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Fan R, Kim J, Kim YC, Chung S. Effects of Fish Oil with Heat Treatment on Obesity, Inflammation, and Gut Microbiota in Ovariectomized Mice. Nutrients 2025; 17:549. [PMID: 39940405 PMCID: PMC11820760 DOI: 10.3390/nu17030549] [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] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/17/2025] [Accepted: 01/28/2025] [Indexed: 02/16/2025] Open
Abstract
Background/Objectives: Menopause induces substantial metabolic changes, including a reduction in metabolic rate and an elevated risk of developing metabolic diseases. Fish oil (FO) supplementation has been shown to ameliorate menopause-associated metabolic risks. Hyperthermia treatment (HT) has recently gained attention for its potential to improve metabolic and immune health. However, it remains to be determined whether HT can confer metabolic benefits comparable to those of FO supplementation or enhance the metabolic benefits of FO supplementation. This study aims to delineate the distinctive and collaborative effects of HT and FO supplementation in mitigating menopause-associated metabolic dysfunction. Methods: Female C57BL/6 ovariectomized (OVX) mice were randomly assigned to four groups (n = 12/group) to evaluate the individual and combined effects of FO supplementation (5% w/w) and HT treatment. For HT, whole-body heat exposure was conducted at 40-41 °C for 30 min, 5 days per week. After 12 weeks, animals were used to evaluate the changes in glucose and lipid metabolism, obesity outcome, and inflammatory markers. The gut microbiome analysis was conducted from cecal content by 16S rRNA sequencing. Acute inflammation was induced by lipopolysaccharide (LPS) injection to evaluate inflammatory responses. Results: HT alone distinctively reduced weight gain, lowered core body temperature, and attenuated insulin resistance comparable to FO supplement in OVX mice. The collaborative effect of FO and HT was not evident in metabolic parameters but more prominent in attenuating proinflammatory responses and microbiota modulation. Conclusions: Our findings suggest that the combined treatment of FO supplementation and HT may serve as an effective strategy to mitigate menopause-associated immune susceptibility and metabolic dysfunction. These benefits are likely mediated, at least in part, through the reduction in inflammation and modulation of the gut microbiota.
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Affiliation(s)
| | | | | | - Soonkyu Chung
- Department of Nutrition, University of Massachusetts, Amherst, MA 01003, USA; (R.F.); (J.K.); (Y.-C.K.)
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Zhu BT, Liao QQ, Tian HY, Yu DJ, Xie T, Sun XL, Zhou XM, Han YX, Zhao YJ, El-Kassas M, Liu XX, Sun XD, Zhang YY. Estrogen: the forgotten player in metaflammation. Front Pharmacol 2024; 15:1478819. [PMID: 39575382 PMCID: PMC11578702 DOI: 10.3389/fphar.2024.1478819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 10/21/2024] [Indexed: 11/24/2024] Open
Abstract
Metaflammation is low-grade inflammation triggered by chronic metabolic imbalance and caused by dysregulated metabolites in metabolic inflammatory syndrome (MIS), which includes four diseases: obesity, type 2 diabetes mellitus (T2DM), atherosclerosis (AS), and nonalcoholic fatty liver diseases (NAFLD, recently proposed to be replaced by metabolic dysfunction-associated steatotic liver disease, MASLD). These diseases exhibit apparent sex dimorphism as regards MIS. Estrogen not only plays a crucial role in gender differences in adults but also possesses an anti-inflammatory effect on many metabolic diseases. In this study, we present a prediction of the differential proteins and signal transduction of estrogen in MIS through network pharmacology and review the validated studies on obesity, T2DM, AS, and NAFLD. Subsequently, we compared them to obtain valuable targets, identify current gaps, and provide perspectives for future research on the mechanisms of estrogen in metaflammation.
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Affiliation(s)
- Bao-Ting Zhu
- West China School of Pharmacy, West China School of Basic Medical Sciences and Forensic Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Qing-Qing Liao
- West China School of Pharmacy, West China School of Basic Medical Sciences and Forensic Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Hai-Ying Tian
- West China School of Pharmacy, West China School of Basic Medical Sciences and Forensic Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Dao-Jiang Yu
- West China School of Pharmacy, West China School of Basic Medical Sciences and Forensic Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, China
| | - Teng Xie
- West China School of Pharmacy, West China School of Basic Medical Sciences and Forensic Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Xi-Lu Sun
- West China School of Pharmacy, West China School of Basic Medical Sciences and Forensic Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Xin-Meng Zhou
- West China School of Pharmacy, West China School of Basic Medical Sciences and Forensic Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Ying-Xuan Han
- West China School of Pharmacy, West China School of Basic Medical Sciences and Forensic Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Yu-Jie Zhao
- Medical College, Tibet University, Lasa, China
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
- Liver Disease Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Steatotic Liver Disease Study Foundation in Middle East and North Africa (SLMENA), Cairo, Egypt
| | - Xiu-Xiu Liu
- West China School of Pharmacy, West China School of Basic Medical Sciences and Forensic Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Xiao-Dong Sun
- West China School of Pharmacy, West China School of Basic Medical Sciences and Forensic Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
- Medical College, Tibet University, Lasa, China
| | - Yuan-Yuan Zhang
- West China School of Pharmacy, West China School of Basic Medical Sciences and Forensic Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, China
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He J, Zhang B, Fan Y, Wang Y, Zhang M, Li C, Zhang L, Guo P, Zhang M. Comparison of bioelectrical body and visceral fat indices and anthropometric measures in relation to type 2 diabetes by sex among Chinese adults, a cross-sectional study. Front Public Health 2023; 11:1001397. [PMID: 38026280 PMCID: PMC10661931 DOI: 10.3389/fpubh.2023.1001397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Accepted: 10/24/2023] [Indexed: 12/01/2023] Open
Abstract
Objectives We aim to compare the efficacies of the bioelectrical indices (percentage of body fat, PBF; visceral fat area, VFA) with the conventional anthropometric measures (body mass index, BMI; waist-hip ratio, WHR) for predicting type 2 diabetes (T2D) risk by sex and to determine the sex-specific optimal adiposity indices to predict the T2D risk. Design Cross-sectional design. Setting Tianjin First Central Hospital and Tianjin Union Medical Center, Tianjin, China. Participants A total of 9,332 adults (41.35% men) undergoing physical examination. Primary and secondary outcome measures T2D was defined using the WHO's criteria: fasting blood glucose (FBG) ≥7.0 mmol/L and/or previous diagnosis of T2D. Height, weight, waist, hip, PBF, VFA, and fasting plasma glucose were measured. Results All studied adiposity indices were associated with T2D among both males and females, and the observed associations differed by sex. The standardized aORs of BMI, WHR, PBF and VFA for T2D were 1.60 (95% CI 1.42-1.81), 1.43 (95% CI 1.25-1.64), 1.42 (95% CI 1.23-1.62) and 1.53 (95% CI 1.35-1.75) for females, and 1.47 (95% CI 1.31-1.66), 1.40 (95% CI 1.25-1.58), 1.54 (95% CI 1.36-1.74) and 1.47 (95% CI 1.31-1.65) for males, respectively. The AUCs of VFA, WHR and BMI were 0.743, 0.742 and 0.717 in women, respectively, whereas none of the indices had AUC larger than 0.70 in men. The AUCs were not significantly different between VFA and WHR, while both demonstrate larger AUCs than BMI and PBF in females (all p < 0.05). The optimal cutoff values of VFA, WHR, and BMI for T2D in women were 103.55 cm2, 0.905, and 24.15 kg/m2, respectively. Conclusion Although BMI, WHR, and PBF and VFA as measured by bioelectrical impedance analysis (BIA) were all positively associated with T2D, their efficacy for predicting the risk of T2D differed by sex. VFA, WHR and BMI could be used as biomarkers to predict T2D risk in women, however none of the study indicators demonstrated favorable efficacy of predicting T2D risk in men.
