/kg exerted beneficial effects on lipid and carbohydrate metabolism in the fructose-mediated MetS model; therefore, quercetin may have great potential in the prevention and treatment of metabolic disorders.
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Affiliation(s)
| | - Serkan Şen
- Ataturk Vocational School of Health Services, Afyonkarahisar University of Health Sciences, Afyon, Turkey
| | - Belkıs Narlı
- Department of Medical Biochemistry, Gazi University Faculty of Medicine, Ankara, Turkey
| | - Cemile Merve Seymen
- Department of Histology and Embryology, Gazi University Faculty of Medicine, Ankara, Turkey
| | - Canan Yılmaz
- Department of Medical Biochemistry, Gazi University Faculty of Medicine, Ankara, Turkey
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24
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Li Z, Zhang X, Zhu W, Zhang C, Sadak K, Halberstam AA, Brown JR, Perry CJ, Bunn A, Braun DA, Adeniran A, Lee S, Wang A, Perry RJ. FGF-21 Conducts a Liver-Brain-Kidney Axis to Promote Renal Cell Carcinoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.12.536558. [PMID: 37090652 PMCID: PMC10120688 DOI: 10.1101/2023.04.12.536558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/25/2023]
Abstract
Metabolic homeostasis is one of the most exquisitely tuned systems in mammalian physiology. Metabolic homeostasis requires multiple redundant systems to cooperate to maintain blood glucose concentrations in a narrow range, despite a multitude of physiological and pathophysiological pressures. Cancer is one of the canonical pathophysiological settings in which metabolism plays a key role. In this study, we utilized REnal Gluconeogenesis Analytical Leads (REGAL), a liquid chromatography-mass spectrometry/mass spectrometry-based stable isotope tracer method that we developed to show that in conditions of metabolic stress, the fasting hepatokine fibroblast growth factor-21 (FGF-21)1,2 coordinates a liver-brain-kidney axis to promote renal gluconeogenesis. FGF-21 promotes renal gluconeogenesis by enhancing β2 adrenergic receptor (Adrb2)-driven, adipose triglyceride lipase (ATGL)-mediated intrarenal lipolysis. Further, we show that this liver-brain-kidney axis promotes gluconeogenesis in the renal parenchyma in mice and humans with renal cell carcinoma (RCC). This increased gluconeogenesis is, in turn, associated with accelerated RCC progression. We identify Adrb2 blockade as a new class of therapy for RCC in mice, with confirmatory data in human patients. In summary, these data reveal a new metabolic function of FGF-21 in driving renal gluconeogenesis, and demonstrate that inhibition of renal gluconeogenesis by FGF-21 antagonism deserves attention as a new therapeutic approach to RCC.
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Affiliation(s)
- Zongyu Li
- Department of Internal Medicine, Yale University School of Medicine
- Department of Cellular & Molecular Physiology, Yale University School of Medicine
| | - Xinyi Zhang
- Department of Internal Medicine, Yale University School of Medicine
- Department of Cellular & Molecular Physiology, Yale University School of Medicine
| | - Wanling Zhu
- Department of Internal Medicine, Yale University School of Medicine
- Department of Cellular & Molecular Physiology, Yale University School of Medicine
| | - Cuiling Zhang
- Department of Internal Medicine, Yale University School of Medicine
- Department of Immunobiology, Yale University School of Medicine
| | - Katherine Sadak
- Department of Internal Medicine, Yale University School of Medicine
| | - Alexandra A Halberstam
- Department of Internal Medicine, Yale University School of Medicine
- Department of Cellular & Molecular Physiology, Yale University School of Medicine
| | - Jason R Brown
- Department of Internal Medicine, Division of Medical Oncology, University Hospitals Seidman Cancer Center
- Case Western Reserve University
| | - Curtis J Perry
- Department of Internal Medicine, Yale University School of Medicine
| | - Azia Bunn
- Department of Internal Medicine, Yale University School of Medicine
- Yale Cancer Center, Yale University School of Medicine
| | - David A Braun
- Department of Internal Medicine, Yale University School of Medicine
- Yale Cancer Center, Yale University School of Medicine
| | | | - Sangwon Lee
- Department of Pharmacology, Yale University School of Medicine
| | - Andrew Wang
- Department of Internal Medicine, Yale University School of Medicine
- Department of Immunobiology, Yale University School of Medicine
| | - Rachel J Perry
- Department of Internal Medicine, Yale University School of Medicine
- Department of Cellular & Molecular Physiology, Yale University School of Medicine
- Yale Cancer Center, Yale University School of Medicine
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25
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Régnier M, Carbinatti T, Parlati L, Benhamed F, Postic C. The role of ChREBP in carbohydrate sensing and NAFLD development. Nat Rev Endocrinol 2023; 19:336-349. [PMID: 37055547 DOI: 10.1038/s41574-023-00809-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/31/2023] [Indexed: 04/15/2023]
Abstract
Excessive sugar consumption and defective glucose sensing by hepatocytes contribute to the development of metabolic diseases including type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). Hepatic metabolism of carbohydrates into lipids is largely dependent on the carbohydrate-responsive element binding protein (ChREBP), a transcription factor that senses intracellular carbohydrates and activates many different target genes, through the activation of de novo lipogenesis (DNL). This process is crucial for the storage of energy as triglycerides in hepatocytes. Furthermore, ChREBP and its downstream targets represent promising targets for the development of therapies for the treatment of NAFLD and T2DM. Although lipogenic inhibitors (for example, inhibitors of fatty acid synthase, acetyl-CoA carboxylase or ATP citrate lyase) are currently under investigation, targeting lipogenesis remains a topic of discussion for NAFLD treatment. In this Review, we discuss mechanisms that regulate ChREBP activity in a tissue-specific manner and their respective roles in controlling DNL and beyond. We also provide in-depth discussion of the roles of ChREBP in the onset and progression of NAFLD and consider emerging targets for NAFLD therapeutics.
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Affiliation(s)
- Marion Régnier
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France.
| | - Thaïs Carbinatti
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Lucia Parlati
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Fadila Benhamed
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Catherine Postic
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France.
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26
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Brinker EJ, Towns TJ, Watanabe R, Ma X, Bashir A, Cole RC, Wang X, Graff EC. Direct activation of the fibroblast growth factor-21 pathway in overweight and obese cats. Front Vet Sci 2023; 10:1072680. [PMID: 36756310 PMCID: PMC9900002 DOI: 10.3389/fvets.2023.1072680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 01/03/2023] [Indexed: 01/24/2023] Open
Abstract
Introduction Feline obesity is common, afflicting ~25-40% of domestic cats. Obese cats are predisposed to many metabolic dyscrasias, such as insulin resistance, altered blood lipids, and feline hepatic lipidosis. Fibroblast Growth Factor-21 (FGF21) is an endocrine hormone that mediates the fat-liver axis, and in humans and animals, FGF21 can ameliorate insulin resistance, non-alcoholic fatty liver disease, and obesity. Activation of the FGF21 pathway may have therapeutic benefits for obese cats. Methods In this preliminary cross-sectional study, ad libitum fed, purpose-bred, male-neutered, 6-year-old, obese and overweight cats were administered either 10 mg/kg/day of an FGF21 mimetic (FGF21; n = 4) or saline (control; n = 3) for 14 days. Body weight, food, and water intake were quantified daily during and 2 weeks following treatment. Changes in metabolic and liver parameters, intrahepatic triglyceride content, liver elasticity, and gut microbiota were evaluated. Results Treatment with FGF21 resulted in significant weight loss (~5.93%) compared to control and a trend toward decreased intrahepatic triglyceride content. Cats treated with FGF21 had decreased serum alkaline phosphatase. No significant changes were noted in liver elasticity, serum, liver, or metabolic parameters, or gut microbiome composition. Discussion In obese and overweight cats, activation of the FGF21 pathway can safely induce weight loss with trends to improve liver lipid content. This exploratory study is the first to evaluate the FGF21 pathway in cats. Manipulation of the FGF21 pathway has promising potential as a therapeutic for feline obesity. Further studies are needed to see if FGF21-pathway manipulation can be therapeutic for feline hepatic lipidosis.
