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Gómez-Hernández A, de las Heras N, Gálvez BG, Fernández-Marcelo T, Fernández-Millán E, Escribano Ó. New Mediators in the Crosstalk between Different Adipose Tissues. Int J Mol Sci 2024; 25:4659. [PMID: 38731880 PMCID: PMC11083914 DOI: 10.3390/ijms25094659] [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: 03/22/2024] [Revised: 04/19/2024] [Accepted: 04/22/2024] [Indexed: 05/13/2024] Open
Abstract
Adipose tissue is a multifunctional organ that regulates many physiological processes such as energy homeostasis, nutrition, the regulation of insulin sensitivity, body temperature, and immune response. In this review, we highlight the relevance of the different mediators that control adipose tissue activity through a systematic review of the main players present in white and brown adipose tissues. Among them, inflammatory mediators secreted by the adipose tissue, such as classical adipokines and more recent ones, elements of the immune system infiltrated into the adipose tissue (certain cell types and interleukins), as well as the role of intestinal microbiota and derived metabolites, have been reviewed. Furthermore, anti-obesity mediators that promote the activation of beige adipose tissue, e.g., myokines, thyroid hormones, amino acids, and both long and micro RNAs, are exhaustively examined. Finally, we also analyze therapeutic strategies based on those mediators that have been described to date. In conclusion, novel regulators of obesity, such as microRNAs or microbiota, are being characterized and are promising tools to treat obesity in the future.
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Affiliation(s)
- Almudena Gómez-Hernández
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal, s/n, 28040 Madrid, Spain; (A.G.-H.); (B.G.G.); (T.F.-M.); (E.F.-M.)
| | - Natalia de las Heras
- Departamento de Fisiología, Facultad de Medicina, Universidad Complutense de Madrid, Plaza Ramón y Cajal, s/n, 28040 Madrid, Spain;
| | - Beatriz G. Gálvez
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal, s/n, 28040 Madrid, Spain; (A.G.-H.); (B.G.G.); (T.F.-M.); (E.F.-M.)
| | - Tamara Fernández-Marcelo
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal, s/n, 28040 Madrid, Spain; (A.G.-H.); (B.G.G.); (T.F.-M.); (E.F.-M.)
| | - Elisa Fernández-Millán
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal, s/n, 28040 Madrid, Spain; (A.G.-H.); (B.G.G.); (T.F.-M.); (E.F.-M.)
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Óscar Escribano
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal, s/n, 28040 Madrid, Spain; (A.G.-H.); (B.G.G.); (T.F.-M.); (E.F.-M.)
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
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Li Z, Chen L, Sepulveda M, Wang P, Rasic M, Tullius SG, Perkins D, Alegre ML. Microbiota-dependent and -independent effects of obesity on transplant rejection and hyperglycemia. Am J Transplant 2023; 23:1526-1535. [PMID: 37356668 PMCID: PMC10543612 DOI: 10.1016/j.ajt.2023.06.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 06/11/2023] [Indexed: 06/27/2023]
Abstract
Obesity is associated with dysbiosis and a state of chronic inflammation that contributes to the pathogenesis of metabolic diseases, including diabetes. We have previously shown that obese mice develop glucose intolerance, increased alloreactivity, and accelerated transplant rejection. In the present study, we investigated the influence of the microbiota on diet-induced obesity (DIO)-associated transplant rejection and hyperglycemia. Antibiotic treatment prolonged graft survival and reduced fasting glycemia in high-fat diet (HFD)-fed specific-pathogen-free (SPF) mice, supporting a role for the microbiota in promoting accelerated graft rejection and hyperglycemia induced by DIO. Further supporting a microbiota-dependent effect, fecal microbiota transfer from DIO SPF mice into germ-free mice also accelerated graft rejection when compared with lean mice-fecal microbiota transfer. Notably, HFD could be also detrimental to the graft independently from microbiota, obesity, and hyperglycemia. Thus, whereas HFD-associated hyperglycemia was exclusively microbiota-dependent, HFD affected transplant outcomes via both microbiota-dependent and -independent mechanisms. Importantly, hyperglycemia in DIO SPF mice could be reduced by the addition of the gut commensal Alistipes onderdonkii, which alleviated both HFD-induced inflammation and glucose intolerance. Thus, microbial dysbiosis can be manipulated via antibiotics or select probiotics to counter some of the pathogenic effects of obesity in transplantation.
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Affiliation(s)
- Zhipeng Li
- Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Luqiu Chen
- Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Martin Sepulveda
- Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Peter Wang
- Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Mladen Rasic
- Department of Nephrology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Stefan G Tullius
- Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - David Perkins
- Department of Nephrology, University of Illinois at Chicago, Chicago, Illinois, USA
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PET/MRI-evaluated brown adipose tissue activity may be related to dietary MUFA and omega-6 fatty acids intake. Sci Rep 2022; 12:4112. [PMID: 35260768 PMCID: PMC8904502 DOI: 10.1038/s41598-022-08125-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 03/03/2022] [Indexed: 12/17/2022] Open
Abstract
An investigation of new ways to activate brown adipose tissue (BAT) is highly valuable, as it is a possible tool for obesity prevention and treatment. The aim of our study was to evaluate the relationships between dietary intake and BAT activity. The study group comprised 28 healthy non-smoking males aged 21–42 years. All volunteers underwent a physical examination and 75-g OGTT and completed 3-day food intake diaries to evaluate macronutrients and fatty acid intake. Body composition measurements were assessed using DXA scanning. An FDG-18 PET/MR was performed to visualize BAT activity. Brown adipose tissue was detected in 18 subjects (67% normal-weight individuals and 33% overweight/obese). The presence of BAT corresponded with a lower visceral adipose tissue (VAT) content (p = 0.04, after adjustment for age, daily kcal intake, and DXA Lean mass). We noted significantly lower omega-6 fatty acids (p = 0.03) and MUFA (p = 0.02) intake in subjects with detected BAT activity after adjustment for age, daily average kcal intake, and DXA Lean mass, whereas omega-3 fatty acids intake was comparable between the two groups. BAT presence was positively associated with the concentration of serum IL-6 (p = 0.01) during cold exposure. Our results show that BAT activity may be related to daily omega-6 fatty acids intake.
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Gomez-Hernandez A, Lopez-Pastor AR, Rubio-Longas C, Majewski P, Beneit N, Viana-Huete V, García-Gómez G, Fernandez S, Hribal ML, Sesti G, Escribano O, Benito M. Specific knockout of p85α in brown adipose tissue induces resistance to high-fat diet-induced obesity and its metabolic complications in male mice. Mol Metab 2019; 31:1-13. [PMID: 31918912 PMCID: PMC6977168 DOI: 10.1016/j.molmet.2019.10.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 10/14/2019] [Accepted: 10/30/2019] [Indexed: 12/19/2022] Open
Abstract
Objective An increase in mass and/or brown adipose tissue (BAT) functionality leads to an increase in energy expenditure, which may be beneficial for the prevention and treatment of obesity. Moreover, distinct class I PI3K isoforms can participate in metabolic control as well as in systemic dysfunctions associated with obesity. In this regard, we analyzed in vivo whether the lack of p85α in BAT (BATp85αKO) could modulate the activity and insulin signaling of this tissue, thereby improving diet-induced obesity and its associated metabolic complications. Methods We generated BATp85αKO mice using Cre-LoxP technology, specifically deleting p85α in a conditional manner. To characterize this new mouse model, we used mice of 6 and 12 months of age. In addition, BATp85αKO mice were submitted to a high-fat diet (HFD) to challenge BAT functionality. Results Our results suggest that the loss of p85α in BAT improves its thermogenic functionality, high-fat diet–induced adiposity and body weight, insulin resistance, and liver steatosis. The potential mechanisms involved in the improvement of obesity include (1) increased insulin signaling and lower activation of JNK in BAT, (2) enhanced insulin receptor isoform B (IRB) expression and association with IRS-1 in BAT, (3) lower production of proinflammatory cytokines by the adipose organ, (4) increased iWAT browning, and (5) improved liver steatosis. Conclusions Our results provide new mechanisms involved in the resistance to obesity development, supporting the hypothesis that the gain of BAT activity induced by the lack of p85α has a direct impact on the prevention of diet-induced obesity and its associated metabolic complications.