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Affiliation(s)
- Jiangshan He
- School of Medicine, Nankai University, Tianjin, China
| | - Binbin Zhang
- School of Medicine, Nankai University, Tianjin, China
| | - Yaqi Fan
- School of Medicine, Nankai University, Tianjin, China
| | - Yuxue Wang
- School of Medicine, Nankai University, Tianjin, China
| | - Mianzhi Zhang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
- Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China
| | - Chunjun Li
- Tianjin Union Medical Center, Tianjin, China
| | - Li Zhang
- Tianjin First Central Hospital, Tianjin, China
| | - Pei Guo
- School of Medicine, Nankai University, Tianjin, China
| | - Minying Zhang
- School of Medicine, Nankai University, Tianjin, China
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Vail GM, Walley SN, Yasrebi A, Maeng A, Degroat TJ, Conde KM, Roepke TA. Implications of estrogen receptor alpha (ERa) with the intersection of organophosphate flame retardants and diet-induced obesity in adult mice. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2022; 85:397-413. [PMID: 35045790 PMCID: PMC8916992 DOI: 10.1080/15287394.2022.2026849] [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] [Indexed: 05/09/2023]
Abstract
Previously, organophosphate flame retardants (OPFRs) were found to produce intersecting disruptions of energy homeostasis using an adult mouse model of diet-induced obesity. Using the same mixture consisting of 1 mg/kg/day of each triphenyl phosphate, tricresyl phosphate, and tris(1,3-dichloro-2-propyl)phosphate, the current study aimed to identify the role of estrogen receptor alpha (ERα) in OPFR-induced disruption, utilizing ERα knockout (ERαKO) mice fed either a low-fat diet (LFD) or high-fat diet (HFD). Body weight and composition, food intake patterns, glucose and insulin tolerance, circulating peptide hormones, and expression of hypothalamic genes associated with energy homeostasis were measured. When fed HFD, no marked direct effects of OPFR were observed in mice lacking ERα, suggesting a role for ERα in generating previously reported wildtype (WT) findings. Male ERαKO mice fed LFD experienced decreased feeding efficiency and altered insulin tolerance, whereas their female counterparts displayed less fat mass and circulating ghrelin when exposed to OPFRs. These effects were not noted in the previous WT study, indicating that loss of ERα may sensitize animals fed LFD to alternate pathways of endocrine disruption by OFPRs. Collectively, these data demonstrate both direct and indirect actions of OPFRs on ERα-mediated pathways governing energy homeostasis and support a growing body of evidence urging concern for risk of human exposure.
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Affiliation(s)
- Gwyndolin M. Vail
- Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, NJ. USA
| | - Sabrina N. Walley
- Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, NJ. USA
| | - Ali Yasrebi
- Department of Animal Sciences, School of Environmental & Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ. USA
| | - Angela Maeng
- Department of Animal Sciences, School of Environmental & Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ. USA
| | - Thomas J. Degroat
- Graduate Program in Endocrinology and Animal Biosciences, School of Environmental & Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ. USA
| | - Kristie M. Conde
- Graduate Program in Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ. USA
| | - Troy A. Roepke
- Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, NJ. USA
- Department of Animal Sciences, School of Environmental & Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ. USA
- Graduate Program in Endocrinology and Animal Biosciences, School of Environmental & Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ. USA
- Graduate Program in Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ. USA
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Vail GM, Walley SN, Yasrebi A, Maeng A, Degroat TJ, Conde KM, Roepke TA. Implications of peroxisome proliferator-activated receptor gamma (PPARY) with the intersection of organophosphate flame retardants and diet-induced obesity in adult mice. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2022; 85:381-396. [PMID: 35000574 PMCID: PMC8897244 DOI: 10.1080/15287394.2021.2023716] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
Previously, organophosphate flame retardants (OPFRs) were demonstrated to dysregulate homeostatic parameters of energy regulation within an adult mouse model of diet-induced obesity. Using the same OPFR mixture consisting of 1 mg/kg/day of each triphenyl phosphate, tricresyl phosphate, and tris(1,3-dichloro-2-propyl)phosphate, the current study examined the role of peroxisome proliferator-activated receptor gamma (PPARγ) in OPFR-induced disruption by utilizing mice with brain-specific deletion of PPARγ (PPARγKO) fed either a low-fat diet (LFD) or high-fat diet (HFD). Body weight and composition, feeding behavior, glucose and insulin tolerance, circulating peptide hormones, and expression of hypothalamic genes associated with energy homeostasis were recorded. When fed HFD, the effects of OPFR on body weight and feeding behavior observed in the previous wild-type (WT) study were absent in mice lacking neuronal PPARγ. This posits PPARγ as an important target for eliciting OPFR disruption in a diet-induced obesity model. Interestingly, female PPARγKO mice, but not males, experienced many novel OPFR effects not noted in WT mice, including decreased fat mass, altered feeding behavior and efficiency, improved insulin sensitivity, elevated plasma ghrelin and hypothalamic expression of its receptor. Taken together, these data suggest both direct roles for PPARγ in OPFR disruption of obese mice and indirect sensitization of pathways alternative to PPARγ when neuronal expression is deleted.
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Affiliation(s)
- Gwyndolin M. Vail
- Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, NJ. USA
| | - Sabrina N. Walley
- Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, NJ. USA
| | - Ali Yasrebi
- Department of Animal Sciences, School of Environmental & Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ. USA
| | - Angela Maeng
- Department of Animal Sciences, School of Environmental & Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ. USA
| | - Thomas J. Degroat
- Graduate Program in Endocrinology and Animal Biosciences, School of Environmental & Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ. USA
| | - Kristie M. Conde
- Graduate Program in Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ. USA
| | - Troy A. Roepke
- Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, NJ. USA
- Department of Animal Sciences, School of Environmental & Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ. USA
- Graduate Program in Endocrinology and Animal Biosciences, School of Environmental & Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ. USA
- Graduate Program in Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ. USA
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6
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Berberine remodels adipose tissue to attenuate metabolic disorders by activating sirtuin 3. Acta Pharmacol Sin 2022; 43:1285-1298. [PMID: 34417576 PMCID: PMC9061715 DOI: 10.1038/s41401-021-00736-y] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Accepted: 06/29/2021] [Indexed: 12/19/2022]
Abstract
Adipose tissue remodelling is considered a critical pathophysiological hallmark of obesity and related metabolic diseases. Berberine (BBR), a natural isoquinoline alkaloid, has potent anti-hyperlipidaemic and anti-hyperglycaemic effects. This study aimed to explore the role of BBR in modulating adipose tissue remodelling and the underlying mechanisms. BBR protected high fat diet (HFD)-fed mice against adiposity, insulin resistance and hyperlipidemia. BBR alleviated adipose tissue inflammation and fibrosis by inhibiting macrophage infiltration, pro-inflammatory macrophage polarization and the abnormal deposition of extracellular matrix, and the effect was mediated by BBR directly binding and activating the deacetylase Sirtuin 3 (SIRT3) and suppressing the activation of the mitogen-activated protein kinases and nuclear factor-κB signalling pathways. Furthermore, BBR decreased microRNA-155-5p secretion by macrophages, which in turn ameliorated liver injury. Moreover, BBR mitigated inflammatory responses in both LPS-stimulated macrophages and TNF-α-treated adipocytes and suppressed macrophage migration towards adipocytes by activating SIRT3. Collectively, this study revealed that BBR improved adipose tissue remodelling, and subsequently inhibited the secretion of microRNA-155-5p by macrophages, which alleviated adiposity, insulin resistance and liver injury in obese mice. The modulation of adipose tissue remodelling by activating SIRT3 could contribute to the anti-hyperlipidemic and anti-hyperglycemic effects of BBR.