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Affiliation(s)
- Emily J. Brinker
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States,Scott Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, United States
| | - T. Jordan Towns
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States,Scott Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, United States
| | - Rie Watanabe
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States
| | - Xiaolei Ma
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States,School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Adil Bashir
- Department of Electrical and Computer Engineering, Samuel Ginn College of Engineering, Auburn University, Auburn, AL, United States
| | - Robert C. Cole
- Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL, United States
| | - Xu Wang
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States,Scott Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, United States,Center for Advanced Science, Innovation and Commerce, Alabama Agricultural Experiment Station, Auburn, AL, United States,HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States
| | - Emily C. Graff
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States,Scott Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, United States,*Correspondence: Emily C. Graff ✉
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27
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Corbee RJ, van Everdingen DL, Kooistra HS, Penning LC. Fibroblast growth factor-21 (FGF21) analogs as possible treatment options for diabetes mellitus in veterinary patients. Front Vet Sci 2023; 9:1086987. [PMID: 36699319 PMCID: PMC9868460 DOI: 10.3389/fvets.2022.1086987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 12/13/2022] [Indexed: 01/10/2023] Open
Abstract
Fibroblast growth factors (FGFs) are involved in numerous metabolic processes. The endocrine subfamily of FGFs, consisting of FGF19, FGF21, and FGF23, might have beneficial effects in the treatment of diabetes mellitus (DM) and/or obesity. The analog with the greatest potential, FGF21, lowers blood glucose levels, improves insulin sensitivity, and induces weight loss in several animal models. In this review we summarize recent (pre)clinical findings with FGF21 analogs in animal models and men. Furthermore, possible applications of FGF21 analogs for pets with DM will be discussed. As currently, information about the use of FGF21 analogs in pet animals is scarce.
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28
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Seo JY, Cho EJ, Kim MJ, Kwak MS, Yang JI, Chung SJ, Yim JY, Yoon JW, Chung GE. The relationship between metabolic dysfunction-associated fatty liver disease and low muscle mass in an asymptomatic Korean population. J Cachexia Sarcopenia Muscle 2022; 13:2953-2960. [PMID: 36222309 PMCID: PMC9745451 DOI: 10.1002/jcsm.13099] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 08/23/2022] [Accepted: 09/06/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Metabolic (dysfunction)-associated fatty liver disease (MAFLD) emphasizes the metabolic dysfunction in nonalcoholic fatty liver disease (NAFLD). Although the relationship between low muscle mass and NAFLD has been suggested, the effect of MAFLD on low muscle mass is yet to be investigated. In this study, we examined the relationship between MAFLD and low muscle mass in an asymptomatic Korean population. METHODS Examinees who underwent FibroScan® and bioelectrical impedance analyses on the same day during the period of June 2017 to December 2019 were included. Hepatic steatosis was diagnosed using controlled attenuation parameter (CAP) with two cut-off values of 248 and 294 dB/m. Low muscle mass was defined based on appendicular skeletal muscle mass/body weight (wt) or body mass index (BMI) ratios of two standard deviations below the sex-specific mean for healthy young adults. Subjects were divided into four subgroups: diabetic MAFLD (presence of diabetes mellitus [DM]), metabolic dysfunction (MD) MAFLD (≥2 metabolic abnormalities without DM), overweight MAFLD (overweight/obese without DM and <2 metabolic abnormalities) and no MAFLD. RESULTS Among all of the 6414 subjects (mean 53.9 years of age; 85.4% male), the prevalence of MAFLD was 49.9% and 22.7% for CAP cut-off values of 248 and 294 dB/m, respectively. In the multivariate analysis, MAFLD was associated with an increased risk of both low muscle mass_wt (odds ratio [OR] 1.80, 95% confidence interval [CI] 1.38-2.35, P < 0.001) and low muscle mass_BMI (OR 1.31, 95% CI 1.01-1.70, P = 0.042). The risk of low muscle mass_wt and low muscle mass_BMI increased the most in the diabetic MAFLD subgroup compared with the no-MAFLD group (OR 2.11, 95% CI 1.51-2.96, P < 0.001 and OR 1.51, 95% CI 1.08-2.13, P = 0.017). There was an increased risk of low muscle mass_wt in the MD MAFLD subgroup (OR 1.73, 95% CI 1.31-2.28, P < 0.001). Comparable results were observed when the CAP cut-off value of 294 dB/m was applied. CONCLUSIONS The presence of MAFLD is significantly associated with increased risk of low muscle mass with varying risks according to the MAFLD subgroups. Clinicians should be aware of the differentiated risk of low muscle mass across the subgroups of MAFLD.
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Affiliation(s)
- Ji Yeon Seo
- Department of Gastroenterology and Hepatology, Internal Medicine and Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, South Korea
| | - Eun Ju Cho
- Department of Gastroenterology and Hepatology, Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul, South Korea
| | - Min Joo Kim
- Department of Endocrinology, Internal Medicine and Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, South Korea
| | - Min-Sun Kwak
- Department of Gastroenterology and Hepatology, Internal Medicine and Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, South Korea
| | - Jong In Yang
- Department of Gastroenterology and Hepatology, Internal Medicine and Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, South Korea
| | - Su Jin Chung
- Department of Gastroenterology and Hepatology, Internal Medicine and Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, South Korea
| | - Jeong Yoon Yim
- Department of Gastroenterology and Hepatology, Internal Medicine and Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, South Korea
| | - Ji Won Yoon
- Department of Endocrinology, Internal Medicine and Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, South Korea
| | - Goh Eun Chung
- Department of Gastroenterology and Hepatology, Internal Medicine and Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, South Korea
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29
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Zhang X, Halberstam AA, Zhu W, Leitner BP, Thakral D, Bosenberg MW, Perry RJ. Isotope tracing reveals distinct substrate preference in murine melanoma subtypes with differing anti-tumor immunity. Cancer Metab 2022; 10:21. [PMID: 36457136 PMCID: PMC9714036 DOI: 10.1186/s40170-022-00296-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 11/07/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Research about tumor "metabolic flexibility"-the ability of cells to toggle between preferred nutrients depending on the metabolic context-has largely focused on obesity-associated cancers. However, increasing evidence for a key role for nutrient competition in the tumor microenvironment, as well as for substrate regulation of immune function, suggests that substrate metabolism deserves reconsideration in immunogenic tumors that are not strongly associated with obesity. METHODS We compare two murine models: immunologically cold YUMM1.7 and immunologically-hot YUMMER1.7. We utilize stable isotope and radioisotope tracer-based metabolic flux studies as well as gas and liquid chromatography-based metabolomics analyses to comprehensively probe substrate preference in YUMM1.7 and YUMMER1.7 cells, with a subset of studies on the impact of available metabolites across a panel of five additional melanoma cell lines. We analyze bulk RNA-seq data and identify increased expression of amino acid and glucose metabolism genes in YUMMER1.7. Finally, we analyze melanoma patient RNA-seq data to identify potential prognostic predictors rooted in metabolism. RESULTS We demonstrate using stable isotope tracer-based metabolic flux studies as well as gas and liquid chromatography-based metabolomics that immunologically-hot melanoma utilizes more glutamine than immunologically-cold melanoma in vivo and in vitro. Analyses of human melanoma RNA-seq data demonstrate that glutamine transporter and other anaplerotic gene expression positively correlates with lymphocyte infiltration and function. CONCLUSIONS Here, we highlight the importance of understanding metabolism in non-obesity-associated cancers, such as melanoma. This work advances the understanding of the correlation between metabolism and immunogenicity in the tumor microenvironment and provides evidence supporting metabolic gene expression as potential prognostic factors of melanoma progression and may inform investigations of adjunctive metabolic therapy in melanoma. TRIAL REGISTRATION Deidentified data from The Cancer Genome Atlas were analyzed.
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Affiliation(s)
- Xinyi Zhang
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, P.O. Box 208026, 333 Cedar St., SHM BE36-B, New Haven, CT, 06520-8026, USA
- Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, USA
| | - Alexandra A Halberstam
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, P.O. Box 208026, 333 Cedar St., SHM BE36-B, New Haven, CT, 06520-8026, USA
- Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, USA
| | - Wanling Zhu
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, P.O. Box 208026, 333 Cedar St., SHM BE36-B, New Haven, CT, 06520-8026, USA
- Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, USA
| | - Brooks P Leitner
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, P.O. Box 208026, 333 Cedar St., SHM BE36-B, New Haven, CT, 06520-8026, USA
- Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, USA
| | - Durga Thakral
- Department of Pathology, Yale School of Medicine, New Haven, USA
| | - Marcus W Bosenberg
- Department of Pathology, Yale School of Medicine, New Haven, USA
- Department of Dermatology, Yale School of Medicine, New Haven, USA
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
- Yale Stem Cell Center, New Haven, CT, USA
- Yale Cancer Center, New Haven, CT, USA
- Yale Center for Immuno-Oncology, New Haven, CT, USA
| | - Rachel J Perry
- Department of Internal Medicine (Endocrinology), Yale School of Medicine, P.O. Box 208026, 333 Cedar St., SHM BE36-B, New Haven, CT, 06520-8026, USA.
- Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, USA.