The lack of p85α in brown adipose tissue confers obesity resistance. BATp85αKO mice show improved thermogenic function, fatty liver and insulin resistance. High IRB levels in BAT and iWAT browning might explain the improvement of obesity. Increase in BAT functionality has a direct impact on the prevention of obesity.
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Affiliation(s)
- Almudena Gomez-Hernandez
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Spain; Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain; CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Spain.
| | - Andrea R Lopez-Pastor
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Spain; Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain.
| | - Carlota Rubio-Longas
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Spain.
| | - Patrik Majewski
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Spain.
| | - Nuria Beneit
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Spain; Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain.
| | - Vanesa Viana-Huete
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Spain; Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain.
| | - Gema García-Gómez
- Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain; CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Spain.
| | - Silvia Fernandez
- Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain; CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Spain.
| | - Marta Letizia Hribal
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Italy.
| | - Giorgio Sesti
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Italy.
| | - Oscar Escribano
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Spain; Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain; CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Spain.
| | - Manuel Benito
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Spain; Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain; CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Spain.
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Saxton SN, Clark BJ, Withers SB, Eringa EC, Heagerty AM. Mechanistic Links Between Obesity, Diabetes, and Blood Pressure: Role of Perivascular Adipose Tissue. Physiol Rev 2019; 99:1701-1763. [PMID: 31339053 DOI: 10.1152/physrev.00034.2018] [Citation(s) in RCA: 168] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Obesity is increasingly prevalent and is associated with substantial cardiovascular risk. Adipose tissue distribution and morphology play a key role in determining the degree of adverse effects, and a key factor in the disease process appears to be the inflammatory cell population in adipose tissue. Healthy adipose tissue secretes a number of vasoactive adipokines and anti-inflammatory cytokines, and changes to this secretory profile will contribute to pathogenesis in obesity. In this review, we discuss the links between adipokine dysregulation and the development of hypertension and diabetes and explore the potential for manipulating adipose tissue morphology and its immune cell population to improve cardiovascular health in obesity.
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Affiliation(s)
- Sophie N Saxton
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; School of Environment and Life Sciences, University of Salford, Salford, United Kingdom; and Department of Physiology, VU University Medical Centre, Amsterdam, Netherlands
| | - Ben J Clark
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; School of Environment and Life Sciences, University of Salford, Salford, United Kingdom; and Department of Physiology, VU University Medical Centre, Amsterdam, Netherlands
| | - Sarah B Withers
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; School of Environment and Life Sciences, University of Salford, Salford, United Kingdom; and Department of Physiology, VU University Medical Centre, Amsterdam, Netherlands
| | - Etto C Eringa
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; School of Environment and Life Sciences, University of Salford, Salford, United Kingdom; and Department of Physiology, VU University Medical Centre, Amsterdam, Netherlands
| | - Anthony M Heagerty
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; School of Environment and Life Sciences, University of Salford, Salford, United Kingdom; and Department of Physiology, VU University Medical Centre, Amsterdam, Netherlands
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Lopez-Pastor AR, Gomez-Hernandez A, Diaz-Castroverde S, Gonzalez-Aseguinolaza G, Gonzalez-Rodriguez A, Garcia G, Fernandez S, Escribano O, Benito M. Liver-specific insulin receptor isoform A expression enhances hepatic glucose uptake and ameliorates liver steatosis in a mouse model of diet-induced obesity. Dis Model Mech 2019; 12:dmm.036186. [PMID: 30642871 PMCID: PMC6398497 DOI: 10.1242/dmm.036186] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 01/03/2019] [Indexed: 12/12/2022] Open
Abstract
Among the main complications associated with obesity are insulin resistance and altered glucose and lipid metabolism within the liver. It has previously been described that insulin receptor isoform A (IRA) favors glucose uptake and glycogen storage in hepatocytes compared with isoform B (IRB), improving glucose homeostasis in mice lacking liver insulin receptor. Thus, we hypothesized that IRA could also improve glucose and lipid metabolism in a mouse model of high-fat-diet-induced obesity. We addressed the role of insulin receptor isoforms in glucose and lipid metabolism in vivo. We expressed IRA or IRB specifically in the liver by using adeno-associated viruses (AAVs) in a mouse model of diet-induced insulin resistance and obesity. IRA, but not IRB, expression induced increased glucose uptake in the liver and muscle, improving insulin tolerance. Regarding lipid metabolism, we found that AAV-mediated IRA expression also ameliorated hepatic steatosis by decreasing the expression of Fasn, Pgc1a, Acaca and Dgat2 and increasing Scd-1 expression. Taken together, our results further unravel the role of insulin receptor isoforms in hepatic glucose and lipid metabolism in an insulin-resistant scenario. Our data strongly suggest that IRA is more efficient than IRB at favoring hepatic glucose uptake, improving insulin tolerance and ameliorating hepatic steatosis. Therefore, we conclude that a gene therapy approach for hepatic IRA expression could be a safe and promising tool for the regulation of hepatic glucose consumption and lipid metabolism, two key processes in the development of non-alcoholic fatty liver disease associated with obesity. This article has an associated First Person interview with the first author of the paper. Summary: Adeno-associated-virus-mediated gene therapy for insulin receptor isoform A expression in the liver improves glucose disposal and alleviates lipid accumulation in wild-type mice under a high-fat diet.