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7
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Alemany M. Estrogens and the regulation of glucose metabolism. World J Diabetes 2021; 12:1622-1654. [PMID: 34754368 PMCID: PMC8554369 DOI: 10.4239/wjd.v12.i10.1622] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/10/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
The main estrogens: estradiol, estrone, and their acyl-esters have been studied essentially related to their classical estrogenic and pharmacologic functions. However, their main effect in the body is probably the sustained control of core energy metabolism. Estrogen nuclear and membrane receptors show an extraordinary flexibility in the modulation of metabolic responses, and largely explain gender and age differences in energy metabolism: part of these mechanisms is already sufficiently known to justify both. With regard to energy, the estrogen molecular species act essentially through four key functions: (1) Facilitation of insulin secretion and control of glucose availability; (2) Modulation of energy partition, favoring the use of lipid as the main energy substrate when more available than carbohydrates; (3) Functional protection through antioxidant mechanisms; and (4) Central effects (largely through neural modulation) on whole body energy management. Analyzing the different actions of estrone, estradiol and their acyl esters, a tentative classification based on structure/effects has been postulated. Either separately or as a group, estrogens provide a comprehensive explanation that not all their quite diverse actions are related solely to specific molecules. As a group, they constitute a powerful synergic action complex. In consequence, estrogens may be considered wardens of energy homeostasis.
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Affiliation(s)
- Marià Alemany
- Faculty of Biology, University of Barcelona, Barcelona 08028, Catalonia, Spain
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8
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Poret JM, Guidry JJ, Simon L, Molina PE. Chronic binge alcohol and ovariectomy dysregulate omental adipose tissue metaboproteome in simian immunodeficiency virus-infected female macaques. Physiol Genomics 2021; 53:358-371. [PMID: 34252326 DOI: 10.1152/physiolgenomics.00001.2021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Effective antiretroviral therapy (ART) has significantly reduced mortality of people living with HIV (PLWH), and the prevalence of at-risk alcohol use is higher among PLWH. Increased survival and aging of PLWH is associated with increased prevalence of metabolic comorbidities especially among menopausal women, and adipose tissue metabolic dysregulation may be a significant contributing factor. We examined the differential effects of chronic binge alcohol (CBA) administration and ovariectomy (OVX) on the omental adipose tissue (OmAT) proteome in a subset of simian immunodeficiency virus (SIV)-infected macaques of a longitudinal parent study. Quantitative discovery-based proteomics identified 1,429 differentially expressed proteins. Ingenuity Pathway Analysis (IPA) was used to calculate z-scores, or activation predictions, for functional pathways and diseases. Results revealed that protein changes associated with functional pathways centered around the "OmAT metaboproteome profile." Based on z-scores, CBA did not affect functional pathways of metabolic disease but dysregulated proteins involved in adenosine monophosphate-activated protein kinase (AMPK) signaling and lipid metabolism. OVX-mediated proteome changes were predicted to promote pathways involved in glucose- and lipid-associated metabolic disease. Proteins involved in apoptosis, necrosis, and reactive oxygen species (ROS) pathways were also predicted to be activated by OVX and these were predicted to be inhibited by CBA. These results provide evidence for the role of ovarian hormone loss in mediating OmAT metaboproteome dysregulation in SIV and suggest that CBA modifies OVX-associated changes. In the context of OVX, CBA administration produced larger metabolic and cellular effects, which we speculate may reflect a protective role of estrogen against CBA-mediated adipose tissue injury in female SIV-infected macaques.
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Affiliation(s)
- Jonquil M Poret
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana.,Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Jessie J Guidry
- Department of Biochemistry and The Proteomic Core Facility, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Liz Simon
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana.,Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Patricia E Molina
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana.,Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana
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Yang M, Ma F, Guan M. Role of Steroid Hormones in the Pathogenesis of Nonalcoholic Fatty Liver Disease. Metabolites 2021; 11:metabo11050320. [PMID: 34067649 PMCID: PMC8156407 DOI: 10.3390/metabo11050320] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/10/2021] [Accepted: 05/12/2021] [Indexed: 01/10/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and may progress to cirrhosis or even hepatocellular carcinoma. A number of steroid hormones are important regulators of lipid homeostasis through fine tuning the expression of genes related to lipid synthesis, export, and metabolism. Dysregulation of such pathways has been implicated in the pathogenesis of NAFLD. The aim of this review is to clarify the potential impact of steroid hormones on NAFLD. We also highlight potential interventions through modulating steroid hormone levels or the activities of their cognate receptors as therapeutic strategies for preventing NAFLD.
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Affiliation(s)
- Meng Yang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Biochemistry and Molecular Biology, Institute of Aging Research, Guangdong Medical University, Dongguan 523808, China;
- Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China;
| | - Feng Ma
- Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China;
| | - Min Guan
- Center for Human Tissues and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China;
- Correspondence: ; Tel.: +86-755-86585232
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10
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Malinská H, Hüttl M, Miklánková D, Trnovská J, Zapletalová I, Poruba M, Marková I. Ovariectomy-Induced Hepatic Lipid and Cytochrome P450 Dysmetabolism Precedes Serum Dyslipidemia. Int J Mol Sci 2021; 22:ijms22094527. [PMID: 33926097 PMCID: PMC8123580 DOI: 10.3390/ijms22094527] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/23/2021] [Accepted: 04/23/2021] [Indexed: 12/13/2022] Open
Abstract
Ovarian hormone deficiency leads to increased body weight, visceral adiposity, fatty liver and disorders associated with menopausal metabolic syndrome. To better understand the underlying mechanisms of these disorders in their early phases of development, we investigated the effect of ovariectomy on lipid and glucose metabolism. Compared to sham-operated controls, ovariectomized Wistar female rats markedly increased whole body and visceral adipose tissue weight (p ˂ 0.05) and exhibited insulin resistance in peripheral tissues. Severe hepatic triglyceride accumulation (p ˂ 0.001) after ovariectomy preceded changes in both serum lipids and glucose intolerance, reflecting alterations in some CYP proteins. Increased CYP2E1 (p ˂ 0.05) and decreased CYP4A (p ˂ 0.001) after ovariectomy reduced fatty acid oxidation and induced hepatic steatosis. Decreased triglyceride metabolism and secretion from the liver contributed to hepatic triglyceride accumulation in response to ovariectomy. In addition, interscapular brown adipose tissue of ovariectomized rats exhibited decreased fatty acid oxidation (p ˂ 0.01), lipogenesis (p ˂ 0.05) and lipolysis (p ˂ 0.05) despite an increase in tissue weight. The results provide evidence that impaired hepatic triglycerides and dysregulation of some CYP450 proteins may have been involved in the development of hepatic steatosis. The low metabolic activity of brown adipose tissue may have contributed to visceral adiposity as well as triglyceride accumulation during the postmenopausal period.
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Affiliation(s)
- Hana Malinská
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic; (M.H.); (D.M.); (J.T.); (I.M.)
- Correspondence: ; Tel.: +420-261-365-369; Fax: +420-261-363-027
| | - Martina Hüttl
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic; (M.H.); (D.M.); (J.T.); (I.M.)
| | - Denisa Miklánková
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic; (M.H.); (D.M.); (J.T.); (I.M.)
| | - Jaroslava Trnovská
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic; (M.H.); (D.M.); (J.T.); (I.M.)
| | - Iveta Zapletalová
- Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, 77900 Olomouc, Czech Republic; (I.Z.); (M.P.)
| | - Martin Poruba
- Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, 77900 Olomouc, Czech Republic; (I.Z.); (M.P.)
| | - Irena Marková
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic; (M.H.); (D.M.); (J.T.); (I.M.)