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30
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Patel S, Haider A, Alvarez-Guaita A, Bidault G, El-Sayed Moustafa JS, Guiu-Jurado E, Tadross JA, Warner J, Harrison J, Virtue S, Scurria F, Zvetkova I, Blüher M, Small KS, O'Rahilly S, Savage DB. Combined genetic deletion of GDF15 and FGF21 has modest effects on body weight, hepatic steatosis and insulin resistance in high fat fed mice. Mol Metab 2022; 65:101589. [PMID: 36064109 PMCID: PMC9486046 DOI: 10.1016/j.molmet.2022.101589] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 08/26/2022] [Accepted: 08/28/2022] [Indexed: 11/28/2022] Open
Abstract
OBJECTIVES Obesity in humans and mice is associated with elevated levels of two hormones responsive to cellular stress, namely GDF15 and FGF21. Over-expression of each of these is associated with weight loss and beneficial metabolic changes but where they are secreted from and what they are required for physiologically in the context of overfeeding remains unclear. METHODS Here we used tissue selective knockout mouse models and human transcriptomics to determine the source of circulating GDF15 in obesity. We then generated and characterized the metabolic phenotypes of GDF15/FGF21 double knockout mice. RESULTS Circulating GDF15 and FGF21 are both largely derived from the liver, rather than adipose tissue or skeletal muscle, in obese states. Combined whole body deletion of FGF21 and GDF15 does not result in any additional weight gain in response to high fat feeding but it does result in significantly greater hepatic steatosis and insulin resistance than that seen in GDF15 single knockout mice. CONCLUSIONS Collectively the data suggest that overfeeding activates a stress response in the liver which is the major source of systemic rises in GDF15 and FGF21. These hormones then activate pathways which reduce this metabolic stress.
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Affiliation(s)
- Satish Patel
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UK; MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
| | - Afreen Haider
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UK; MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
| | - Anna Alvarez-Guaita
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UK
| | - Guillaume Bidault
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UK
| | | | - Esther Guiu-Jurado
- Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany
| | - John A Tadross
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UK; East Midlands and East of England Genomic Laboratory Hub & Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - James Warner
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UK
| | - James Harrison
- Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK
| | - Samuel Virtue
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UK
| | - Fabio Scurria
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UK
| | - Ilona Zvetkova
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UK
| | - Matthias Blüher
- Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München, University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - Kerrin S Small
- Department of Twin Research and Genetic Epidemiology, King's College London, St Thomas' Campus, London, SE1 7EH, UK
| | - Stephen O'Rahilly
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UK; MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - David B Savage
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UK; MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
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Western Diet-Fed ApoE Knockout Male Mice as an Experimental Model of Non-Alcoholic Steatohepatitis. Curr Issues Mol Biol 2022; 44:4692-4703. [PMID: 36286035 PMCID: PMC9600038 DOI: 10.3390/cimb44100320] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/05/2022] [Accepted: 10/06/2022] [Indexed: 11/23/2022] Open
Abstract
One of the consequences of the Western lifestyle and high-fat diet is non-alcoholic fatty liver disease (NAFLD) and its aggressive form, non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma (HCC) and is rapidly becoming the leading cause of end-stage liver disease or liver transplantation. Currently, rodent NASH models lack significant aspects of the full NASH spectrum, representing a major problem for NASH research. Therefore, this work aimed to characterize a fast rodent model with all characteristic features of NASH. Eight-week-old male ApoE KO mice were fed with Western diet (WD), high fatty diet (HFD) or normal chow (Chow) for 7 weeks. Whole-body fat was increased by ~2 times in WD mice and HFD mice and was associated with increased glucose intolerance, hepatic triglycerides, and plasma ALT and plasma AST compared with Chow mice. WD mice also showed increased galectin-3 expression compared with Chow or HFD mice and increased plasma cholesterol compared with Chow mice. WD and HFD displayed increased hepatic fibrosis and increased F4/80 expression. WD mice also displayed increased levels of plasma MCP-1. Hepatic inflammatory markers were evaluated, and WD mice showed increased levels of TNF-α, MCP-1, IL-6 and IFN-γ. Taken together, these data demonstrated that the ApoE KO mouse fed with WD is a great model for NASH research, once it presents the fundamental parameters of the disease, including hepatic steatosis, fibrosis, inflammation, and metabolic syndrome.
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Hou HW, Bishop CA, Huckauf J, Broer I, Klaus S, Nausch H, Buyel JF. Seed- and leaf-based expression of FGF21-transferrin fusion proteins for oral delivery and treatment of non-alcoholic steatohepatitis. FRONTIERS IN PLANT SCIENCE 2022; 13:998596. [PMID: 36247628 PMCID: PMC9557105 DOI: 10.3389/fpls.2022.998596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 08/29/2022] [Indexed: 06/16/2023]
Abstract
Non-alcoholic steatohepatitis (NASH) is a global disease with no effective medication. The fibroblast growth factor 21 (FGF21) can reverse this liver dysfunction, but requires targeted delivery to the liver, which can be achieved via oral administration. Therefore, we fused FGF21 to transferrin (Tf) via a furin cleavage site (F), to promote uptake from the intestine into the portal vein, yielding FGF21-F-Tf, and established its production in both seeds and leaves of commercial Nicotiana tabacum cultivars, compared their expression profile and tested the bioavailability and bioactivity in feeding studies. Since biopharmaceuticals need to be produced in a contained environment, e.g., greenhouses in case of plants, the seed production was increased in this setting from 239 to 380 g m-2 a-1 seed mass with costs of 1.64 € g-1 by side branch induction, whereas leaves yielded 8,193 g m-2 a-1 leave mass at 0.19 € g-1. FGF21-F-Tf expression in transgenic seeds and leaves yielded 6.7 and 5.6 mg kg-1 intact fusion protein, but also 4.5 and 2.3 mg kg-1 additional Tf degradation products. Removing the furin site and introducing the liver-targeting peptide PLUS doubled accumulation of intact FGF21-transferrin fusion protein when transiently expressed in Nicotiana benthamiana from 0.8 to 1.6 mg kg-1, whereas truncation of transferrin (nTf338) and reversing the order of FGF21 and nTf338 increased the accumulation to 2.1 mg kg-1 and decreased the degradation products to 7% for nTf338-FGF21-PLUS. Application of partially purified nTf338-FGF21-PLUS to FGF21-/- mice by oral gavage proved its transfer from the intestine into the blood circulation and acutely affected hepatic mRNA expression. Hence, the medication of NASH via oral delivery of nTf338-FGF21-PLUS containing plants seems possible.
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Affiliation(s)
- Hsuan-Wu Hou
- Department Bioprocess Engineering, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Aachen, Germany
- Chair for Agrobiotechnology, University of Rostock, Rostock, Germany
| | - Christopher A. Bishop
- Department of Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
- Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
| | - Jana Huckauf
- Chair for Agrobiotechnology, University of Rostock, Rostock, Germany
| | - Inge Broer
- Chair for Agrobiotechnology, University of Rostock, Rostock, Germany
| | - Susanne Klaus
- Department of Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
- Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
| | - Henrik Nausch
- Department Bioprocess Engineering, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Aachen, Germany
| | - Johannes F. Buyel
- Department Bioprocess Engineering, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Aachen, Germany
- Institute of Molecular Biotechnology, RWTH Aachen University, Aachen, Germany
- Department of Biotechnology (DBT), Institute of Bioprocess Science and Engineering (IBSE), University of Natural Resources and Life Sciences (BOKU), Vienna, Austria
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Harrison SA, Ruane PJ, Freilich B, Neff G, Patil R, Behling C, Hu C, Shringarpure R, de Temple B, Fong E, Tillman EJ, Rolph T, Cheng A, Yale K. A randomized, double-blind, placebo-controlled phase IIa trial of efruxifermin for patients with compensated NASH cirrhosis. JHEP Rep 2022; 5:100563. [PMID: 36644237 PMCID: PMC9832280 DOI: 10.1016/j.jhepr.2022.100563] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 08/03/2022] [Indexed: 01/18/2023] Open
Abstract
Background & Aims Efruxifermin has shown clinical efficacy in patients with non-alcoholic steatohepatitis (NASH) and F1-F3 fibrosis. The primary objective of the BALANCED Cohort C was to assess the safety and tolerability of efruxifermin in patients with compensated NASH cirrhosis. Methods Patients with NASH and stage 4 fibrosis (n = 30) were randomized 2:1 to receive efruxifermin 50 mg (n = 20) or placebo (n = 10) once-weekly for 16 weeks. The primary endpoint was safety and tolerability of efruxifermin. Secondary and exploratory endpoints included evaluation of non-invasive markers of liver injury and fibrosis, glucose and lipid metabolism, and changes in histology in a subset of patients who consented to end-of-study liver biopsy. Results Efruxifermin was safe and well-tolerated; most adverse events (AEs) were grade 1 (n = 7, 23.3%) or grade 2 (n = 19, 63.3%). The most frequent AEs were gastrointestinal, including transient, mild to moderate diarrhea, and/or nausea. Significant improvements were noted in key markers of liver injury (alanine aminotransferase) and glucose and lipid metabolism. Sixteen-week treatment with efruxifermin was associated with significant reductions in non-invasive markers of fibrosis including Pro-C3 (least squares mean change from baseline [LSMCFB] -9 μg/L efruxifermin vs. -3.4 μg/L placebo; p = 0.0130) and ELF score (-0.4 efruxifermin vs. +0.4 placebo; p = 0.0036), with a trend towards reduced liver stiffness (LSMCFB -5.7 kPa efruxifermin vs. -1.1 kPa placebo; n.s.). Of 12 efruxifermin-treated patients with liver biopsy after 16 weeks, 4 (33%) achieved fibrosis improvement of at least one stage without worsening of NASH, while an additional 3 (25%) achieved resolution of NASH, compared to 0 of 5 placebo-treated patients. Conclusions Efruxifermin appeared safe and well-tolerated with encouraging improvements in markers of liver injury, fibrosis, and glucose and lipid metabolism following 16 weeks of treatment, warranting confirmation in larger and longer term studies. Lay summary Cirrhosis resulting from non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease, represents a major unmet medical need. Currently there are no approved drugs for the treatment of NASH. This proof-of-concept randomized, double-blind clinical trial demonstrated the potential therapeutic benefit of efruxifermin treatment compared to placebo in patients with cirrhosis due to NASH. Clinical Trial Number NCT03976401.