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Affiliation(s)
- Andrea Raposo Lopez-Pastor
- Department of Biochemistry and Molecular Biology, School of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain
| | - Almudena Gomez-Hernandez
- Department of Biochemistry and Molecular Biology, School of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain.,CIBER of Diabetes and Related Diseases (CIBERDEM), Health Institute Carlos III (ISCIII), 28029 Madrid, Spain
| | - Sabela Diaz-Castroverde
- Department of Biochemistry and Molecular Biology, School of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain.,CIBER of Diabetes and Related Diseases (CIBERDEM), Health Institute Carlos III (ISCIII), 28029 Madrid, Spain
| | - Gloria Gonzalez-Aseguinolaza
- Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain
| | - Agueda Gonzalez-Rodriguez
- Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, Amadeo Vives 2, 28009 Madrid, Spain.,CIBER of Hepatic and Digestive Diseases (CIBERehd), 28029 Madrid, Spain
| | - Gema Garcia
- CIBER of Diabetes and Related Diseases (CIBERDEM), Health Institute Carlos III (ISCIII), 28029 Madrid, Spain
| | - Silvia Fernandez
- CIBER of Diabetes and Related Diseases (CIBERDEM), Health Institute Carlos III (ISCIII), 28029 Madrid, Spain
| | - Oscar Escribano
- Department of Biochemistry and Molecular Biology, School of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain .,CIBER of Diabetes and Related Diseases (CIBERDEM), Health Institute Carlos III (ISCIII), 28029 Madrid, Spain
| | - Manuel Benito
- Department of Biochemistry and Molecular Biology, School of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain.,CIBER of Diabetes and Related Diseases (CIBERDEM), Health Institute Carlos III (ISCIII), 28029 Madrid, Spain
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Supplementation with an insoluble fiber obtained from carob pod (Ceratonia siliqua L.) rich in polyphenols prevents dyslipidemia in rabbits through SIRT1/PGC-1α pathway. Eur J Nutr 2017; 58:357-366. [DOI: 10.1007/s00394-017-1599-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Accepted: 12/14/2017] [Indexed: 02/07/2023]
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Gómez-Hernández A, Beneit N, Díaz-Castroverde S, Escribano Ó. Differential Role of Adipose Tissues in Obesity and Related Metabolic and Vascular Complications. Int J Endocrinol 2016; 2016:1216783. [PMID: 27766104 PMCID: PMC5059561 DOI: 10.1155/2016/1216783] [Citation(s) in RCA: 125] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2016] [Revised: 07/19/2016] [Accepted: 08/04/2016] [Indexed: 12/18/2022] Open
Abstract
This review focuses on the contribution of white, brown, and perivascular adipose tissues to the pathophysiology of obesity and its associated metabolic and vascular complications. Weight gain in obesity generates excess of fat, usually visceral fat, and activates the inflammatory response in the adipocytes and then in other tissues such as liver. Therefore, low systemic inflammation responsible for insulin resistance contributes to atherosclerotic process. Furthermore, an inverse relationship between body mass index and brown adipose tissue activity has been described. For these reasons, in recent years, in order to combat obesity and its related complications, as a complement to conventional treatments, a new insight is focusing on the role of the thermogenic function of brown and perivascular adipose tissues as a promising therapy in humans. These lines of knowledge are focused on the design of new drugs, or other approaches, in order to increase the mass and/or activity of brown adipose tissue or the browning process of beige cells from white adipose tissue. These new treatments may contribute not only to reduce obesity but also to prevent highly prevalent complications such as type 2 diabetes and other vascular alterations, such as hypertension or atherosclerosis.
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Affiliation(s)
- Almudena Gómez-Hernández
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Madrid, Spain
- CIBER of Diabetes and Associated Metabolic Diseases, Madrid, Spain
- Instituto de Investigación Sanitaria Hospital Clínico San Carlos, IdISSC, Instituto de Salud Carlos III, Madrid, Spain
| | - Nuria Beneit
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Madrid, Spain
- CIBER of Diabetes and Associated Metabolic Diseases, Madrid, Spain
- Instituto de Investigación Sanitaria Hospital Clínico San Carlos, IdISSC, Instituto de Salud Carlos III, Madrid, Spain
| | - Sabela Díaz-Castroverde
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Madrid, Spain
- CIBER of Diabetes and Associated Metabolic Diseases, Madrid, Spain
- Instituto de Investigación Sanitaria Hospital Clínico San Carlos, IdISSC, Instituto de Salud Carlos III, Madrid, Spain
| | - Óscar Escribano
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Madrid, Spain
- CIBER of Diabetes and Associated Metabolic Diseases, Madrid, Spain
- Instituto de Investigación Sanitaria Hospital Clínico San Carlos, IdISSC, Instituto de Salud Carlos III, Madrid, Spain
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Rapamycin negatively impacts insulin signaling, glucose uptake and uncoupling protein-1 in brown adipocytes. Biochim Biophys Acta Mol Cell Biol Lipids 2016; 1861:1929-1941. [PMID: 27686967 DOI: 10.1016/j.bbalip.2016.09.016] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 09/20/2016] [Accepted: 09/22/2016] [Indexed: 11/21/2022]
Abstract
New onset diabetes after transplantation (NODAT) is a metabolic disorder that affects 40% of patients on immunosuppressive agent (IA) treatment, such as rapamycin (also known as sirolimus). IAs negatively modulate insulin action in peripheral tissues including skeletal muscle, liver and white fat. However, the effects of IAs on insulin sensitivity and thermogenesis in brown adipose tissue (BAT) have not been investigated. We have analyzed the impact of rapamycin on insulin signaling, thermogenic gene-expression and mitochondrial respiration in BAT. Treatment of brown adipocytes with rapamycin for 16h significantly decreased insulin receptor substrate 1 (IRS1) protein expression and insulin-mediated protein kinase B (Akt) phosphorylation. Consequently, both insulin-induced glucose transporter 4 (GLUT4) translocation to the plasma membrane and glucose uptake were decreased. Early activation of the N-terminal Janus activated kinase (JNK) was also observed, thereby increasing IRS1 Ser 307 phosphorylation. These effects of rapamycin on insulin signaling in brown adipocytes were partly prevented by a JNK inhibitor. In vivo treatment of rats with rapamycin for three weeks abolished insulin-mediated Akt phosphorylation in BAT. Rapamycin also inhibited norepinephrine (NE)-induced lipolysis, the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and uncoupling protein (UCP)-1 in brown adipocytes. Importantly, basal mitochondrial respiration, proton leak and maximal respiratory capacity were significantly decreased in brown adipocytes treated with rapamycin. In conclusion, we demonstrate, for the first time the important role of brown adipocytes as target cells of rapamycin, suggesting that insulin resistance in BAT might play a major role in NODAT development.
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Kaji H. Adipose Tissue‐Derived Plasminogen Activator Inhibitor‐1 Function and Regulation. Compr Physiol 2016; 6:1873-1896. [DOI: 10.1002/cphy.c160004] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Gómez-Hernández A, Beneit N, Escribano Ó, Díaz-Castroverde S, García-Gómez G, Fernández S, Benito M. Severe Brown Fat Lipoatrophy Aggravates Atherosclerotic Process in Male Mice. Endocrinology 2016; 157:3517-28. [PMID: 27414981 DOI: 10.1210/en.2016-1148] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Obesity is one of the major risk factors for the development of cardiovascular diseases and is characterized by abnormal accumulation of adipose tissue, including perivascular adipose tissue (PVAT). However, brown adipose tissue (BAT) activation reduces visceral adiposity. To demonstrate that severe brown fat lipoatrophy might accelerate atherosclerotic process, we generated a new mouse model without insulin receptor (IR) in BAT and without apolipoprotein (Apo)E (BAT-specific IR knockout [BATIRKO];ApoE(-/-) mice) and assessed vascular and metabolic alterations associated to obesity. In addition, we analyzed the contribution of the adipose organ to vascular inflammation. Brown fat lipoatrophy induces visceral adiposity, mainly in gonadal depot (gonadal white adipose tissue [gWAT]), severe glucose intolerance, high postprandial glucose levels, and a severe defect in acute insulin secretion. BATIRKO;ApoE(-/-) mice showed greater hypertriglyceridemia than the obtained in ApoE(-/-) and hypercholesterolemia similar to ApoE(-/-) mice. BATIRKO;ApoE(-/-) mice, in addition to primary insulin resistance in BAT, also showed a significant decrease in insulin signaling in liver, gWAT, heart, aorta artery, and thoracic PVAT. More importantly, our results suggest that severe brown fat lipoatrophy aggravates the atherosclerotic process, characterized by a significant increase of lipid depots, atherosclerotic coverage, lesion size and complexity, increased macrophage infiltration, and proinflammatory markers expression. Finally, an increase of TNF-α and leptin as well as a decrease of adiponectin by BAT, gWAT, and thoracic PVAT might also be responsible of vascular damage. Our results suggest that severe brown lipoatrophy aggravates atherosclerotic process. Thus, BAT activation might protect against obesity and its associated metabolic alterations.