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11
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Sex Hormone-Dependent Physiology and Diseases of Liver. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17082620. [PMID: 32290381 PMCID: PMC7216036 DOI: 10.3390/ijerph17082620] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 04/04/2020] [Accepted: 04/07/2020] [Indexed: 12/12/2022]
Abstract
Sexual dimorphism is associated not only with somatic and behavioral differences between men and women, but also with physiological differences reflected in organ metabolism. Genes regulated by sex hormones differ in expression in various tissues, which is especially important in the case of liver metabolism, with the liver being a target organ for sex hormones as its cells express estrogen receptors (ERs: ERα, also known as ESR1 or NR3A; ERβ; GPER (G protein-coupled ER, also known as GPR 30)) and the androgen receptor (AR) in both men and women. Differences in sex hormone levels and sex hormone-specific gene expression are mentioned as some of the main variations in causes of the incidence of hepatic diseases; for example, hepatocellular carcinoma (HCC) is more common in men, while women have an increased risk of autoimmune liver disease and show more acute liver failure symptoms in alcoholic liver disease. In non-alcoholic fatty liver disease (NAFLD), the distinction is less pronounced, but increased incidences are suggested among men and postmenopausal women, probably due to an increased tendency towards visceral fat accumulation.
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Pimenta FDS, Tose H, Waichert É, da Cunha MRH, Campos FV, Vasquez EC, Mauad H. Lipectomy associated to obesity produces greater fat accumulation in the visceral white adipose tissue of female compared to male rats. Lipids Health Dis 2019; 18:44. [PMID: 30738429 PMCID: PMC6368803 DOI: 10.1186/s12944-019-0988-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 01/24/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Mobility of fat deposited in adipocytes among different fatty territories can play a crucial role in the pathogenesis of obesity-related diseases. Our goal was to investigate which of the remaining fat pads assume the role of accumulating lipids after surgical removal of parietal WAT (lipectomy; LIPEC) in rats of both sexes displaying MSG-induced obesity. METHODS The animals entered the study straight after birth, being separated according to gender and randomly divided into CON (control, saline-treated) and MSG (monosodium glutamate-treated) groups. Next, the animals underwent LIPEC or sham-operated surgery (SHAM). Obesity was induced by the injection of MSG (4 mg/g/day) during neonatal stage (2nd to 11th day from birth). LIPEC was performed on the 12th week, consisting in the withdrawal of parietal WAT. On the 16th week, the following WATs were isolated and collected: peri-epididymal-WAT (EP-WAT); parametrial-WAT (PM-WAT); omental-WAT (OM-WAT); perirenal-WAT (PR-WAT) and retroperitoneal-WAT (RP-WAT). RESULTS The adiposity index was significantly increased in both male (3.2 ± 0.2** vs 1.8 ± 0.1) and female (4.9 ± 0.7* vs 2.6 ± 0.3) obese rats compared to their respective control groups. LIPEC in obese animals produced fat accumulation in visceral fat sites in a more accentuated manner in female (3.6 ± 0.3** vs 2.8 ± 0.3 g/100 g) rather than in male (1.8 ± 0.2* vs 1.5 ± 0.1 g/100 g) rats compared to obese non-lipectomized animals. Among the visceral WATs, the greater differences were observed between gonadal WATs of obese lipectomized rats, with higher accumulation having been observed in PM-WAT (2.8 ± 0.3* vs 2.1 ± 0.2 g/100 g) rather than in EP-WAT (1.0 ± 0.1 ± 0.9 ± 0.1 g/100 g) when compared to obese non-lipectomized animals. CONCLUSIONS The results of the present study led us to conclude that obesity induced by MSG treatment occurs differently in male and female rats. When associated with parietal LIPEC, there was a significant increase in the deposition of visceral fat, which was significantly higher in obese female rats than in males, indicating that fat mobility among WATs in lipectomized-obese rats can occur more expressively in particular sites of remaining WATs.
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Affiliation(s)
- Fábio da Silva Pimenta
- Laboratory of Translational Physiology and Pharmacology, Pharmaceutical Sciences Graduate Program, Vila Velha University (UVV), Avenida Comissário José Dantas de Melo, 21 Bairro Boa Vista II, Vila Velha, ES, CEP 29102-920, Brazil
| | - Hadnan Tose
- Departament of Medical Clinic, Escola Superior de Ciências da Santa Casa de Misericórdia de Vitória (EMESCAM), Av. Nossa Sra. da Penha, 2190 - Bela Vista, Vitória, ES, CEP 29027-502, Brazil
| | - Élio Waichert
- Faculdade Estácio, Av. Dr. Herwan Modenese Wanderley, 1001. Bairro Jardim Camburi, Vitória, ES, CEP 29092-095, Brazil
| | - Márcia Regina Holanda da Cunha
- Sports Department, Center for Physical Education and Sports, Federal University of Espírito Santo, Avenida Fernando Ferrari, 514. Bairro Goiabeiras, Vitória, ES, CEP 29075-910, Brazil
| | - Fabiana Vasconcelos Campos
- Department of Physiological Sciences, Health Sciences Center, Federal University of Espírito Santo, Av. Marechal Campos 1468, Vitória, ES, CEP 29042-751, Brazil
| | - Elisardo Corral Vasquez
- Laboratory of Translational Physiology and Pharmacology, Pharmaceutical Sciences Graduate Program, Vila Velha University (UVV), Avenida Comissário José Dantas de Melo, 21 Bairro Boa Vista II, Vila Velha, ES, CEP 29102-920, Brazil
| | - Hélder Mauad
- Department of Physiological Sciences, Health Sciences Center, Federal University of Espírito Santo, Av. Marechal Campos 1468, Vitória, ES, CEP 29042-751, Brazil.
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Renner S, Blutke A, Dobenecker B, Dhom G, Müller TD, Finan B, Clemmensen C, Bernau M, Novak I, Rathkolb B, Senf S, Zöls S, Roth M, Götz A, Hofmann SM, Hrabĕ de Angelis M, Wanke R, Kienzle E, Scholz AM, DiMarchi R, Ritzmann M, Tschöp MH, Wolf E. Metabolic syndrome and extensive adipose tissue inflammation in morbidly obese Göttingen minipigs. Mol Metab 2018; 16:180-190. [PMID: 30017782 PMCID: PMC6157610 DOI: 10.1016/j.molmet.2018.06.015] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Revised: 06/16/2018] [Accepted: 06/25/2018] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE The worldwide prevalence of obesity has increased to 10% in men and 15% in women and is associated with severe comorbidities such as diabetes, cancer, and cardiovascular disease. Animal models of obesity are central to experimental studies of disease mechanisms and therapeutic strategies. Diet-induced obesity (DIO) models in rodents have provided important insights into the pathophysiology of obesity and, in most instances, are the first in line for exploratory pharmacology studies. To deepen the relevance towards translation to human patients, we established a corresponding DIO model in Göttingen minipigs (GM). METHODS Young adult female ovariectomized GM were fed a high-fat/high-energy diet for a period of 70 weeks. The ration was calculated to meet the requirements and maintain body weight (BW) of lean adult minipigs (L-GM group) or increased stepwise to achieve an obese state (DIO-GM group). Body composition, blood parameters and intravenous glucose tolerance were determined at regular intervals. A pilot chronic treatment trial with a GLP1 receptor agonist was conducted in DIO-GM. At the end of the study, the animals were necropsied and a biobank of selected tissues was established. RESULTS DIO-GM developed severe subcutaneous and visceral adiposity (body fat >50% of body mass vs. 22% in L-GM), increased plasma cholesterol, triglyceride, and free fatty acid levels, insulin resistance (HOMA-IR >5 vs. 2 in L-GM), impaired glucose tolerance and increased heart rate when resting and active. However, fasting glucose concentrations stayed within normal range throughout the study. Treatment with a long-acting GLP1 receptor agonist revealed substantial reduction of food intake and body weight within four weeks, with increased drug sensitivity relative to observations in other DIO animal models. Extensive adipose tissue inflammation and adipocyte necrosis was observed in visceral, but not subcutaneous, adipose tissue of DIO-GM. CONCLUSIONS The Munich DIO-GM model resembles hallmarks of the human metabolic syndrome with extensive adipose tissue inflammation and adipocyte necrosis reported for the first time. DIO-GM may be used for evaluating novel treatments of obesity and associated comorbidities. They may help to identify triggers and mechanisms of fat tissue inflammation and mechanisms preventing complete metabolic decompensation despite morbid obesity.