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Key Words
- ADA(s), anti-drug antibody(ies)
- AE, adverse event
- ALP, alkaline phosphatase
- ALT, alanine aminotransferase
- ANCOVA, analysis of covariance
- AST, aspartate aminotransferase
- CFB, change from baseline
- CTX-1, C-terminal telopeptide of type 1 collagen
- C–P, Child-Pugh
- DXA, dual-energy X-ray absorptiometry
- ELF, enhanced liver fibrosis
- FGF21
- FGF21, fibroblast growth factor-21
- FGFR, fibroblast growth factor receptor
- GGT, gamma-glutamyltransferase
- HDL-C, HDL-cholesterol
- HOMA-IR, homeostatic model assessment of insulin resistance
- HPA, hypothalamic-pituitary-adrenal
- HbA1c, hemoglobin A1c
- INR, international normalized ratio
- IRT, interactive response technology
- LDL-C, LDL-cholesterol
- LS, least squares
- MELD, model for end-stage liver disease
- NAFLD, non-alcoholic fatty liver disease
- NAS, NAFLD activity score
- NASH, non-alcoholic steatohepatitis
- NAb, neutralizing antibody
- Non-HDL-C, non-HDL-cholesterol
- P1NP, procollagen type-I N-terminal propeptide
- P3NP, procollagen type III N-terminal propeptide
- PAI-1, plasminogen activator inhibitor-1
- Pro-C3, N-terminal type III collagen propeptide
- TEAE, treatment-emergent adverse event
- TIMP-1, tissue inhibitor of metalloproteinase-1
- ULN, upper limit of normal
- cirrhosis
- clinical trial
- efruxifermin
- histopathology
- hs-CRP, high-sensitivity C-reactive protein
- liver disease
- non-alcoholic steatohepatitis/NASH
- nonalcoholic fatty liver disease/NAFLD
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Affiliation(s)
| | - Peter J. Ruane
- Ruane Clinical Research Group Inc., Los Angeles, CA, United States
| | | | - Guy Neff
- Covenant Metabolic Specialists, LLC, Sarasota, FL, United States
| | - Rashmee Patil
- South Texas Research Institute, Edinburg, TX, United States
| | | | - Chen Hu
- MedPace, INC, Cincinnati, OH, United States
| | | | | | - Erica Fong
- Akero Therapeutics, South San Francisco, CA, United States
| | | | - Timothy Rolph
- Akero Therapeutics, South San Francisco, CA, United States
| | - Andrew Cheng
- Akero Therapeutics, South San Francisco, CA, United States
| | - Kitty Yale
- Akero Therapeutics, South San Francisco, CA, United States,Corresponding author. Address: 601 Gateway Blvd, Suite 350, South San Francisco, CA 94080, United States; Tel.: 415 823 7554.
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Kaur N, Gare SR, Shen J, Raja R, Fonseka O, Liu W. Multi-organ FGF21-FGFR1 signaling in metabolic health and disease. Front Cardiovasc Med 2022; 9:962561. [PMID: 35983184 PMCID: PMC9378980 DOI: 10.3389/fcvm.2022.962561] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 07/11/2022] [Indexed: 11/23/2022] Open
Abstract
Metabolic syndrome is a chronic systemic disease that is particularly manifested by obesity, diabetes, and hypertension, affecting multiple organs. The increasing prevalence of metabolic syndrome poses a threat to public health due to its complications, such as liver dysfunction and cardiovascular disease. Impaired adipose tissue plasticity is another factor contributing to metabolic syndrome. Emerging evidence demonstrates that fibroblast growth factors (FGFs) are critical players in organ crosstalk via binding to specific FGF receptors (FGFRs) and their co-receptors. FGFRs activation modulates intracellular responses in various cell types under metabolic stress. FGF21, in particular is considered as the key regulator for mediating systemic metabolic effects by binding to receptors FGFR1, FGFR3, and FGFR4. The complex of FGFR1 and beta Klotho (β-KL) facilitates endocrine and paracrine communication networks that physiologically regulate global metabolism. This review will discuss FGF21-mediated FGFR1/β-KL signaling pathways in the liver, adipose, and cardiovascular systems, as well as how this signaling is involved in the interplay of these organs during the metabolic syndrome. Furthermore, the clinical implications and therapeutic strategies for preventing metabolic syndrome and its complications by targeting FGFR1/β-KL are also discussed.
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Affiliation(s)
| | | | - Jiahan Shen
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, United Kingdom
| | - Rida Raja
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, United Kingdom
| | - Oveena Fonseka
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, United Kingdom
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Chen W, Zhang Z, Yung KKL, Ko JKS. MUC1 is responsible for the pro-metastatic potential of calycosin in pancreatic ductal adenocarcinoma. Am J Cancer Res 2022; 12:3242-3258. [PMID: 35968328 PMCID: PMC9360244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 06/11/2022] [Indexed: 06/15/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a prominent type of pancreatic cancer. We have recently unveiled that the anti-tumor adjuvant calycosin concurrently possesses growth-inhibitory and pro-metastatic potential in PDAC development by regulating transforming growth factor β (TGF-β), which plays dual roles as both tumor suppressor and tumor promoter. Hence, we are interested to explore if the pro-metastatic property of the drug could be attenuated for effective treatment of PDAC. Through network pharmacology, MUC1 had been identified as the most common drug target of herbal Astragalus constituents (including calycosin) in treating PDAC. Following MUC1 gene silencing, the drug effects of calycosin on migratory activity, growth and metabolic regulation of PDAC cells were assessed by using immunofluorescence microscopy, quantitative real-time polymerase chain reaction (qRT-PCR), Western immunoblotting, co-immunoprecipitation (Co-IP), wound healing assay and flow cytometry, respectively. Through in vivo experiments, we further validated the working relationship between MUC1 and TGF-β. Results have elucidated that MUC1 gene suppression could switch off the migratory and pro-metastatic drive of calycosin while retaining its growth-inhibitory power by inducing apoptosis and cell cycle arrest, as well as facilitating autophagy and metabolic regulation. The underlying mechanism involves downregulation of TGF-β that acts via modulation of AMP-activated protein kinase (AMPK), Sirtuin 1 (Sirt1) and fibroblast growth factor 21 (FGF21) signaling. These findings have provided new insights in the safe and target-specific treatment of PDAC.
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Affiliation(s)
- Wenqing Chen
- Department of Biology, Hong Kong Baptist UniversityHong Kong SAR, China
- Teaching and Research Division, School of Chinese Medicine, Hong Kong Baptist UniversityHong Kong SAR, China
| | - Zhu Zhang
- Department of Biology, Hong Kong Baptist UniversityHong Kong SAR, China
| | - Ken Kin-Lam Yung
- Department of Biology, Hong Kong Baptist UniversityHong Kong SAR, China
| | - Joshua Ka-Shun Ko
- Teaching and Research Division, School of Chinese Medicine, Hong Kong Baptist UniversityHong Kong SAR, China
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist UniversityHong Kong SAR, China
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Dai Y, Kou H, Gui S, Guo X, Liu H, Gong Z, Sun X, Wang H, Guo Y. Prenatal dexamethasone exposure induced pancreatic β-cell dysfunction and glucose intolerance of male offspring rats: Role of the epigenetic repression of ACE2. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 826:154095. [PMID: 35219660 DOI: 10.1016/j.scitotenv.2022.154095] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 02/01/2022] [Accepted: 02/19/2022] [Indexed: 06/14/2023]
Abstract
The prevalence of diabetes in children and adolescents has been rising gradually, which is relevant to adverse environment during development, especially prepartum. We aimed to explore the effects of prenatal dexamethasone exposure (PDE) on β-cell function and glucose homeostasis in juvenile offspring rats. Pregnant Wistar rats were subcutaneously administered with dexamethasone [0.1, 0.2, 0.4mg/(kg.d)] from gestational day 9 to 20. PDE impaired glucose tolerance in the male offspring rather than the females. In male offspring, PDE impaired the development and function of β-cells, accompanied with lower H3K9ac, H3K14ac and H3K27ac levels in the promoter region of angiotensin-converting enzyme 2 (ACE2) as well as suppressed ACE2 expression. Meanwhile, PDE increased expression of glucocorticoid receptor (GR) and histone deacetylase 3 (HDAC3) in fetal pancreas. Dexamethasone also inhibited ACE2 expression and insulin production in vitro. Recombinant expression of ACE2 restored insulin production inhibited by dexamethasone. In addition, dexamethasone activated GR and HDAC3, increased protein interaction of GR with HDAC3, and promoted the binding of GR-HDAC3 complex to ACE2 promoter region. Both RU486 and TSA abolished dexamethasone-induced decline of histone acetylation and ACE2 expression. In summary, suppression of ACE2 is involved in PDE induced β-cell dysfunction and glucose intolerance in juvenile male offspring rats.