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Affiliation(s)
- Almudena Gómez-Hernández
- Biochemistry and Molecular Biology II Department, School of Pharmacy, Complutense University of Madrid; Health Research Institute of San Carlos Clinic Hospital; and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas 28020 Madrid, Spain
| | - Nuria Beneit
- Biochemistry and Molecular Biology II Department, School of Pharmacy, Complutense University of Madrid; Health Research Institute of San Carlos Clinic Hospital; and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas 28020 Madrid, Spain
| | - Óscar Escribano
- Biochemistry and Molecular Biology II Department, School of Pharmacy, Complutense University of Madrid; Health Research Institute of San Carlos Clinic Hospital; and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas 28020 Madrid, Spain
| | - Sabela Díaz-Castroverde
- Biochemistry and Molecular Biology II Department, School of Pharmacy, Complutense University of Madrid; Health Research Institute of San Carlos Clinic Hospital; and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas 28020 Madrid, Spain
| | - Gema García-Gómez
- Biochemistry and Molecular Biology II Department, School of Pharmacy, Complutense University of Madrid; Health Research Institute of San Carlos Clinic Hospital; and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas 28020 Madrid, Spain
| | - Silvia Fernández
- Biochemistry and Molecular Biology II Department, School of Pharmacy, Complutense University of Madrid; Health Research Institute of San Carlos Clinic Hospital; and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas 28020 Madrid, Spain
| | - Manuel Benito
- Biochemistry and Molecular Biology II Department, School of Pharmacy, Complutense University of Madrid; Health Research Institute of San Carlos Clinic Hospital; and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas 28020 Madrid, Spain
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Viana-Huete V, Guillén C, García-Aguilar A, García G, Fernández S, Kahn CR, Benito M. Essential Role of IGFIR in the Onset of Male Brown Fat Thermogenic Function: Regulation of Glucose Homeostasis by Differential Organ-Specific Insulin Sensitivity. Endocrinology 2016; 157:1495-511. [PMID: 26910308 PMCID: PMC6285213 DOI: 10.1210/en.2015-1623] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Brown fat is a thermogenic tissue that generates heat to maintain body temperature in cold environments and dissipate excess energy in response to overfeeding. We have addressed the role of the IGFIR in the brown fat development and function. Mice lacking IGFIR exhibited normal brown adipose tissue/body weight in knockout (KO) vs control mice. However, lack of IGFIR decreased uncoupling protein 1 expression in interscapular brown fat and beige cells in inguinal fat. More importantly, the lack of IGFIR resulted in an impaired cold acclimation. No differences in the total fat volume were found in the KO vs control mice. Epididymal fat showed larger adipocytes but with a lower number of adipocytes in KO vs control mice at age 12 months. In addition, KO mice showed a sustained moderate hyperinsulinemia and hypertriglyceridemia upon time and hepatic insulin insensitivity associated with lipid accumulation, with the outcome of a global insulin resistance. In addition, we found that the expression of uncoupling protein 3 in the skeletal muscle was decreased and its expression was increased in the heart in parallel with the expression of beta-2 adrenergic receptors. Upon nonobesogenic high-fat diet, we found a severe insulin resistance in the liver and in the skeletal muscle, but unchanged insulin sensitivity in the heart. In conclusion, our data suggest that IGFIR it is not an essential growth factor in the brown fat development in the presence of the IR and very high plasma levels of IGF-I, but it is indispensable for full brown fat functionality.
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Affiliation(s)
- Vanesa Viana-Huete
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Complutense University-Madrid, Madrid 28040, Spain; Spanish Diabetes and Metabolic Research Network (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Institute of Health Carlos III, Madrid 28029, Spain; and Joslin Diabetes Center (C.R.K.), Harvard Medical School, Boston, MA 02215
| | - Carlos Guillén
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Complutense University-Madrid, Madrid 28040, Spain; Spanish Diabetes and Metabolic Research Network (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Institute of Health Carlos III, Madrid 28029, Spain; and Joslin Diabetes Center (C.R.K.), Harvard Medical School, Boston, MA 02215
| | - Ana García-Aguilar
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Complutense University-Madrid, Madrid 28040, Spain; Spanish Diabetes and Metabolic Research Network (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Institute of Health Carlos III, Madrid 28029, Spain; and Joslin Diabetes Center (C.R.K.), Harvard Medical School, Boston, MA 02215
| | - Gema García
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Complutense University-Madrid, Madrid 28040, Spain; Spanish Diabetes and Metabolic Research Network (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Institute of Health Carlos III, Madrid 28029, Spain; and Joslin Diabetes Center (C.R.K.), Harvard Medical School, Boston, MA 02215
| | - Silvia Fernández
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Complutense University-Madrid, Madrid 28040, Spain; Spanish Diabetes and Metabolic Research Network (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Institute of Health Carlos III, Madrid 28029, Spain; and Joslin Diabetes Center (C.R.K.), Harvard Medical School, Boston, MA 02215
| | - C R Kahn
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Complutense University-Madrid, Madrid 28040, Spain; Spanish Diabetes and Metabolic Research Network (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Institute of Health Carlos III, Madrid 28029, Spain; and Joslin Diabetes Center (C.R.K.), Harvard Medical School, Boston, MA 02215
| | - Manuel Benito
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Complutense University-Madrid, Madrid 28040, Spain; Spanish Diabetes and Metabolic Research Network (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Institute of Health Carlos III, Madrid 28029, Spain; and Joslin Diabetes Center (C.R.K.), Harvard Medical School, Boston, MA 02215
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13
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Gunawardana SC, Piston DW. Insulin-independent reversal of type 1 diabetes in nonobese diabetic mice with brown adipose tissue transplant. Am J Physiol Endocrinol Metab 2015; 308:E1043-55. [PMID: 25898954 PMCID: PMC4469812 DOI: 10.1152/ajpendo.00570.2014] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 04/11/2015] [Indexed: 02/07/2023]
Abstract
Traditional therapies for type 1 diabetes (T1D) involve insulin replacement or islet/pancreas transplantation and have numerous limitations. Our previous work demonstrated the ability of embryonic brown adipose tissue (BAT) transplants to establish normoglycemia without insulin in chemically induced models of insulin-deficient diabetes. The current study sought to extend the technique to an autoimmune-mediated T1D model and document the underlying mechanisms. In nonobese diabetic (NOD) mice, BAT transplants result in complete reversal of T1D associated with rapid and long-lasting euglycemia. In addition, BAT transplants placed prior to the onset of diabetes on NOD mice can prevent or significantly delay the onset of diabetes. As with streptozotocin (STZ)-diabetic models, euglycemia is independent of insulin and strongly correlates with decrease of inflammation and increase of adipokines. Plasma insulin-like growth factor-I (IGF-I) is the first hormone to increase following BAT transplants. Adipose tissue of transplant recipients consistently express IGF-I compared with little or no expression in controls, and plasma IGF-I levels show a direct negative correlation with glucose, glucagon, and inflammatory cytokines. Adipogenic and anti-inflammatory properties of IGF-I may stimulate regeneration of new healthy white adipose tissue, which in turn secretes hypoglycemic adipokines that substitute for insulin. IGF-I can also directly decrease blood glucose through activating insulin receptor. These data demonstrate the potential for insulin-independent reversal of autoimmune-induced T1D with BAT transplants and implicate IGF-I as a likely mediator in the resulting equilibrium.