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Affiliation(s)
- Simone Renner
- Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Feodor-Lynen-Str. 25, 81377, Munich, Germany; Center for Innovative Medical Models (CiMM), Department of Veterinary Sciences, LMU Munich, Hackerstr. 27, 85764, Oberschleißheim, Germany; German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
| | - Andreas Blutke
- Institute of Veterinary Pathology, Center for Clinical Veterinary Medicine, LMU Munich, Veterinärstr. 13, 80539, Munich, Germany
| | - Britta Dobenecker
- Chair of Animal Nutrition and Dietetics, Department of Veterinary Sciences, LMU Munich, Schönleutnerstr. 8, 85764, Oberschleißheim, Germany
| | - Georg Dhom
- Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Feodor-Lynen-Str. 25, 81377, Munich, Germany; Center for Innovative Medical Models (CiMM), Department of Veterinary Sciences, LMU Munich, Hackerstr. 27, 85764, Oberschleißheim, Germany
| | - Timo D Müller
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany; Institute for Diabetes and Obesity (IDO), Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität, Ismaninger Str. 22, 81675, Munich, Germany
| | - Brian Finan
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany; Institute for Diabetes and Obesity (IDO), Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität, Ismaninger Str. 22, 81675, Munich, Germany
| | - Christoffer Clemmensen
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany; Institute for Diabetes and Obesity (IDO), Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität, Ismaninger Str. 22, 81675, Munich, Germany
| | - Maren Bernau
- Livestock Center of the Veterinary Faculty, LMU Munich, St.-Hubertus-Str. 12, 85764, Oberschleißheim, Germany
| | - Istvan Novak
- Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Feodor-Lynen-Str. 25, 81377, Munich, Germany; Center for Innovative Medical Models (CiMM), Department of Veterinary Sciences, LMU Munich, Hackerstr. 27, 85764, Oberschleißheim, Germany
| | - Birgit Rathkolb
- Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Feodor-Lynen-Str. 25, 81377, Munich, Germany; Center for Innovative Medical Models (CiMM), Department of Veterinary Sciences, LMU Munich, Hackerstr. 27, 85764, Oberschleißheim, Germany; German Mouse Clinic (GMC), Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
| | - Steffanie Senf
- Clinic for Swine, Center for Clinical Veterinary Medicine, LMU Munich, Sonnenstr. 16, 85764, Oberschleißheim, Germany
| | - Susanne Zöls
- Clinic for Swine, Center for Clinical Veterinary Medicine, LMU Munich, Sonnenstr. 16, 85764, Oberschleißheim, Germany
| | - Mirjam Roth
- Animal aspects, 88400, Biberach an der Riss, Germany
| | - Anna Götz
- Institute for Diabetes and Obesity (IDO), Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany; Department of Internal Medicine I, University Hospital RWTH Aachen, Pauwelstr. 30, 52074, Aachen, Germany
| | - Susanna M Hofmann
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany; Institute of Diabetes and Regeneration Research (IDR), Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany; Medizinische Klinik und Poliklinik IV, Klinikum der LMU, Ziemssenstr, 180336, Munich, Germany
| | - Martin Hrabĕ de Angelis
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany; German Mouse Clinic (GMC), Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany; Genome Analysis Center (GAC), Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health and Chair of Experimental Genetics, Technische Universität, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany
| | - Rüdiger Wanke
- Institute of Veterinary Pathology, Center for Clinical Veterinary Medicine, LMU Munich, Veterinärstr. 13, 80539, Munich, Germany
| | - Ellen Kienzle
- Chair of Animal Nutrition and Dietetics, Department of Veterinary Sciences, LMU Munich, Schönleutnerstr. 8, 85764, Oberschleißheim, Germany
| | - Armin M Scholz
- Livestock Center of the Veterinary Faculty, LMU Munich, St.-Hubertus-Str. 12, 85764, Oberschleißheim, Germany
| | - Richard DiMarchi
- Novo Nordisk Research Center Indianapolis, 5225 Exploration Drive, Indianapolis, IN, 46241, USA; Department of Chemistry, Indiana University, 800 E. Kirkwood Ave., Bloomington, IN, 47405-7102, USA
| | - Mathias Ritzmann
- Clinic for Swine, Center for Clinical Veterinary Medicine, LMU Munich, Sonnenstr. 16, 85764, Oberschleißheim, Germany
| | - Matthias H Tschöp
- German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany; Institute for Diabetes and Obesity (IDO), Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität, Ismaninger Str. 22, 81675, Munich, Germany
| | - Eckhard Wolf
- Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Feodor-Lynen-Str. 25, 81377, Munich, Germany; Center for Innovative Medical Models (CiMM), Department of Veterinary Sciences, LMU Munich, Hackerstr. 27, 85764, Oberschleißheim, Germany; German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany; Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, Feodor-Lynen-Str. 25, 81377, Munich, Germany
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Sharma G, Prossnitz ER. G-Protein-Coupled Estrogen Receptor (GPER) and Sex-Specific Metabolic Homeostasis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1043:427-453. [PMID: 29224106 DOI: 10.1007/978-3-319-70178-3_20] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Obesity and metabolic syndrome display disparate prevalence and regulation between males and females. Human, as well as rodent, females with regular menstrual/estrous cycles exhibit protection from weight gain and associated chronic diseases. These beneficial effects are predominantly attributed to the female hormone estrogen, specifically 17β-estradiol (E2). E2 exerts its actions via multiple receptors, nuclear and extranuclear estrogen receptor (ER) α and ERβ, and the G-protein-coupled estrogen receptor (GPER, previously termed GPR30). The roles of GPER in metabolic homeostasis are beginning to emerge but are complex and remain unclear. The discovery of GPER-selective pharmacological agents (agonists and antagonists) and the availability of GPER knockout mice have significantly enhanced our understanding of the functions of GPER in normal physiology and disease. GPER action manifests pleiotropic effects in metabolically active tissues such as the pancreas, adipose, liver, and skeletal muscle. Cellular and animal studies have established that GPER is involved in the regulation of body weight, feeding behavior, inflammation, as well as glucose and lipid homeostasis. GPER deficiency leads to increased adiposity, insulin resistance, and metabolic dysfunction in mice. In contrast, pharmacologic stimulation of GPER in vivo limits weight gain and improves metabolic output, revealing a promising novel therapeutic potential for the treatment of obesity and diabetes.
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Affiliation(s)
- Geetanjali Sharma
- Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
| | - Eric R Prossnitz
- Division of Molecular Medicine, Department of Internal Medicine, and Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
- University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
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Jurrissen TJ, Olver TD, Winn NC, Grunewald ZI, Lin GS, Hiemstra JA, Edwards JC, Gastecki ML, Welly RJ, Emter CA, Vieira-Potter, VJ, Padilla J. Endothelial dysfunction occurs independently of adipose tissue inflammation and insulin resistance in ovariectomized Yucatan miniature-swine. Adipocyte 2018; 7:35-44. [PMID: 29283284 DOI: 10.1080/21623945.2017.1405191] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
In rodents, experimentally-induced ovarian hormone deficiency increases adiposity and adipose tissue (AT) inflammation, which is thought to contribute to insulin resistance and increased cardiovascular disease risk. However, whether this occurs in a translationally-relevant large animal model remains unknown. Herein, we tested the hypothesis that ovariectomy would promote visceral and perivascular AT (PVAT) inflammation, as well as subsequent insulin resistance and peripheral vascular dysfunction in female swine. At sexual maturity (7 months of age), female Yucatan mini-swine either remained intact (control, n = 9) or were ovariectomized (OVX, n = 7). All pigs were fed standard chow (15-20 g/kg), and were euthanized 6 months post-surgery. Uterine mass and plasma estradiol levels were decreased by ∼10-fold and 2-fold, respectively, in OVX compared to control pigs. Body mass, glucose homeostasis, and markers of insulin resistance were not different between control and OVX pigs; however, OVX animals exhibited greater plasma triglycerides and triglyceride:HDL ratio. Ovariectomy enhanced visceral adipocyte expansion, although this was not accompanied by brachial artery PVAT adipocyte expansion, AT inflammation in either depot, or increased systemic inflammation assessed by plasma C-reactive protein concentrations. Despite the lack of AT inflammation and insulin resistance, OVX pigs exhibited depressed brachial artery endothelial-dependent vasorelaxation, which was rescued with blockade of endothelin receptor A. Together, these findings indicate that in female Yucatan mini-swine, increased AT inflammation and insulin resistance are not required for loss of ovarian hormones to induce endothelial dysfunction.