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Affiliation(s)
- Yongguo Dai
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, Hubei Province, People's Republic of China.
| | - Hao Kou
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan 430060, Hubei Province, People's Republic of China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, Hubei Province, People's Republic of China
| | - Shuxia Gui
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, Hubei Province, People's Republic of China
| | - Xiaoling Guo
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, Hubei Province, People's Republic of China
| | - Heze Liu
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, Hubei Province, People's Republic of China
| | - Zheng Gong
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, Hubei Province, People's Republic of China
| | - Xiaoxiang Sun
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, Hubei Province, People's Republic of China
| | - Hui Wang
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, Hubei Province, People's Republic of China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, Hubei Province, People's Republic of China.
| | - Yu Guo
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, Hubei Province, People's Republic of China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, Hubei Province, People's Republic of China.
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Balakrishnan R, Thurmond DC. Mechanisms by Which Skeletal Muscle Myokines Ameliorate Insulin Resistance. Int J Mol Sci 2022; 23:4636. [PMID: 35563026 PMCID: PMC9102915 DOI: 10.3390/ijms23094636] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 04/17/2022] [Accepted: 04/18/2022] [Indexed: 12/17/2022] Open
Abstract
The skeletal muscle is the largest organ in the body and secretes circulating factors, including myokines, which are involved in various cellular signaling processes. Skeletal muscle is vital for metabolism and physiology and plays a crucial role in insulin-mediated glucose disposal. Myokines have autocrine, paracrine, and endocrine functions, serving as critical regulators of myogenic differentiation, fiber-type switching, and maintaining muscle mass. Myokines have profound effects on energy metabolism and inflammation, contributing to the pathophysiology of type 2 diabetes (T2D) and other metabolic diseases. Myokines have been shown to increase insulin sensitivity, thereby improving glucose disposal and regulating glucose and lipid metabolism. Many myokines have now been identified, and research on myokine signaling mechanisms and functions is rapidly emerging. This review summarizes the current state of the field regarding the role of myokines in tissue cross-talk, including their molecular mechanisms, and their potential as therapeutic targets for T2D.
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Affiliation(s)
| | - Debbie C. Thurmond
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Beckman Research Institute, 1500 E. Duarte Road, Duarte, CA 91010, USA;
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Berthou F, Sobolewski C, Abegg D, Fournier M, Maeder C, Dolicka D, Correia de Sousa M, Adibekian A, Foti M. Hepatic PTEN Signaling Regulates Systemic Metabolic Homeostasis through Hepatokines-Mediated Liver-to-Peripheral Organs Crosstalk. Int J Mol Sci 2022; 23:ijms23073959. [PMID: 35409319 PMCID: PMC8999584 DOI: 10.3390/ijms23073959] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/25/2022] [Accepted: 03/31/2022] [Indexed: 11/16/2022] Open
Abstract
Liver-derived circulating factors deeply affect the metabolism of distal organs. Herein, we took advantage of the hepatocyte-specific PTEN knockout mice (LPTENKO), a model of hepatic steatosis associated with increased muscle insulin sensitivity and decreased adiposity, to identify potential secreted hepatic factors improving metabolic homeostasis. Our results indicated that protein factors, rather than specific metabolites, released by PTEN-deficient hepatocytes trigger an improved muscle insulin sensitivity and a decreased adiposity in LPTENKO. In this regard, a proteomic analysis of conditioned media from PTEN-deficient primary hepatocytes identified seven hepatokines whose expression/secretion was deregulated. Distinct expression patterns of these hepatokines were observed in hepatic tissues from human/mouse with NAFLD. The expression of specific factors was regulated by the PTEN/PI3K, PPAR or AMPK signaling pathways and/or modulated by classical antidiabetic drugs. Finally, loss-of-function studies identified FGF21 and the triad AHSG, ANGPTL4 and LECT2 as key regulators of insulin sensitivity in muscle cells and in adipocytes biogenesis, respectively. These data indicate that hepatic PTEN deficiency and steatosis alter the expression/secretion of hepatokines regulating insulin sensitivity in muscles and the lipid metabolism in adipose tissue. These hepatokines could represent potential therapeutic targets to treat obesity and insulin resistance.
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Affiliation(s)
- Flavien Berthou
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; (F.B.); (C.S.); (M.F.); (C.M.); (D.D.); (M.C.d.S.)
| | - Cyril Sobolewski
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; (F.B.); (C.S.); (M.F.); (C.M.); (D.D.); (M.C.d.S.)
| | - Daniel Abegg
- Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA; (D.A.); (A.A.)
| | - Margot Fournier
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; (F.B.); (C.S.); (M.F.); (C.M.); (D.D.); (M.C.d.S.)
| | - Christine Maeder
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; (F.B.); (C.S.); (M.F.); (C.M.); (D.D.); (M.C.d.S.)
| | - Dobrochna Dolicka
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; (F.B.); (C.S.); (M.F.); (C.M.); (D.D.); (M.C.d.S.)
| | - Marta Correia de Sousa
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; (F.B.); (C.S.); (M.F.); (C.M.); (D.D.); (M.C.d.S.)
| | - Alexander Adibekian
- Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA; (D.A.); (A.A.)
| | - Michelangelo Foti
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland; (F.B.); (C.S.); (M.F.); (C.M.); (D.D.); (M.C.d.S.)
- Diabetes Center, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland
- Correspondence: ; Tel.: +41-(22)-379-52-04
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Ursic-Bedoya J, Chavey C, Desandré G, Meunier L, Dupuy AM, Gonzalez-Dopeso Reyes I, Tordjmann T, Assénat E, Hibner U, Gregoire D. Fibroblast Growth Factor 19 stimulates water intake. Mol Metab 2022; 60:101483. [PMID: 35367668 PMCID: PMC9019402 DOI: 10.1016/j.molmet.2022.101483] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 03/18/2022] [Accepted: 03/27/2022] [Indexed: 11/30/2022] Open
Affiliation(s)
- José Ursic-Bedoya
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France; Department of Hepatogastroenterology, Hepatology and Liver Transplantation Unit, Saint Eloi Hospital, University of Montpellier, France
| | - Carine Chavey
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Guillaume Desandré
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Lucy Meunier
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France; Department of Hepatogastroenterology, Hepatology and Liver Transplantation Unit, Saint Eloi Hospital, University of Montpellier, France
| | - Anne-Marie Dupuy
- Biochemistry and Hormonology Department, Lapeyronie Hospital, University of Montpellier, Montpellier, France
| | | | - Thierry Tordjmann
- Université Paris Saclay, Faculté des Sciences d'Orsay, INSERM U.1193, Bât. 443, 91405, Orsay, France
| | - Eric Assénat
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France; Department of Hepatogastroenterology, Hepatology and Liver Transplantation Unit, Saint Eloi Hospital, University of Montpellier, France
| | - Urszula Hibner
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Damien Gregoire
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France.
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Flippo KH, Trammell SAJ, Gillum MP, Aklan I, Perez MB, Yavuz Y, Smith NK, Jensen-Cody SO, Zhou B, Claflin KE, Beierschmitt A, Fink-Jensen A, Knop FK, Palmour RM, Grueter BA, Atasoy D, Potthoff MJ. FGF21 suppresses alcohol consumption through an amygdalo-striatal circuit. Cell Metab 2022; 34:317-328.e6. [PMID: 35108517 PMCID: PMC9093612 DOI: 10.1016/j.cmet.2021.12.024] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 11/11/2021] [Accepted: 12/23/2021] [Indexed: 02/08/2023]
Abstract
Excessive alcohol consumption is a major health and social issue in our society. Pharmacologic administration of the endocrine hormone fibroblast growth factor 21 (FGF21) suppresses alcohol consumption through actions in the brain in rodents, and genome-wide association studies have identified single nucleotide polymorphisms in genes involved with FGF21 signaling as being associated with increased alcohol consumption in humans. However, the neural circuit(s) through which FGF21 signals to suppress alcohol consumption are unknown, as are its effects on alcohol consumption in higher organisms. Here, we demonstrate that administration of an FGF21 analog to alcohol-preferring non-human primates reduces alcohol intake by 50%. Further, we reveal that FGF21 suppresses alcohol consumption through a projection-specific subpopulation of KLB-expressing neurons in the basolateral amygdala. Our results illustrate how FGF21 suppresses alcohol consumption through a specific population of neurons in the brain and demonstrate its therapeutic potential in non-human primate models of excessive alcohol consumption.