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Affiliation(s)
- Subhadra C Gunawardana
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - David W Piston
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
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14
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Chen YI, Tzeng CY, Cheng YW, Hsu TH, Ho WJ, Liang ZC, Hsieh CW, Tzen JTC, Chang SL. The Involvement of Serotonin in the Hypoglycemic Effects Produced by Administration of the Aqueous Extract of Xylaria nigripes with Steroid-Induced Insulin-Resistant Rats. Phytother Res 2015; 29:770-6. [PMID: 25712886 DOI: 10.1002/ptr.5314] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Revised: 01/08/2015] [Accepted: 01/28/2015] [Indexed: 11/09/2022]
Abstract
Xylaria nigripes (XN) is a medicinal fungus with a high-economic value. The aim of this study was to explore the hypoglycemic effects and mechanisms of the XN aqueous extract in steroid-induced insulin-resistant (SIIR) rats. Significant hypoglycemic effects were observed 60 min after administration of XN aqueous extract. In normal Wistar, hypoglycemic effects were 21% (the plasma glucose level decreased from 128.6 ± 12.5 to 100.9 ± 10.7 mg/dL). In SIIR, hypoglycemic effects were 26% (the plasma glucose level decreased from 177.6 ± 12.5 to 133.3 ± 29.7 mg/dL) rats refer to their baseline. The signaling proteins for insulin-receptor substrate-1 and glucose transporter-4 increased 0.51-fold and 1.12-fold, respectively, as determined by Western blotting; the increase in the proteins was 13% and 9%, respectively, as determined by immunohistochemistry. The serotonin antagonist, α-p-chlorophenylalanine, effectively blocked the hypoglycemic effects and increased the signaling protein levels. After XN administration, none of the animals showed significant changes in plasma-free fatty acids in 60 min. In summary, the XN extract may have hypoglycemic effects in normal Wistar and SIIR rats that may have a serotonin-related hypoglycemic effect and enhance insulin sensitivity in the SIIR rats.
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Affiliation(s)
- Ying-I Chen
- Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan
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15
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Ro SH, Semple I, Ho A, Park HW, Lee JH. Sestrin2, a Regulator of Thermogenesis and Mitohormesis in Brown Adipose Tissue. Front Endocrinol (Lausanne) 2015; 6:114. [PMID: 26257706 PMCID: PMC4513567 DOI: 10.3389/fendo.2015.00114] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Accepted: 07/11/2015] [Indexed: 12/11/2022] Open
Abstract
Sestrin2 is a stress-inducible protein that functions as an antioxidant and inhibitor of mTOR complex 1. In a recent study, we found that Sestrin2 overexpression in brown adipocytes interfered with normal metabolism by reducing mitochondrial respiration through the suppression of uncoupling protein 1 (UCP1) expression. The metabolic effects of Sestrin2 in brown adipocytes were dependent on its antioxidant activity, and chemical antioxidants produced similar effects in inhibiting UCP1-dependent thermogenesis. These observations suggest that low levels of reactive oxygen species (ROS) in brown adipocytes can actually be beneficial and necessary for proper metabolic homeostasis. In addition, considering that Sestrins are ROS inducible and perform ROS detoxifying as well as other metabolism-controlling functions, they are potential regulators of mitohormesis. This is a concept in which overall beneficial effects result from low-level oxidative stress stimuli, such as the ones induced by caloric restriction or physical exercise. In this perspective, we incorporate our recent insight obtained from the Sestrin2 study toward a better understanding of the relationship between ROS, Sestrin2, and mitochondrial metabolism in the context of brown adipocyte physiology.
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Affiliation(s)
- Seung-Hyun Ro
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Ian Semple
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Allison Ho
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Hwan-Woo Park
- Department of Cell Biology, College of Medicine, Konyang University, Daejeon, South Korea
| | - Jun Hee Lee
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
- *Correspondence: Jun Hee Lee, Institute of Gerontology, Department of Molecular and Integrative Physiology, University of Michigan Medical School, 109 Zina Pitcher Place, 3019 BSRB, Ann Arbor, MI 48109, USA,
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16
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Almabrouk TAM, Ewart MA, Salt IP, Kennedy S. Perivascular fat, AMP-activated protein kinase and vascular diseases. Br J Pharmacol 2014; 171:595-617. [PMID: 24490856 DOI: 10.1111/bph.12479] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Revised: 10/04/2013] [Accepted: 10/16/2013] [Indexed: 12/15/2022] Open
Abstract
Perivascular adipose tissue (PVAT) is an active endocrine and paracrine organ that modulates vascular function, with implications for the pathophysiology of cardiovascular disease (CVD). Adipocytes and stromal cells contained within PVAT produce mediators (adipokines, cytokines, reactive oxygen species and gaseous compounds) with a range of paracrine effects modulating vascular smooth muscle cell contraction, proliferation and migration. However, the modulatory effect of PVAT on the vascular system in diseases, such as obesity, hypertension and atherosclerosis, remains poorly characterized. AMP-activated protein kinase (AMPK) regulates adipocyte metabolism, adipose biology and vascular function, and hence may be a potential therapeutic target for metabolic disorders such as type 2 diabetes mellitus (T2DM) and the vascular complications associated with obesity and T2DM. The role of AMPK in PVAT or the actions of PVAT have yet to be established, however. Activation of AMPK by pharmacological agents, such as metformin and thiazolidinediones, may modulate the activity of PVAT surrounding blood vessels and thereby contribute to their beneficial effect in cardiometabolic diseases. This review will provide a current perspective on how PVAT may influence vascular function via AMPK. We will also attempt to demonstrate how modulating AMPK activity using pharmacological agents could be exploited therapeutically to treat cardiometabolic diseases.