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Affiliation(s)
- Thomas J. Jurrissen
- Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, United States
| | - T. Dylan Olver
- Biomedical Sciences, University of Missouri, Columbia, MO, United States
| | - Nathan C. Winn
- Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, United States
| | - Zachary I. Grunewald
- Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, United States
| | - Gabriela S. Lin
- Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, United States
- Biology, Barry University, Miami, FL, United States
| | | | - Jenna C. Edwards
- Biomedical Sciences, University of Missouri, Columbia, MO, United States
| | - Michelle L. Gastecki
- Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, United States
| | - Rebecca J. Welly
- Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, United States
| | - Craig A. Emter
- Biomedical Sciences, University of Missouri, Columbia, MO, United States
| | | | - Jaume Padilla
- Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, United States
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, United States
- Child Health, University of Missouri, Columbia, MO, United States
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Gavin KM, Sullivan TM, Kohrt WM, Majka SM, Klemm DJ. Ovarian Hormones Regulate the Production of Adipocytes From Bone Marrow-Derived Cells. Front Endocrinol (Lausanne) 2018; 9:276. [PMID: 29892267 PMCID: PMC5985395 DOI: 10.3389/fendo.2018.00276] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 05/11/2018] [Indexed: 01/02/2023] Open
Abstract
Sex differences in body fat distribution and menopause-associated shifts in regional adiposity suggest that sex hormones play an important role in regulating the differentiation and distribution of adipocytes, but the underlying mechanisms have not been fully explained. The aim of this study was to determine whether ovarian hormone status influences the production and distribution of adipocytes in adipose tissue arising from bone marrow-derived cells. Nine- to ten-week-old ovariectomized (OVX), surgery naïve (WT), and estrogen receptor alpha knockout (αERKO) mice underwent bone marrow transplantation from luciferase or green fluorescent protein expressing donors. A subset of OVX animals had estradiol (E2) added back. Eight-weeks posttransplant, whole body and gonadal fat BM-derived adipocyte production was highest in OVX and αERKO mice, which was attenuated in OVX mice by E2 add-back. All groups demonstrated the highest bone marrow derived adipocyte (BMDA) production in the gonadal adipose depot, a visceral fat depot in mice. Taken together, the loss of ovarian hormones increases the production of BMDAs. If translatable across species, production of BMDA may be a mechanism by which visceral adiposity increases in estrogen-deficient postmenopausal women.
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Affiliation(s)
- Kathleen M. Gavin
- Division of Geriatric Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Geriatric Research, Education and Clinical Center, VA Eastern Colorado Heath Care System, Denver, CO, United States
- *Correspondence: Kathleen M. Gavin,
| | - Timothy M. Sullivan
- Geriatric Research, Education and Clinical Center, VA Eastern Colorado Heath Care System, Denver, CO, United States
- Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Cardiovascular Pulmonary Research Laboratory, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Wendy M. Kohrt
- Division of Geriatric Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Geriatric Research, Education and Clinical Center, VA Eastern Colorado Heath Care System, Denver, CO, United States
| | - Susan M. Majka
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Dwight J. Klemm
- Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Geriatric Research, Education and Clinical Center, VA Eastern Colorado Heath Care System, Denver, CO, United States
- Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Cardiovascular Pulmonary Research Laboratory, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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Andreone L, Gimeno ML, Perone MJ. Interactions Between the Neuroendocrine System and T Lymphocytes in Diabetes. Front Endocrinol (Lausanne) 2018; 9:229. [PMID: 29867762 PMCID: PMC5966545 DOI: 10.3389/fendo.2018.00229] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Accepted: 04/20/2018] [Indexed: 12/16/2022] Open
Abstract
It is well established that there is a fine-tuned bidirectional communication between the immune and neuroendocrine tissues in maintaining homeostasis. Several types of immune cells, hormones, and neurotransmitters of different chemical nature are involved as communicators between organs. Apart of being key players of the adaptive arm of the immune system, it has been recently described that T lymphocytes are involved in the modulation of metabolism of several tissues in health and disease. Diabetes may result mainly from lack of insulin production (type 1 diabetes) or insufficient insulin and insulin resistance (type 2 diabetes), both influenced by genetic and environmental components. Herein, we discuss accumulating data regarding the role of the adaptive arm of the immune system in the pathogenesis of diabetes; including the action of several hormones and neurotransmitters influencing on central and peripheral T lymphocytes development and maturation, particularly under the metabolic burden triggered by diabetes. In addition, we comment on the role of T-effector lymphocytes in adipose and liver tissues during diabetes, which together enhances pancreatic β-cell stress aggravating the disease.
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The Role of Sex and Sex Hormones in Regulating Obesity-Induced Inflammation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1043:65-86. [PMID: 29224091 DOI: 10.1007/978-3-319-70178-3_5] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Metabolic and non-metabolic complications due to obesity are becoming more prevalent, yet our understanding of the mechanisms driving these is not. This is due to individual risk factor variability making it difficult to predict disease outcomes such as diabetes and insulin resistance. Gender is a critical factor in obesity outcomes with women having more adiposity but reduced metabolic complications compared to men. The role of immune system activation during obesity is an emerging field that links adiposity to metabolic syndrome. Furthermore, evidence from animal models suggests that sex differences exist in immune responses and, therefore, could be a possible mechanism leading to sex differences in metabolic disease. While there is still much to learn in the area of sex-differences research, this chapter will review the current knowledge and literature detailing the role of sex and sex hormones on adiposity and metabolically induced inflammation in obesity.
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Ryuk JA, Ko BS, Lee HW, Kim DS, Kang S, Lee YH, Park S. Tetragonia tetragonioides (Pall.) Kuntze protects estrogen-deficient rats against disturbances of energy and glucose metabolism and decreases proinflammatory cytokines. Exp Biol Med (Maywood) 2016; 242:593-605. [PMID: 28241734 DOI: 10.1177/1535370216683835] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Tetragonia tetragonioides (Pall.) Kuntze (TTK) and JakYakGamCho-Tang (JGT) have been used for improving women's health and treating inflammatory diseases. We determined that the long-term consumption of these herbal extracts alleviates the progression of postmenopausal symptoms in high-fat-diet fed ovariectomized (OVX) rats, and further explored the mechanisms involved. Five groups of OVX rats were fed high fat diets that were supplemented with either 2% dextrin (control), 2% TTK (70% ethanol extract), 2% JGT (water extract), 1% JGT + 1% TTK (JGTT), or 30 µg/kg body weight/day of 17β-estradiol (positive control). After eight weeks of dietary intervention, the herbal treatments did not change the serum concentrations of 17β-estradiol or uterine weight in control rats, but they were higher in the positive-control group. TTK rats exhibited higher daily energy expenditure, particularly fat oxidation, without modifying the energy intake than the controls. TTK lowered the fat mass but lean body mass of the abdomen and leg were increased. JGT decreased periuterine fat mass and lean body mass more than the control but the decrease was not as much as TTK. TTK resulted in substantially lower serum concentrations of the proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1, than the control and JGT had lesser effect than TTK. Insulin resistance, determined by homeostasis model assessment estimate for assessing insulin resistance (HOMA-IR) and insulin tolerance test, was reduced in the decreasing order of control, JGT, JGTT, and TTK and the HOMA-IR of TTK was similar to the positive control. TTK, but not JGT, enhanced glucose tolerance compared with the control, although the serum insulin levels in TTK were lower compared to the control. Interestingly, the β-cell masses were much greater in the TTK and JGTT groups than in the control, and they were comparable to the positive control. The increases in β-cell masses in TTK and JGTT groups were associated with enhanced β-cell proliferation and suppressed apoptosis, which was related to the decreased TNF-α and interleukin-1β expressions. In conclusion, JGTT did not improve menopausal symptoms better than TTK itself. TTK itself prevented the OVX-induced impairments in energy, lipid, and glucose metabolism, similar to the positive control, without changing serum 17β-estradiol levels and potentiating insulin signaling and decreasing proinflammatory cytokines. TTK may be a useful intervention to alleviate some menopausal symptoms similar to selective estrogen receptor modulators and should be investigated with further human study. Impact statement Menopause decreases the quality of life in middle-aged women and herbal remedies are sometimes used as alternatives for hormone replacement therapy, which may have detrimental side effects. Although several herbal extracts have been studied, no remedies improve all the menopausal symptoms. In this study, the 70% ethanol extract of Tetragonia tetragonioides (Pall.) Kuntze (TTK) reduced the symptoms of hot flushes and improved energy, glucose, and lipid metabolism in estrogen-deficient animals without increasing serum 17β-estradiol levels. This extract acts like a selective estrogen receptor modulator and it may be a useful intervention for alleviating menopausal symptoms. This is the first study to show that the 70% ethanol extract of TTK has the potential to treat menopause-associated symptoms and metabolic disturbances. It may be a useful intervention for alleviating the symptoms of menopause in women if its efficacy can be confirmed in human studies.