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Affiliation(s)
- Kyle H Flippo
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
| | - Samuel A J Trammell
- Section for Nutrient and Metabolite Sensing, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Matthew P Gillum
- Section for Nutrient and Metabolite Sensing, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Iltan Aklan
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Misty B Perez
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Yavuz Yavuz
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Nicholas K Smith
- Department of Anesthesiology, Vanderbilt University, Nashville, TN 37323, USA
| | - Sharon O Jensen-Cody
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Bolu Zhou
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Kristin E Claflin
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Amy Beierschmitt
- School of Veterinary Medicine, Ross University, Basseterre KN 0101, Saint Kitts and Nevis; Behavioral Science Foundation, Basseterre KN 0101, Saint Kitts and Nevis
| | - Anders Fink-Jensen
- Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen and University Hospital of Copenhagen, Edel Sauntes Allé 10, DK-2100 Copenhagen, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Gentofte Hospitalsvej 7, 3rd floor, DK-2900 Hellerup, Denmark; Steno Diabetes Center Copenhagen, 2820 Gentofte, Denmark
| | - Roberta M Palmour
- Behavioral Science Foundation, Basseterre KN 0101, Saint Kitts and Nevis; Departments of Psychiatry and Human Genetics, McGill University, Montreal, QC, Canada
| | - Brad A Grueter
- Department of Anesthesiology, Vanderbilt University, Nashville, TN 37323, USA
| | - Deniz Atasoy
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Matthew J Potthoff
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Department of Veterans Affairs Medical Center, Iowa City, IA 52242, USA.
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Wang Y, Liu H, Zhang R, Xiang Y, Lu J, Xia B, Peng L, Wu J. AdipoRon exerts opposing effects on insulin sensitivity via fibroblast growth factor FGF21-mediated time-dependent mechanisms. J Biol Chem 2022; 298:101641. [PMID: 35090894 PMCID: PMC8861110 DOI: 10.1016/j.jbc.2022.101641] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 11/27/2022] Open
Abstract
Increasing evidence has shown that AdipoRon, a synthetic adiponectin receptor agonist, is involved in the regulation of whole-body insulin sensitivity and energy homeostasis. However, the mechanisms underlying these alterations remain unclear. Here, using hyperinsulinemic-euglycemic clamp and isotopic tracing techniques, we show that short-term (10 days) AdipoRon administration indirectly inhibits lipolysis in white adipose tissue (WAT) via increasing circulating levels of fibroblast growth factor 21 (FGF21) in mice fed a high-fat diet. This led to reduced plasma free fatty acid concentrations and improved lipid-induced whole-body insulin resistance. In contrast, we found that long-term (20 days) AdipoRon administration directly exacerbated WAT lipolysis, increased hepatic gluconeogenesis, and impaired the tricarboxylic acid cycle in the skeletal muscle, resulting in aggravated whole-body insulin resistance. Together, these data provide new insights into the comprehensive understanding of multifaceted functional complexity of AdipoRon.
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Affiliation(s)
- Yongliang Wang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, P. R. China
| | - Huan Liu
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, P. R. China
| | - Ruixin Zhang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, P. R. China
| | - Yuyao Xiang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, P. R. China
| | - Junfeng Lu
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, P. R. China
| | - Bo Xia
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, P. R. China.
| | - Liang Peng
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, P. R. China.
| | - Jiangwei Wu
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, P. R. China.
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Zambon Azevedo V, Silaghi CA, Maurel T, Silaghi H, Ratziu V, Pais R. Impact of Sarcopenia on the Severity of the Liver Damage in Patients With Non-alcoholic Fatty Liver Disease. Front Nutr 2022; 8:774030. [PMID: 35111794 PMCID: PMC8802760 DOI: 10.3389/fnut.2021.774030] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 12/21/2021] [Indexed: 12/12/2022] Open
Abstract
An extensive body of the literature shows a strong interrelationship between the pathogenic pathways of non-alcoholic fatty liver disease (NAFLD) and sarcopenia through the muscle-liver-adipose tissue axis. NAFLD is one of the leading causes of chronic liver diseases (CLD) affecting more than one-quarter of the general population worldwide. The disease severity spectrum ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis, and its complications: end-stage chronic liver disease and hepatocellular carcinoma. Sarcopenia, defined as a progressive loss of the skeletal muscle mass, reduces physical performances, is associated with metabolic dysfunction and, possibly, has a causative role in NAFLD pathogenesis. Muscle mass is a key determinant of the whole-body insulin-mediated glucose metabolism and impacts fatty liver oxidation and energy homeostasis. These mechanisms drive the accumulation of ectopic fat both in the liver (steatosis, fatty liver) and in the muscle (myosteatosis). Myosteatosis rather than the muscle mass per se, seems to be closely associated with the severity of the liver injury. Sarcopenic obesity is a recently described entity which associates both sarcopenia and obesity and may trigger worse clinical outcomes including hepatic fibrosis progression and musculoskeletal disabilities. Furthermore, the muscle-liver-adipose tissue axis has a pivotal role in changes of the body composition, resulting in a distinct clinical phenotype that enables the identification of the "sarcopenic NAFLD phenotype." This review aims to bring some light into the complex relationship between sarcopenia and NAFLD and critically discuss the key mechanisms linking NAFLD to sarcopenia, as well as some of the clinical consequences associated with the coexistence of these two entities: the impact of body composition phenotypes on muscle morphology, the concept of sarcopenic obesity, the relationship between sarcopenia and the severity of the liver damage and finally, the future directions and the existing gaps in the knowledge.
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Affiliation(s)
- Vittoria Zambon Azevedo
- Doctoral School Physiology, Physiopathology and Therapeutics 394, Sorbonne Université, Paris, France
- Centre de Recherche de Cordeliers, INSERM UMRS 1138, Paris, France
| | - Cristina Alina Silaghi
- Department of Endocrinology, “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania
| | - Thomas Maurel
- Institute of Cardiometabolism and Nutrition, Paris, France
- Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France
| | - Horatiu Silaghi
- Department of Surgery V, “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania
| | - Vlad Ratziu
- Centre de Recherche de Cordeliers, INSERM UMRS 1138, Paris, France
- Institute of Cardiometabolism and Nutrition, Paris, France
- Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France
- Sorbonne Université, Paris, France
| | - Raluca Pais
- Institute of Cardiometabolism and Nutrition, Paris, France
- Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France
- Sorbonne Université, Paris, France
- Centre de Recherche Saint Antoine, INSERM UMRS 938, Paris, France
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Xu L, Lu L, Tong A, Chen S, Li W, Zhang H, Ping F, Li Y. New insights on hyperglycemia in 17-hydroxylase/17,20-lyase deficiency. Front Endocrinol (Lausanne) 2022; 13:917420. [PMID: 35937831 PMCID: PMC9354396 DOI: 10.3389/fendo.2022.917420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE The adrenal glands of patients with 17-hydroxylase/17,20-lyase deficiency (17OHD) synthesize excessive 11-deoxycorticosterone(DOC) and progesterone, and produce less amount of sex steroid production. Mineralocorticoids and sex hormones play an important role in regulating glucose homeostasis. This study aimed to describe the glucose metabolism in 17OHD patients diagnosed at Peking Union Medical College Hospital (PUMCH). DESIGN/METHODS A total of 69 patients diagnosed with 17OHD after adolescence in PUMCH from 1995 to June in 2021. Among them 23 patients underwent a 3-hours oral glucose tolerance test (3hOGTT) after being diagnosed with 17OHD. Insulin response in patients with normal glucose tolerance (NGT) were further compared between the study two groups with different kalemia status. Another 19 patients were followed up to 30 years and older. All clinical data were obtained from the hospital information system of PUMCH. RESULTS Baseline: (1) The average body mass index(BMI) of all patients at baseline was 20.3 ± 3.7kg/m2. Twenty-three patients underwent 3hOGTT, of whom three were diagnosed with diabetes mellitus, and one with impaired glucose tolerance (IGT). Positive correlation between the ratio of progesterone to upper limit of normal range (P times) and hyperglycaemia was exist(r=0.707, P=0.005). (2) In 19 NGT patients, the insulin concentrations at 0 minute, results of the homeostasis model assessment for β-cell function and insulin resistance were lower in the hypokalaemia group than in the normal kalemia group(7.0(5.8-13.2) vs 12.4(8.9-14.9) μIU/ml, P=0.017; 115.5(88.2-240.9) vs 253.1(177.2-305.8), P=0.048; 1.54(1.17-2.61) vs 2.47(1.91-2.98), P=0.022, respectively). Follow-up: Four patients had IGT, while seven patients had diabetes mellitus. Of the 19 patients,11 had hyperglycaemia. P times was significantly higher(7.6(5.0-11.0) vs 3.75(2.2-5.3), P=0.008) in hyperglycemia group than in the normal glucose group. CONCLUSIONS Abnormal glucose metabolism was common in 17OHD patients, which was possibly associated with hypokalaemia and high progesterone levels. Routine monitoring on glucose metabolism in 17OHD patient should be conducted.