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Affiliation(s)
- T A M Almabrouk
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, UK
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17
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Gunawardana SC. Benefits of healthy adipose tissue in the treatment of diabetes. World J Diabetes 2014; 5:420-430. [PMID: 25126390 PMCID: PMC4127579 DOI: 10.4239/wjd.v5.i4.420] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 03/24/2014] [Accepted: 06/03/2014] [Indexed: 02/05/2023] Open
Abstract
The major malfunction in diabetes mellitus is severe perturbation of glucose homeostasis caused by deficiency of insulin. Insulin deficiency is either absolute due to destruction or failure of pancreatic β cells, or relative due to decreased sensitivity of peripheral tissues to insulin. The primary lesion being related to insulin, treatments for diabetes focus on insulin replacement and/or increasing sensitivity to insulin. These therapies have their own limitations and complications, some of which can be life-threatening. For example, exogenous insulin administration can lead to fatal hypoglycemic episodes; islet/pancreas transplantation requires life-long immunosuppressive therapy; and anti-diabetic drugs have dangerous side effects including edema, heart failure and lactic acidosis. Thus the need remains for better safer long term treatments for diabetes. The ultimate goal in treating diabetes is to re-establish glucose homeostasis, preferably through endogenously generated hormones. Recent studies increasingly show that extra-pancreatic hormones, particularly those arising from adipose tissue, can compensate for insulin, or entirely replace the function of insulin under appropriate circumstances. Adipose tissue is a versatile endocrine organ that secretes a variety of hormones with far-reaching effects on overall metabolism. While unhealthy adipose tissue can exacerbate diabetes through limiting circulation and secreting of pro-inflammatory cytokines, healthy uninflamed adipose tissue secretes beneficial adipokines with hypoglycemic and anti-inflammatory properties, which can complement and/or compensate for the function of insulin. Administration of specific adipokines is known to alleviate both type 1 and 2 diabetes, and leptin mono-therapy is reported to reverse type 1 diabetes independent of insulin. Although specific adipokines may correct diabetes, administration of individual adipokines still carries risks similar to those of insulin monotherapy. Thus a better approach is to achieve glucose homeostasis with endogenously-generated adipokines through transplantation or regeneration of healthy adipose tissue. Our recent studies on mouse models show that type 1 diabetes can be reversed without insulin through subcutaneous transplantation of embryonic brown adipose tissue, which leads to replenishment of recipients’ white adipose tissue; increase of a number of beneficial adipokines; and fast and long-lasting euglycemia. Insulin-independent glucose homeostasis is established through a combination of endogenously generated hormones arising from the transplant and/or newly-replenished white adipose tissue. Transplantation of healthy white adipose tissue is reported to alleviate type 2 diabetes in rodent models on several occasions, and increasing the content of endogenous brown adipose tissue is known to combat obesity and type 2 diabetes in both humans and animal models. While the underlying mechanisms are not fully documented, the beneficial effects of healthy adipose tissue in improving metabolism are increasingly reported, and are worthy of attention as a powerful tool in combating metabolic disease.
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18
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Gómez-Hernández A, Perdomo L, de las Heras N, Beneit N, Escribano O, Otero YF, Guillén C, Díaz-Castroverde S, Gozalbo-López B, Cachofeiro V, Lahera V, Benito M. Antagonistic effect of TNF-alpha and insulin on uncoupling protein 2 (UCP-2) expression and vascular damage. Cardiovasc Diabetol 2014; 13:108. [PMID: 25077985 PMCID: PMC4149264 DOI: 10.1186/s12933-014-0108-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Accepted: 06/27/2014] [Indexed: 12/11/2022] Open
Abstract
Background It has been reported that increased expression of UCP-2 in the vasculature may prevent the development of atherosclerosis in patients with increased production of reactive oxygen species, as in the diabetes, obesity or hypertension. Thus, a greater understanding in the modulation of UCP-2 could improve the atherosclerotic process. However, the effect of TNF-α or insulin modulating UCP-2 in the vascular wall is completely unknown. In this context, we propose to study new molecular mechanisms that help to explain whether the moderate hyperinsulinemia or lowering TNF-α levels might have a protective role against vascular damage mediated by UCP-2 expression levels. Methods We analyzed the effect of insulin or oleic acid in presence or not of TNF-α on UCP-2 expression in murine endothelial and vascular smooth muscle cells. At this step, we wondered if some mechanisms studied in vitro could be of any relevance in vivo. We used the following experimental models: ApoE−/− mice under Western type diet for 2, 6, 12 or 18 weeks, BATIRKO mice under high-fat diet for 16 weeks and 52-week-old BATIRKO mice with o without anti-TNF-α antibody pre-treatment. Results Firstly, we found that TNF-α pre-treatment reduced UCP-2 expression induced by insulin in vascular cells. Secondly, we observed a progressive reduction of UCP-2 levels together with an increase of lipid depots and lesion area in aorta from ApoE−/− mice. In vivo, we also observed that moderate hyperinsulinemic obese BATIRKO mice have lower TNF-α and ROS levels and increased UCP-2 expression levels within the aorta, lower lipid accumulation, vascular dysfunction and macrovascular damage. We also observed that the anti-TNF-α antibody pre-treatment impaired the loss of UCP-2 expression within the aorta and relieved vascular damage observed in 52-week-old BATIRKO mice. Finally, we observed that the pretreatment with iNOS inhibitor prevented UCP-2 reduction induced by TNF-α in vascular cells. Moreover, iNOS levels are augmented in aorta from mice with lower UCP-2 levels and higher TNF-α levels. Conclusions Our data suggest that moderate hyperinsulinemia in response to insulin resistance or lowering of TNF-α levels within the aorta attenuates vascular damage, this protective effect being mediated by UCP-2 expression levels through iNOS. Electronic supplementary material The online version of this article (doi:10.1186/s12933-014-0108-9) contains supplementary material, which is available to authorized users.
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Aprahamian TR. Elevated adiponectin expression promotes adipose tissue vascularity under conditions of diet-induced obesity. Metabolism 2013; 62:1730-8. [PMID: 23993424 PMCID: PMC3834157 DOI: 10.1016/j.metabol.2013.07.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Revised: 07/22/2013] [Accepted: 07/23/2013] [Indexed: 12/17/2022]
Abstract
OBJECTIVE Despite the clinical prevalence of obesity, only recently has the importance of adipose tissue microenvironment been addressed at a molecular level. Here, I focused on the fat-derived cytokine adiponectin as a model system to understand the mechanism underlying adipose tissue vascularity, perfusion, inflammation, and systemic metabolic function. MATERIALS/METHODS Wild type, adiponectin-deficient, and adiponectin transgenic-overexpressing mice were maintained on chow diet or high fat/high sucrose diet for 32weeks. Vascularization of adipose tissue was examined by confocal microscopy and perfusion was determined by recovery of injected microspheres. Adipose tissue inflammation and systemic metabolic function were also assessed. RESULTS Modest over-expression of adiponectin led to a marked increase in adipose tissue vascularity and perfusion, and this was associated with diminished hypoxia and an increase in vascular endothelial growth factor-A (VEGF-A) expression in the obese mice. Adiponectin over-expression in diet-induced obese mice also led to the virtual absence of macrophage infiltration and the elimination of crown-like structures. Adiponectin transgenic mice also displayed a remarkable sensitivity to insulin and diminished hepatic steatosis. Under the conditions of these experiments, adiponectin deficiency did not diminish adipose tissue perfusion or worsen metabolic function compared to wild type mice fed the high fat/high sucrose diet. CONCLUSION These data demonstrate that increased circulating adiponectin levels, and the obese environment, are associated with increased adipose tissue vascularization and perfusion, and improved metabolic function under conditions of long term diet-induced obesity.