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Affiliation(s)
- Jin Ah Ryuk
- 1 Korea Institute of Oriental Medicine, Daejeon 305-811, Korea
| | - Byoung-Seob Ko
- 1 Korea Institute of Oriental Medicine, Daejeon 305-811, Korea
| | - Hye Won Lee
- 1 Korea Institute of Oriental Medicine, Daejeon 305-811, Korea
| | - Da Sol Kim
- 2 Food and Nutrition, Obesity/Diabetes Center, Hoseo University, Asan 336-795, Korea
| | - Suna Kang
- 2 Food and Nutrition, Obesity/Diabetes Center, Hoseo University, Asan 336-795, Korea
| | - Yong Hyen Lee
- 3 Department of Nanobiomechatronics, Hoseo University, Asan 336-795, Korea
| | - Sunmin Park
- 2 Food and Nutrition, Obesity/Diabetes Center, Hoseo University, Asan 336-795, Korea
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20
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Nilsson J, Ericsson M, Joibari MM, Anderson F, Carlsson L, Nilsson SK, Sjödin A, Burén J. A low-carbohydrate high-fat diet decreases lean mass and impairs cardiac function in pair-fed female C57BL/6J mice. Nutr Metab (Lond) 2016; 13:79. [PMID: 27891164 PMCID: PMC5111238 DOI: 10.1186/s12986-016-0132-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 10/13/2016] [Indexed: 11/29/2022] Open
Abstract
Background Excess body fat is a major health issue and a risk factor for the development of numerous chronic diseases. Low-carbohydrate diets like the Atkins Diet are popular for rapid weight loss, but the long-term consequences remain the subject of debate. The Scandinavian low-carbohydrate high-fat (LCHF) diet, which has been popular in Scandinavian countries for about a decade, has very low carbohydrate content (~5 E %) but is rich in fat and includes a high proportion of saturated fatty acids. Here we investigated the metabolic and physiological consequences of a diet with a macronutrient composition similar to the Scandinavian LCHF diet and its effects on the organs, tissues, and metabolism of weight stable mice. Methods Female C57BL/6J mice were iso-energetically pair-fed for 4 weeks with standard chow or a LCHF diet. We measured body composition using echo MRI and the aerobic capacity before and after 2 and 4 weeks on diet. Cardiac function was assessed by echocardiography before and after 4 weeks on diet. The metabolic rate was measured by indirect calorimetry the fourth week of the diet. Mice were sacrificed after 4 weeks and the organ weight, triglyceride levels, and blood chemistry were analyzed, and the expression of key ketogenic, metabolic, hormonal, and inflammation genes were measured in the heart, liver, and adipose tissue depots of the mice using real-time PCR. Results The increase in body weight of mice fed a LCHF diet was similar to that in controls. However, while control mice maintained their body composition throughout the study, LCHF mice gained fat mass at the expense of lean mass after 2 weeks. The LCHF diet increased cardiac triglyceride content, impaired cardiac function, and reduced aerobic capacity. It also induced pronounced alterations in gene expression and substrate metabolism, indicating a unique metabolic state. Conclusions Pair-fed mice eating LCHF increased their percentage of body fat at the expense of lean mass already after 2 weeks, and after 4 weeks the function of the heart deteriorated. These findings highlight the urgent need to investigate the effects of a LCHF diet on health parameters in humans.
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Affiliation(s)
- Jessica Nilsson
- Department of Medical Biosciences, Physiological Chemistry, Umeå University, SE-901 87 Umeå, Sweden.,Department of Public Health and Clinical Medicine, Medicine, Umeå University, Umeå, Sweden
| | - Madelene Ericsson
- Department of Medical Biosciences, Physiological Chemistry, Umeå University, SE-901 87 Umeå, Sweden
| | | | - Fredrick Anderson
- Department of Medical Biosciences, Physiological Chemistry, Umeå University, SE-901 87 Umeå, Sweden
| | - Leif Carlsson
- Umeå Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Stefan K Nilsson
- Department of Medical Biosciences, Physiological Chemistry, Umeå University, SE-901 87 Umeå, Sweden
| | - Anna Sjödin
- Department of Food and Nutrition, Umeå University, Umeå, Sweden
| | - Jonas Burén
- Department of Public Health and Clinical Medicine, Medicine, Umeå University, Umeå, Sweden.,Department of Food and Nutrition, Umeå University, Umeå, Sweden
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21
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Taylor LE, Sullivan JC. Sex differences in obesity-induced hypertension and vascular dysfunction: a protective role for estrogen in adipose tissue inflammation? Am J Physiol Regul Integr Comp Physiol 2016; 311:R714-R720. [PMID: 27511280 PMCID: PMC5142161 DOI: 10.1152/ajpregu.00202.2016] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Accepted: 08/07/2016] [Indexed: 12/12/2022]
Abstract
Obesity is a potent predictor of cardiovascular disease and associated risk factors, including hypertension. Systemic inflammation has been suggested by a number of studies to be an important link between excess adiposity and hypertension, yet the majority of the studies have been conducted exclusively in males. This is problematic since women represent ∼53% of hypertensive cases and are more likely than men to be obese. There is a growing body of literature supporting a central role for immune cell activation in numerous experimental models of hypertension, and both the sex of the subject and the sex of the T cell have been shown to impact blood pressure (BP) responses to hypertensive stimuli. Moreover, sex steroid hormones play an important role in energy homeostasis, as well as in the regulation of immune responses; estrogen, in particular, has a well-known impact on both cardiovascular and metabolic disorders. Therefore, the purpose of this review is to examine whether sex or sex hormones regulate the role of the immune system in the development of hypertension and related vascular dysfunction in response to metabolic changes and stimuli, including a high-fat diet.