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Affiliation(s)
- Lingling Xu
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Lin Lu
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Anli Tong
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Shi Chen
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Wei Li
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Huabing Zhang
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Fan Ping
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Yuxiu Li
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
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Yang S, Zhang Y, Lyu X, Gu Y, Zhang G, Liu P, Zheng Y, Guo Z, Zhang Y, Hou H. The Association Between FGF21 and Diabetic Erectile Dysfunction: Evidence from Clinical and Animal Studies. Front Endocrinol (Lausanne) 2022; 13:874796. [PMID: 36213282 PMCID: PMC9535403 DOI: 10.3389/fendo.2022.874796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 05/06/2022] [Indexed: 11/13/2022] Open
Abstract
Erectile dysfunction (ED), a complication of diabetes mellitus (DM), affects 50-75% of men with diabetes. Fibroblast growth factor 21 (FGF21) is a liver-derived metabolic regulator which plays a role in insulin-independent glucose uptake in adipocytes. We designed a clinical study and an animal experiment to investigate the relationship between FGF21 and DM-induced ED. The clinical study enrolled 93 participants aged > 18 years (61 patients with type 2 DM and 32 healthy controls) from Taian City Central Hospital (TCCH) in Shandong Province, China, amongst whom the association between serum FGF21 and diabetic ED was analyzed. To further validate this association, we developed animal model of diabetic ED using Sprague-Dawley (SD) rats. Serum FGF21 concentration and FGF21 mRNA expression in penile samples of the rats were determined with Western blotting and quantitative real-time PCR. Among the 93 participants, the level of serum FGF21 was negatively correlated with the IIEF-5 score (r = -0.74, P < 0.001). The analysis on the performance of FGF21 for ED diagnosis showed that the area under the receiver operating characteristic (ROC) curve was 0.875 (95% confidence interval [CI]: 0.803 to 0.946). In the animal experiment, the levels of serum FGF21, 2-Δ Δ Ct values of FGF21 mRNA expression, and relative levels of FGF21 in penile samples were higher in the ED group compared to the DM and control groups. Our findings demonstrated an association between the FGF21 level and diabetic ED, indicating the potential of this cytokine in predicting diabetic ED.
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Affiliation(s)
- Song Yang
- Department of Endocrinology, Taian City Central Hospital, Taian, China
| | - Yichun Zhang
- School of Public Health, Shandong First Medical University and Shandong Academy of Medical Sciences, Taian, China
| | - Xiaohui Lyu
- Department of Outpatient Department, Taian City Central Hospital, Taian, China
| | - Yuanyuan Gu
- Department of Pharmacy, Taian City Central Hospital, Taian, China
| | - Guodong Zhang
- Department of Endocrinology, Feicheng Hospital Affiliated to Shandong First Medical University, Taian, China
| | - Pengcheng Liu
- School of Public Health, Shandong First Medical University and Shandong Academy of Medical Sciences, Taian, China
| | - Yulu Zheng
- Centre for Precision Health, School of Medical and Health Sciences, Edith Cowan University, Perth, WA, Australia
| | - Zheng Guo
- Centre for Precision Health, School of Medical and Health Sciences, Edith Cowan University, Perth, WA, Australia
| | - Yanbo Zhang
- The Second Affiliated Hospital of Shandong First Medical University, Taian, China
- *Correspondence: Haifeng Hou, ; Yanbo Zhang,
| | - Haifeng Hou
- School of Public Health, Shandong First Medical University and Shandong Academy of Medical Sciences, Taian, China
- *Correspondence: Haifeng Hou, ; Yanbo Zhang,
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Dorval L, Knapp BI, Majekodunmi OA, Eliseeva S, Bidlack JM. Mice with high FGF21 serum levels had a reduced preference for morphine and an attenuated development of acute antinociceptive tolerance and physical dependence. Neuropharmacology 2022; 202:108858. [PMID: 34715121 PMCID: PMC8627472 DOI: 10.1016/j.neuropharm.2021.108858] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 10/18/2021] [Accepted: 10/23/2021] [Indexed: 01/03/2023]
Abstract
Because of increased opioid misuse, there is a need to identify new targets for minimizing opioid tolerance, and physical and psychological dependence. Previous studies showed that fibroblast growth factor 21 (FGF21) decreased alcohol and sweet preference in mice. In this study, FGF21-transgenic (FGF21-Tg) mice, expressing high FGF21 serum levels, and wildtype (WT) C57BL/6J littermates were treated with morphine and saline to determine if differences exist in their physiological and behavioral responses to opioids. FGF21-Tg mice displayed reduced preference for morphine in the conditioned place preference assay compared to WT littermates. Similarly, FGF21-Tg mice had an attenuation of the magnitude and rate of acute morphine antinociceptive tolerance development, and acute and chronic morphine physical dependence, but exhibited no change in chronic morphine antinociceptive tolerance. The ED50 values for morphine-induced antinociception in the 55 °C hot plate and the 55 °C warm-water tail withdrawal assays were similar in both strains of mice. Likewise, FGF21-Tg and WT littermates had comparable responses to morphine-induced respiratory depression. Overall, FGF21-Tg mice had a decrease in the development of acute analgesic tolerance, and the development of physical dependence, and morphine preference. FGF21 and its receptor have therapeutic potential for reducing opioid withdrawal symptoms and craving, and augmenting opioid therapeutics for acute pain patients to minimize tolerance development.
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Affiliation(s)
- Louben Dorval
- Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, 14642, Rochester, NY, USA
| | - Brian I Knapp
- Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, 14642, Rochester, NY, USA
| | - Olufolake A Majekodunmi
- Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, 14642, Rochester, NY, USA
| | - Sophia Eliseeva
- Department of Medicine, Pulmonary and Critical Care, University of Rochester, School of Medicine and Dentistry, 14642, Rochester, NY, USA
| | - Jean M Bidlack
- Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, 14642, Rochester, NY, USA.
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Fibroblast Growth Factor 21 (FGF21) Administration Sex-Specifically Affects Blood Insulin Levels and Liver Steatosis in Obese Ay Mice. Cells 2021; 10:cells10123440. [PMID: 34943946 PMCID: PMC8700098 DOI: 10.3390/cells10123440] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/01/2021] [Accepted: 12/03/2021] [Indexed: 12/17/2022] Open
Abstract
FGF21 is a promising candidate for treating obesity, diabetes, and NAFLD; however, some of its pharmacological effects are sex-specific in mice with the Ay mutation that evokes melanocortin receptor 4 blockade, obesity, and hepatosteatosis. This suggests that the ability of FGF21 to correct melanocortin obesity may depend on sex. This study compares FGF21 action on food intake, locomotor activity, gene expression, metabolic characteristics, and liver state in obese Ay males and females. Ay mice were administered FGF21 for seven days, and metabolic parameters and gene expression in different tissues were assessed. Placebo-treated females were more obese than males and had lower levels of blood insulin and liver triglycerides, and higher expression of genes for insulin signaling in the liver, white adipose tissue (WAT) and muscles, and pro-inflammatory cytokines in the liver. FGF21 administration did not affect body weight, and increased food intake, locomotor activity, expression of Fgf21 and Ucp1 in brown fat and genes related to lipolysis and insulin action in WAT regardless of sex; however, it decreased hyperinsulinemia and hepatic lipid accumulation and increased muscle expression of Cpt1 and Irs1 only in males. Thus, FGF21’s beneficial effects on metabolic disorders associated with melanocortin obesity are more pronounced in males.
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Eder K, Gessner DK, Ringseis R. Fibroblast growth factor 21 in dairy cows: current knowledge and potential relevance. J Anim Sci Biotechnol 2021; 12:97. [PMID: 34517929 PMCID: PMC8439079 DOI: 10.1186/s40104-021-00621-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 07/12/2021] [Indexed: 12/28/2022] Open
Abstract
Fibroblast growth factor 21 (FGF21) has been identified as an important regulator of carbohydrate and lipid metabolism, which plays an important role for metabolic regulation, particularly under conditions of energy deprivation or stress conditions. Dairy cows are subjected to a negative energy balance and various kinds of stress particularly during the periparturient phase and during early lactation. It has been shown that the plasma concentration of FGF21 in dairy cows is dramatically increased at parturition and remains high during the first weeks of lactation. This finding suggests that FGF21 might exert similar functions in dairy cows than in other species, such as mice or humans. However, the role of FGF21 in dairy cows has been less investigated so far. Following a brief summary of the previous findings about the function of FGF21 in humans and mice, the present review aims to present the current state of knowledge about the role of FGF21 in dairy cows. The first part of the review deals with the tissue localization of FGF21 and with conditions leading to an upregulation of FGF21 expression in the liver of dairy cows. In the second part, the influence of nutrition on FGF21 expression and the role of FGF21 for metabolic diseases in dairy cows is addressed. In the third part, findings of exogenous FGF21 application on metabolism in dairy cows are reported. Finally, the potential relevance of FGF21 in dairy cows is discussed. It is concluded that FGF21 might be of great importance for metabolic adaptation to negative energy balance and stress conditions in dairy cows. However, further studies are needed for a better understanding of the functions of FGF21 in dairy cows.