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Affiliation(s)
- Tamar R Aprahamian
- Department of Medicine-Renal Section, Boston University School of Medicine, 650 Albany Street, X536, Boston, MA 02118, USA.
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20
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Gómez-Hernández A, Escribano Ó, Perdomo L, Otero YF, García-Gómez G, Fernández S, Beneit N, Benito M. Implication of insulin receptor A isoform and IRA/IGF-IR hybrid receptors in the aortic vascular smooth muscle cell proliferation: role of TNF-α and IGF-II. Endocrinology 2013; 154:2352-64. [PMID: 23677929 DOI: 10.1210/en.2012-2161] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
To assess the role of insulin receptor (IR) isoforms (IRA and IRB) in the proliferation of vascular smooth muscle cells (VSMCs) involved in the atherosclerotic process, we generated new VSMC lines bearing IR (wild-type VSMCs; IRLoxP(+/+) VSMCs), lacking IR (IR(-/-) VSMCs) or expressing IRA (IRA VSMCs) or IRB (IRB VSMCs). Insulin and different proatherogenic stimuli induced a significant increase of IRA expression in IRLoxP(+/+) VSMCs. Moreover, insulin, through ERK signaling, and the proatherogenic stimuli, through ERK and p38 signaling, induced a higher proliferation in IRA than IRB VSMCs. The latter effect might be due to IRA cells showing a higher expression of angiotensin II, endothelin 1, and thromboxane 2 receptors and basal association between IRA and these receptors. Furthermore, TNF-α induced in a ligand-dependent manner a higher association between IRA and TNF-α receptor 1 (TNF-R1). On the other hand, IRA overexpression might favor the atherogenic actions of IGF-II. Thereby, IGF-II or TNF-α induced IRA and IGF-I receptor (IGF-IR) overexpression as well as an increase of IRA/IGF-IR hybrid receptors in VSMCs. More importantly, we observed a significant increase of IRA, TNF-R1, and IGF-IR expression as well as higher association of IRA with TNF-R1 or IGF-IR in the aorta from ApoE(-/-) and BATIRKO mice, 2 models showing vascular damage. In addition, anti-TNF-α treatment prevented those effects in BATIRKO mice. Finally, our data suggest that the IRA isoform and its association with TNF-R1 or IGF-IR confers proliferative advantage to VSMCs, mainly in response to TNF-α or IGF-II, which might be of significance in the early atherosclerotic process.
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MESH Headings
- Animals
- Blotting, Western
- Cell Proliferation/drug effects
- Cells, Cultured
- Immunoprecipitation
- Insulin-Like Growth Factor II/pharmacology
- Male
- Mice
- Mice, Knockout
- Muscle, Smooth, Vascular/cytology
- Myocytes, Smooth Muscle/cytology
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/metabolism
- Protein Isoforms/genetics
- Protein Isoforms/metabolism
- Receptor, IGF Type 1/genetics
- Receptor, IGF Type 1/metabolism
- Receptor, Insulin/genetics
- Receptor, Insulin/metabolism
- Tumor Necrosis Factor-alpha/pharmacology
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Affiliation(s)
- Almudena Gómez-Hernández
- Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, Instituto de Investigaciones Sanitarias Hospital Clínico San Carlos, Centro de Investigación Biomédica en Red of Diabetes and Associated Metabolic Diseases, Instituto de Salud Carlos III, Madrid 28040, Spain.
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Finelli C, Tarantino G. Should visceral fat, strictly linked to hepatic steatosis, be depleted to improve survival? Hepatol Int 2013; 7:413-428. [PMID: 26201775 DOI: 10.1007/s12072-012-9406-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Accepted: 10/01/2012] [Indexed: 02/06/2023]
Abstract
Numerous epidemiologic studies have implicated abdominal obesity as a major risk factor for insulin resistance, type 2 diabetes mellitus, cardiovascular disease, stroke, metabolic syndrome and its further expression, i.e., nonalcoholic fatty liver disease and death. Using novel models of visceral obesity, several studies have demonstrated that the relationship between visceral fat and longevity is causal, while the accrual of subcutaneous fat does not appear to play an important role in the etiology of disease risk. The need of reducing the visceral fat to improve survival, mainly taking into account the strict link between nonalcoholic fatty liver disease and the coronary artery disease is discussed.
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Affiliation(s)
- Carmine Finelli
- Center of Obesity and Eating Disorder, Stella Maris Mediterraneo Foundation Chiaromonte, Potenza, Italy
| | - Giovanni Tarantino
- Department of Clinical and Experimental Medicine, Federico II University Medical School of Naples, Naples, Italy.
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22
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Shah RV, Abbasi SA, Heydari B, Rickers C, Jacobs DR, Wang L, Kwong RY, Bluemke DA, Lima JA, Jerosch-Herold M. Insulin resistance, subclinical left ventricular remodeling, and the obesity paradox: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2013; 61:1698-706. [PMID: 23500236 PMCID: PMC4114341 DOI: 10.1016/j.jacc.2013.01.053] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2012] [Revised: 12/21/2012] [Accepted: 01/08/2013] [Indexed: 12/21/2022]
Abstract
OBJECTIVES This study assessed whether impaired fasting glucose (IFG), insulin resistance, and waist-to-hip ratio (WHR) had effects on cardiac remodeling, independent of obesity, in the MESA (Multi-Ethnic Study of Atherosclerosis) trial. BACKGROUND Recent studies have suggested that central obesity and insulin resistance may be primary mediators of obesity-related cardiac remodeling independent of body mass index (BMI). METHODS We investigated 4,364 subjects without diabetes in the MESA trial. IFG (100 to 125 mg/dl) or insulin resistance (by homeostatic model assessment of insulin resistance [HOMA-IR]) and WHR were used for cardiometabolic phenotyping. Multivariate linear regression analysis was used to determine the effects of the cardiometabolic markers on left ventricular (LV) remodeling, assessed primarily through the LV mass-to-volume ratio obtained by cine cardiac magnetic resonance imaging. RESULTS Individuals with IFG were more likely to be older and hypertensive, with increased prevalence of cardiometabolic risk factors regardless of BMI. In each quartile of BMI, subjects with above-median HOMA-IR, above-median WHR, or IFG had a higher LV mass-to-volume ratio (p < 0.05 for all). HOMA-IR (p < 0.0001), WHR (p < 0.0001), and the presence of IFG (p = 0.04), but not BMI (p = 0.24), were independently associated with LV mass-to-volume ratio after adjustment for age, sex, hypertension, race, and dyslipidemia. CONCLUSIONS Insulin resistance and WHR were associated with concentric LV remodeling independent of BMI. These results support the emerging hypothesis that the cardiometabolic phenotype, defined by insulin resistance and central obesity, may play a critical role in LV remodeling independently of BMI.