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Affiliation(s)
- Lia E Taylor
- Department of Physiology, Augusta University, Augusta, Georgia
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22
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Park YM, Rector RS, Thyfault JP, Zidon TM, Padilla J, Welly RJ, Meers GM, Morris ME, Britton SL, Koch LG, Booth FW, Kanaley JA, Vieira-Potter VJ. Effects of ovariectomy and intrinsic aerobic capacity on tissue-specific insulin sensitivity. Am J Physiol Endocrinol Metab 2016; 310:E190-9. [PMID: 26646101 PMCID: PMC4888527 DOI: 10.1152/ajpendo.00434.2015] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 12/02/2015] [Indexed: 12/16/2022]
Abstract
High-capacity running (HCR) rats are protected against the early (i.e., ∼ 11 wk postsurgery) development of ovariectomy (OVX)-induced insulin resistance (IR) compared with low-capacity running (LCR) rats. The purpose of this study was to utilize the hyperinsulinemic euglycemic clamp to determine whether 1) HCR rats remain protected from OVX-induced IR when the time following OVX is extended to 27 wk and 2) tissue-specific glucose uptake differences are responsible for the protection in HCR rats under sedentary conditions. Female HCR and LCR rats (n = 40; aged ∼ 22 wk) randomly received either OVX or sham (SHM) surgeries and then underwent the clamp 27 wk following surgeries. [3-(3)H]glucose was used to determine glucose clearance, whereas 2-[(14)C]deoxyglucose (2-DG) was used to assess glucose uptake in skeletal muscle, brown adipose tissue (BAT), subcutaneous white adipose tissue (WAT), and visceral WAT. OVX decreased the glucose infusion rate and glucose clearance in both lines, but HCR had better insulin sensitivity than LCR (P < 0.05). In both lines, OVX significantly reduced glucose uptake in soleus and gastrocnemius muscles; however, HCR showed ∼ 40% greater gastrocnemius glucose uptake compared with LCR (P < 0.05). HCR also exhibited greater glucose uptake in BAT and visceral WAT compared with LCR (P < 0.05), yet these tissues were not affected by OVX in either line. In conclusion, OVX impairs insulin sensitivity in both HCR and LCR rats, likely driven by impairments in insulin-mediated skeletal muscle glucose uptake. HCR rats have greater skeletal muscle, BAT, and WAT insulin-mediated glucose uptake, which may aid in protection against OVX-associated insulin resistance.
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Affiliation(s)
- Young-Min Park
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri
| | - R Scott Rector
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri; Medicine Division of Gastroenterology and Hepatology, University of Missouri, Columbia, Missouri; Research Service, Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, Missouri
| | - John P Thyfault
- Department of Molecular Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas
| | - Terese M Zidon
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri
| | - Jaume Padilla
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri; Department of Child Health, University of Missouri, Columbia, Missouri; Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
| | - Rebecca J Welly
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri
| | - Grace M Meers
- Research Service, Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, Missouri
| | - Matthew E Morris
- Department of Molecular Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas
| | - Steven L Britton
- Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan; and
| | - Lauren G Koch
- Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan; and
| | - Frank W Booth
- Department of Biomedical Sciences, University of Missouri, Columbia, Missouri
| | - Jill A Kanaley
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri
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23
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ter Horst KW, Gilijamse PW, de Weijer BA, Kilicarslan M, Ackermans MT, Nederveen AJ, Nieuwdorp M, Romijn JA, Serlie MJ. Sexual Dimorphism in Hepatic, Adipose Tissue, and Peripheral Tissue Insulin Sensitivity in Obese Humans. Front Endocrinol (Lausanne) 2015; 6:182. [PMID: 26635731 PMCID: PMC4659894 DOI: 10.3389/fendo.2015.00182] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Accepted: 11/12/2015] [Indexed: 11/29/2022] Open
Abstract
Glucose and lipid metabolism differ between men and women, and women tend to have better whole-body or muscle insulin sensitivity. This may be explained, in part, by differences in sex hormones and adipose tissue distribution. Few studies have investigated gender differences in hepatic, adipose tissue, and whole-body insulin sensitivity between severely obese men and women. In this study, we aimed to determine the differences in glucose metabolism between severely obese men and women using tissue-specific measurements of insulin sensitivity. Insulin sensitivity was compared between age and body mass index (BMI)-matched obese men and women by a two-step euglycemic hyperinsulinemic clamp with infusion of [6,6-(2)H2]glucose. Basal endogenous glucose production (EGP) and insulin sensitivity of the liver, adipose tissue, and peripheral tissues were assessed. Liver fat content was assessed by proton magnetic resonance spectroscopy in a subset of included subjects. We included 46 obese men and women (age, 48 ± 2 vs. 46 ± 2 years, p = 0.591; BMI, 41 ± 1 vs. 41 ± 1 kg/m(2), p = 0.832). There was no difference in basal EGP (14.4 ± 1.0 vs. 15.3 ± 0.5 μmol · kg fat-free mass(-1) · min(-1), p = 0.410), adipose tissue insulin sensitivity (insulin-mediated suppression of free fatty acids, 71.6 ± 3.6 vs. 76.1 ± 2.6%, p = 0.314), or peripheral insulin sensitivity (insulin-stimulated rate of disappearance of glucose, 26.2 ± 2.1 vs. 22.7 ± 1.7 μmol · kg(-1) · min(-1), p = 0.211). Obese men were characterized by lower hepatic insulin sensitivity (insulin-mediated suppression of EGP, 61.7 ± 4.1 vs. 72.8 ± 2.5% in men vs. women, respectively, p = 0.028). Finally, these observations could not be explained by differences in liver fat content (men vs. women, 16.5 ± 3.1 vs. 16.0 ± 2.5%, p = 0.913, n = 27). We conclude that obese men have lower hepatic, but comparable adipose tissue and peripheral tissue, insulin sensitivity compared to similarly obese women. Hepatic insulin resistance may contribute to the higher prevalence of diabetes in obese men. Further insight into the mechanisms underlying this gender difference may reveal novel targets for diabetes prevention and/or therapy.
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Affiliation(s)
- Kasper W. ter Horst
- Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, Netherlands
| | - Pim W. Gilijamse
- Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, Netherlands
| | - Barbara A. de Weijer
- Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, Netherlands
| | - Murat Kilicarslan
- Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, Netherlands
| | - Mariette T. Ackermans
- Laboratory of Endocrinology, Department of Clinical Chemistry, Academic Medical Center, Amsterdam, Netherlands
| | - Aart J. Nederveen
- Department of Radiology, Academic Medical Center, Amsterdam, Netherlands
| | - Max Nieuwdorp
- Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands
| | | | - Mireille J. Serlie
- Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, Netherlands
- *Correspondence: Mireille J. Serlie,
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24
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Shen M, Shi H. Sex Hormones and Their Receptors Regulate Liver Energy Homeostasis. Int J Endocrinol 2015; 2015:294278. [PMID: 26491440 PMCID: PMC4600502 DOI: 10.1155/2015/294278] [Citation(s) in RCA: 143] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Revised: 08/05/2015] [Accepted: 08/09/2015] [Indexed: 02/06/2023] Open
Abstract
The liver is one of the most essential organs involved in the regulation of energy homeostasis. Hepatic steatosis, a major manifestation of metabolic syndrome, is associated with imbalance between lipid formation and breakdown, glucose production and catabolism, and cholesterol synthesis and secretion. Epidemiological studies show sex difference in the prevalence in fatty liver disease and suggest that sex hormones may play vital roles in regulating hepatic steatosis. In this review, we summarize current literature and discuss the role of estrogens and androgens and the mechanisms through which estrogen receptors and androgen receptors regulate lipid and glucose metabolism in the liver. In females, estradiol regulates liver metabolism via estrogen receptors by decreasing lipogenesis, gluconeogenesis, and fatty acid uptake, while enhancing lipolysis, cholesterol secretion, and glucose catabolism. In males, testosterone works via androgen receptors to increase insulin receptor expression and glycogen synthesis, decrease glucose uptake and lipogenesis, and promote cholesterol storage in the liver. These recent integrated concepts suggest that sex hormone receptors could be potential promising targets for the prevention of hepatic steatosis.
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Affiliation(s)
- Minqian Shen
- Cell, Molecular, and Structural Biology, Department of Biology, Miami University, 700 E. High Street, Oxford, OH 45056, USA
| | - Haifei Shi
- Cell, Molecular, and Structural Biology, Department of Biology, Miami University, 700 E. High Street, Oxford, OH 45056, USA
- *Haifei Shi:
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