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Affiliation(s)
- Klaus Eder
- Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 26-32, 35392 Giessen, Germany
| | - Denise K. Gessner
- Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 26-32, 35392 Giessen, Germany
| | - Robert Ringseis
- Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 26-32, 35392 Giessen, Germany
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Pereira S, Moore J, Li JX, Yu WQ, Ghanim H, Vlavcheski F, Joseph YD, Dandona P, Volchuk A, Cummins CL, Tsiani E, Giacca A. 4-Phenylbutyric acid improves free fatty acid-induced hepatic insulin resistance in vivo. Endocr Connect 2021; 10:861-872. [PMID: 34319253 PMCID: PMC8346193 DOI: 10.1530/ec-21-0248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 07/09/2021] [Indexed: 11/08/2022]
Abstract
Plasma free fatty acids (FFAs) are elevated in obesity and can induce insulin resistance via endoplasmic reticulum (ER) stress. However, it is unknown whether hepatic insulin resistance caused by the elevation of plasma FFAs is alleviated by chemical chaperones. Rats received one of the following i.v. treatments for 48 h: saline, intralipid plus heparin (IH), IH plus the chemical chaperone 4-phenylbutyric acid (PBA), or PBA alone and a hyperinsulinemic-euglycemic clamp was performed during the last 2 h. PBA co-infusion normalized IH-induced peripheral insulin resistance, similar to our previous findings with an antioxidant and an IκBα kinase β (IKKβ) inhibitor. Different from our previous results with the antioxidant and IKKβ inhibitor, PBA also improved IH-induced hepatic insulin resistance in parallel with activation of Akt. Unexpectedly, IH did not induce markers of ER stress in the liver, but PBA prevented IH-induced elevation of phosphorylated eukaryotic initiation factor-2α protein in adipose tissue. PBA tended to decrease circulating fetuin-A and significantly increased circulating fibroblast growth factor 21 (FGF21) without affecting markers of activation of hepatic protein kinase C-δ or p38 mitogen-activated protein kinase that we have previously involved in hepatic insulin resistance in this model. In conclusion: (i) PBA prevented hepatic insulin resistance caused by prolonged plasma FFA elevation without affecting hepatic ER stress markers; (ii) the PBA effect is likely due to increased FGF21 and/or decreased fetuin-A, which directly signal to upregulate Akt activation.
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Affiliation(s)
- Sandra Pereira
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Jessy Moore
- Department of Health Sciences, Brock University, St. Catharines, Ontario, Canada
| | - Jia-Xu Li
- Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Wen Qin Yu
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Husam Ghanim
- Division of Endocrinology, Diabetes, and Metabolism, State University of New York at Buffalo, Kaleida Health, Buffalo, New York, USA
| | - Filip Vlavcheski
- Department of Health Sciences, Brock University, St. Catharines, Ontario, Canada
| | | | - Paresh Dandona
- Division of Endocrinology, Diabetes, and Metabolism, State University of New York at Buffalo, Kaleida Health, Buffalo, New York, USA
| | - Allen Volchuk
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Division of Cellular and Molecular Biology, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Carolyn L Cummins
- Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Evangelia Tsiani
- Department of Health Sciences, Brock University, St. Catharines, Ontario, Canada
| | - Adria Giacca
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
- Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
- Correspondence should be addressed to A Giacca:
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Zhou Y, Li C, Wang X, Deng P, He W, Zheng H, Zhao L, Gao H. Integration of FGF21 Signaling and Metabolomics in High-Fat Diet-Induced Obesity. J Proteome Res 2021; 20:3900-3912. [PMID: 34237942 DOI: 10.1021/acs.jproteome.1c00197] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Sex differences in obesity have been well established, but the metabolic mechanism underlying these differences remains unclear. In the present study, we determined the expression levels of endogenous fibroblast growth factor 21 (FGF21) and its related receptors in male and female mice that were fed a high-fat diet (HFD) for 12 weeks. We also analyzed the metabolic changes in serum and livers using a nuclear magnetic resonance-based metabolomics approach. Reverse transcription polymerase chain reaction and western blotting results revealed that the levels of FGFR1, FGFR2, and co-factor β-klotho were upregulated in female mice to alleviate FGF21 resistance induced by HFD. The metabolomics results demonstrated that the serum and liver metabolic patterns of HFD-fed male mice were significantly separated from those of the female HFD-fed group and the normal diet group. Furthermore, low-density lipoprotein/very low density lipoprotein and betaine levels were associated with the resistance of exogenous HFD in female mice. These findings imply that sex-based differences in metabolism and susceptibility to obesity might be mediated by the FGF21 signaling pathway.
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Affiliation(s)
- Yi Zhou
- Institute of Metabonomics & Medical NMR, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Chen Li
- Institute of Metabonomics & Medical NMR, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Xinyi Wang
- Institute of Metabonomics & Medical NMR, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Pengxi Deng
- Institute of Metabonomics & Medical NMR, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Wenting He
- Institute of Metabonomics & Medical NMR, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Hong Zheng
- Institute of Metabonomics & Medical NMR, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Liangcai Zhao
- Institute of Metabonomics & Medical NMR, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Hongchang Gao
- Institute of Metabonomics & Medical NMR, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
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50
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Pérez-López A, Gonzalo-Encabo P, Pérez-Köhler B, García-Honduvilla N, Valadés D. Circulating myokines IL-6, IL-15 and FGF21 response to training is altered by exercise type but not by menopause in women with obesity. Eur J Sport Sci 2021; 22:1426-1435. [PMID: 34086518 DOI: 10.1080/17461391.2021.1939430] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
To examine the effects of a time-matched endurance vs. concurrent training on circulating IL-6, IL-13, IL-15, IL-15Ra, FGF21 levels in postmenopausal women with obesity, and to determine these myokines response to endurance training pre- and postmenopause. Thirty-five sedentary postmenopausal women with obesity were randomly divided into endurance training (EN1, N = 10), concurrent training (CON, N = 13) or no training group (CT, N = 12). Additionally, twelve sedentary premenopausal women with obesity were added to an endurance training group (EN2, N = 12). Participants took part in a 12-week supervised intervention, performing 3 sessions/week of 60 min/session. Before and after the interventions, body composition and fitness were assessed, and blood samples obtained to measure serum myokines levels. Total fat mass decreased in all exercised groups (CON,-5.2%; EN1,-5.3%; EN2,-5.6%). In postmenopausal women, serum IL-6, IL-15 and IL-15Ra decreased after training (P<0.01), finding a pronounced reduction in IL-6 (-42% vs. -16%) and IL-15 (-50% vs. -31%) when comparing EN1 to CON (P<0.05). Serum FGF21 was only reduced in the EN1 (-27%; P=0.012). While EN1 and EN2 comparison, reported differences for IL-15Rα concentration (-28% vs. -40%; P=0.023). Finally, in EN2, the delta change of fat mass and IL-6, IL-15 and IL-15Rα were associated (r = 0.605; r = 0.546; r = 0.515; P<0.05). IL-13 showed undetected concentrations. Circulating IL-6, IL-15 and FGF21 response to training is altered by exercise type but not by menopause in women with obesity. Endurance training promotes a higher reduction of these myokines, potentially activating their intricate immune and fat mass regulation roles in postmenopausal women with obesity.
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Affiliation(s)
- Alberto Pérez-López
- Universidad de Alcalá, Facultad de Medicina y Ciencias de la Salud, Departamento de Ciencias Biomédicas, Área de Educación Física y Deportiva, Madrid, España
| | - Paola Gonzalo-Encabo
- Universidad de Alcalá, Facultad de Medicina y Ciencias de la Salud, Departamento de Ciencias Biomédicas, Área de Educación Física y Deportiva, Madrid, España.,Universidad de Alcalá, Facultad de Medicina y Ciencias de la Salud, Departamento de Medicina y Especialidades Médicas, Madrid, España
| | - Bárbara Pérez-Köhler
- Universidad de Alcalá, Facultad de Medicina y Ciencias de la Salud, Departamento de Medicina y Especialidades Médicas, Madrid, España.,Biomedical Research Networking Centre on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain
| | - Natalio García-Honduvilla
- Universidad de Alcalá, Facultad de Medicina y Ciencias de la Salud, Departamento de Medicina y Especialidades Médicas, Madrid, España.,Biomedical Research Networking Centre on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.,University Center of Defense of Madrid (CUD-ACD), Madrid, Spain
| | - David Valadés
- Universidad de Alcalá, Facultad de Medicina y Ciencias de la Salud, Departamento de Ciencias Biomédicas, Área de Educación Física y Deportiva, Madrid, España
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