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Affiliation(s)
- Ravi V. Shah
- Non-Invasive Cardiovascular Imaging Laboratory, Brigham and Women's Hospital
- Cardiology Division, Department of Medicine, Massachusetts General Hospital
| | - Siddique A. Abbasi
- Non-Invasive Cardiovascular Imaging Laboratory, Brigham and Women's Hospital
| | - Bobak Heydari
- Non-Invasive Cardiovascular Imaging Laboratory, Brigham and Women's Hospital
| | - Carsten Rickers
- Department of Pediatric Cardiology, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - David R. Jacobs
- University of Minnesota, School of Public Health, Division of Epidemiology and Community Health, Minneapolis, MN
| | - Lu Wang
- Harvard School of Public Health, Department of Epidemiology and Biostatistics, Boston, MA
| | - Raymond Y. Kwong
- Non-Invasive Cardiovascular Imaging Laboratory, Brigham and Women's Hospital
| | - David A. Bluemke
- Radiology and Imaging Sciences, National Institutes of Health Clinical Center, National Institute of Biomedical Imaging and Bioengineering
| | - Joao A.C. Lima
- Radiology and Imaging Sciences, National Institutes of Health Clinical Center, National Institute of Biomedical Imaging and Bioengineering
| | - Michael Jerosch-Herold
- Non-Invasive Cardiovascular Imaging Laboratory, Brigham and Women's Hospital
- Department of Radiology,Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02114
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23
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[Role of white adipose tissue in vascular complications due to obesity]. CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS 2013; 25:27-35. [PMID: 23522279 DOI: 10.1016/j.arteri.2012.11.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2012] [Accepted: 11/28/2012] [Indexed: 12/22/2022]
Abstract
The contribution of white adipose tissue to the vascular complications associated with obesity is analysed in this review. White adipose tissue is an active metabolic organ and secretor of several molecules with endocrine, paracrine and autocrine actions. Weight gain produced in the obesity, induces an excess of fat, mainly in the visceral depot, which is responsible for the activation of different signalling pathways, leading to a higher production of proinflammatory cytokines. As adipocytes as infiltrated macrophages and lymphocytes and endothelial cells contribute to a chronic low grade inflammatory situation present in obesity. Moreover, the increase in adiposity activates the inflammatory response in the adipocyte themselves, as well as in the hepatocyte. Finally, proinflammatory and proatherogenic mediators produced by white adipose tissue and liver associated to immune cells generate insulin resistance in peripheral tissues and contribute to the beginning of atherogenic process.
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24
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Gómez-Hernández A, Perdomo L, Escribano Ó, Benito M. [Role of brown and perivascular adipose tissue in vascular complications due to obesity]. CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS : PUBLICACION OFICIAL DE LA SOCIEDAD ESPANOLA DE ARTERIOSCLEROSIS 2013; 25:36-44. [PMID: 23522280 DOI: 10.1016/j.arteri.2012.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2012] [Accepted: 11/28/2012] [Indexed: 06/02/2023]
Abstract
The contribution of brown and perivascular adipose tissues to the pathophysiology of metabolic and vascular complications associated with obesity are analysed in this review. To combat obesity and prevent its highly prevalent metabolic and vascular complications, a new insight on our knowledge of the role of the thermogenic function of brown adipose tissue and its promising therapeutic potential in humans is needed in addition to conventional treatments. Owing to the impact of brown adipose tissue on energy expenditure related to lipid and glucose metabolism, as well as its potential resistance against inflammation along with perivascular adipose tissue, new perspectives in the treatment of obesity treatment could be focused on the design of new drugs, or different regimens or therapies, that increase the amount and activity of brown adipose tissue. These new treatments not only may contribute to combat obesity, but also prevent complications such as type 2 diabetes and other associated metabolic and vascular changes.
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Affiliation(s)
- Almudena Gómez-Hernández
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, España.
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25
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Gunawardana SC. Therapeutic value of brown adipose tissue: Correcting metabolic disease through generating healthy fat. Adipocyte 2012; 1:250-255. [PMID: 23700541 PMCID: PMC3609108 DOI: 10.4161/adip.21042] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Brown adipose tissue (BAT), an important endocrine organ long known for thermogenesis and energy consumption, has received much attention in recent years for its potential to combat obesity. In general, BAT can enhance metabolism and improve overall health. Our recent work demonstrates the ability of embryonic BAT transplants to correct type 1 diabetes (T1D) without insulin, via mechanisms somewhat different from those involved in BAT-associated weight loss. BAT transplants seem to reverse T1D by decreasing inflammation and increasing functionality in the surrounding white adipose tissue (WAT), thereby enabling it to secrete hypoglycemic adipokines, which compensate for the function of insulin. Thus BAT can transform unhealthy WAT to a healthy status, sufficient to replace the function of endocrine pancreas and establish insulin-independent glycemic regulation. Several studies, including ours, demonstrate the remarkable ability of BAT to correct metabolic disorders and hint at its beneficial effects on inflammation. Hence, addition of more BAT to the body, through transplantation or stimulating regeneration, may well be the therapy of the future for the simple correction of numerous diseases.
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26
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Abstract
Type 1 diabetes (T1D) is a serious disease with increasing incidence worldwide, with fatal consequences if untreated. Traditional therapies require direct or indirect insulin replacement, which involves numerous limitations and complications. While insulin is the major regulator of blood glucose, recent reports demonstrate the ability of several extra-pancreatic hormones to decrease blood glucose and improve metabolic homeostasis. Such hormones mainly include adipokines originating from adipose tissue (AT), while specific factors from the gut and liver also contribute to glucose homeostasis. Correction of T1D with adipokines is progressively becoming a realistic option, with the potential to overcome many problems associated with insulin replacement. Several recent studies demonstrate insulin-independent reversal or amelioration of T1D through administration of specific adipokines. Our recent work demonstrates the ability of healthy AT to compensate for the function of endocrine pancreas in long-term correction of T1D. This review discusses the potential of AT-related therapies for T1D as viable alternatives to insulin replacement.
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Affiliation(s)
- Subhadra C Gunawardana
- Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
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27
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Birerdinc A, Jarrar M, Stotish T, Randhawa M, Baranova A. Manipulating molecular switches in brown adipocytes and their precursors: a therapeutic potential. Prog Lipid Res 2012; 52:51-61. [PMID: 22960032 DOI: 10.1016/j.plipres.2012.08.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2012] [Revised: 03/28/2012] [Accepted: 08/11/2012] [Indexed: 01/07/2023]
Abstract
Brown adipocytes constitute a metabolically active tissue responsible for non-shivering thermogenesis and the depletion of excess calories. Differentiation of brown fat adipocytes de novo or stimulation of pre-existing brown adipocytes within white adipose depots could provide a novel method for reducing the obesity and alleviating the consequences of type II diabetes worldwide. In this review, we addressed several molecular mechanisms involved in the control of brown fat activity, namely, the β₃-adrenergic stimulation of thermogenesis during exposure to cold or by catecholamines; the augmentation of thyroid function; the modulation of peroxisome proliferator-activated receptor gamma (PPARγ), transcription factors of the C/EBP family, and the PPARγ co-activator PRDM16; the COX-2-driven expression of UCP1; the stimulation of the vanilloid subfamily receptor TRPV1 by capsaicin and monoacylglycerols; the effects of BMP7 or its analogs; the cannabinoid receptor antagonists and melanogenesis modulating agents. Manipulating one or more of these pathways may provide a solution to the problem of harnessing brown fat's thermogenic potential. However, a better understanding of their interplay and other homeostatic mechanisms is required for the development of novel therapies for millions of obese and/or diabetic individuals.
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Affiliation(s)
- Aybike Birerdinc
- Center for the Study of Chronic Metabolic Diseases, School of Systems Biology, College of Science, George Mason University, Fairfax, VA, USA
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