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2017 | 64 | 3 | 423-429
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Glucagon-like peptide-1 receptor agonist stimulates mitochondrial bioenergetics in human adipocytes

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Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are relatively new pharmacological agents used to normalize glucose level in type 2 diabetes. Recently, GLP-1RAs have been approved for the treatment of obesity to reduce body weight in non-diabetic patients. The extra-pancre-atic effects of GLP-1RAs, as well as their molecular mechanism of action, are still poorly understood. Thus this study was aimed to verify the hypothesis that the mechanism of action of the GLP-1RAs involves mitochondria and that GLP-1RAs administration can improve mitochondrial functions. For this purpose, preadipocytes CHUBS7 were differentiated to mature adipocytes and then stimulated with GLP-1RA, exendin-4 at 100 nM for 24 h. Oxygen consumption rates, mitochondrial membrane potential, intracellular ATP (adenosine triphosphate) level, SIRT1 and SIRT3 gene expression and the histone deacetylases' activity were measured. Exendin-4 was found to uncouple mitochondrial electron transport from ATP synthesis, slightly decreasing mitochondrial membrane potential in mature adipocytes. Routine respiration and uncoupled oxy- gen consumption rates were higher in exendin-4 treated adipocytes than in the non-treated cells. The ATP level remained unchanged. Exendin-4 enhanced SIRT1 and SIRT3 genes expression. Histone deacetylases' activity in the nuclear fraction was not affected by exendin-4, although the activity of class III histone deacetylases was increased. All of the effects on mitochondrial bioenergetics induced by exendin-4 were abolished by addition of glucagon-like peptide 1 receptor antagonist. In conclusion, exendin-4 activates the sirtuin pathway and increases energy expenditure in human adipocytes. Our results suggest another mechanism that may be responsible for body weight reduction observed in patients using GLP-1RAs.
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  • Department of Clinical Biochemistry, Medical College, Jagiellonian University, Kraków, Poland
  • Department of Clinical Biochemistry, Medical College, Jagiellonian University, Kraków, Poland
  • Department of Clinical Biochemistry, Medical College, Jagiellonian University, Kraków, Poland
  • Department of Clinical Biochemistry, Medical College, Jagiellonian University, Kraków, Poland
  • Department of Clinical Biochemistry, Medical College, Jagiellonian University, Kraków, Poland
  • Department of Clinical Biochemistry, Medical College, Jagiellonian University, Kraków, Poland
  • Department of Clinical Biochemistry, Medical College, Jagiellonian University, Kraków, Poland
  • Department of Clinical Biochemistry, Medical College, Jagiellonian University, Kraków, Poland
  • Anandhakrishnan A, Korbonits M (2016) Glucagon-like peptide 1 in the pathophysiology and pharmacotherapy of clinical obesity. World J Diabetes 7: 572-598. doi: 10.4239/wjd.v7.i20.572.
  • Beiroa D, Imbernon M, Gallego R, Senra A, Herranz D, Villarroya F, Serrano M, Fernø J, Salvador J, Escalada J, Dieguez C, Lopez M, Frühbeck G, Nogueiras R (2014) GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes 63: 3346-3358. doi: 10.2337/db14-0302.
  • Bonet ML, Oliver P, Palou A (2013) Pharmacological and nutritional agents promoting browning of white adipose tissue. Biochim Biophys Acta 1831: 969-985. doi: 10.1016/j.bbalip.2012.12.002.
  • Bricambert J, Favre D, Brajkovic S, Bonnefond A, Boutry R, Salvi R, Plaisance V, Chikri M, Chinetti-Gbaguidi G, Staels B, Giusti V, Caiazzo R, Pattou F, Waeber G, Froguel P, Abderrahmani A (2016) Impaired histone deacetylases 5 and 6 expression mimics the effects of obesity and hypoxia on adipocyte function. Mol Metab 5: 1200-1207.
  • Buteau J, El-Assaad W, Rhodes CJ, Rosenberg L, Joly E, Prentki M (2004) Glucagon-like peptide-1 prevents beta cell glucolipotoxicity. Diabetologia 47: 806-815.
  • Butler PC, Dry S, Elashoff R (2010) GLP-1-based therapy for diabetes: what you do not know can hurt you. Diabetes Care 33: 453-455. doi: 10.2337/dc09-1902.
  • Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84: 277-359.
  • Chae YN, Kim TH, Kim MK, Shin CY, Jung IH, Sohn YS, Son MH (2015) Beneficial effects of evogliptin, a novel dipeptidyl peptidase 4 inhibitor, on adiposity with increased Ppargc1a in white adipose tissue in obese mice. PLoS One 10: e0144064. doi: 10.1371/journal.pone.0144064.
  • Chalkiadaki A, Guarente L (2012) Sirtuins mediate mammalian metabolic responses to nutrient availability. Nat Rev Endocrinol 8: 287-296. doi: 10.1038/nrendo.2011.225.
  • Choung JS, Lee YS, Jun HS (2017) Exendin-4 increases oxygen consumption and thermogenic gene expression in muscle cells. J Mol Endocrinol 58: 79-90. doi: 10.1530/JME-16-0078.
  • Decara J, Arrabal S, Beiroa D, Rivera P, Vargas A, Serrano A, Pavón FJ, Ballesteros J, Dieguez C, Nogueiras R, Rodríguez de Fonseca F, Suárez J (2016) Antiobesity efficacy of GLP-1 receptor agonist liraglutide is associated with peripheral tissue-specific modulation of lipid metabolic regulators. Biofactors 42: 600-611. doi: 10.1002/biof.1295.
  • DeNicola M, Du J, Wang Z, Yano N, Zhang L, Wang Y, Qin G, Zhuang S, Zhao TC (2014) Stimulation of glucagon-like peptide-1 receptor through exendin-4 preserves myocardial performance and prevents cardiac remodeling in infarcted myocardium. Am J Physiol Endocrinol Metab 307: E630-E643. doi: 10.1152/ajpendo.00109.2014.
  • Dranka BP, Hill BG, Darley-Usmar VM (2010) Mitochondrial reserve capacity in endothelial cells: The impact of nitric oxide and reactive oxygen species. Free Radic Biol Med 48: 905-914. doi: 10.1016/j.freeradbiomed.2010.01.015.
  • Drucker DJ (2006) The biology of incretin hormones. Cell Metab 3: 153-165.
  • Drucker DJ, Sherman SI, Gorelick FS, Bergenstal RM, Sherwin RS, Buse JB (2010) Incretin-based therapies for the treatment of type 2 diabetes: evaluation of the risks and benefits. Diabetes Care 33: 428-433.
  • Dunham-Snary KJ, Sandel MW, Westbrook DG, Ballinger SW (2014) A method for assessing mitochondrial bioenergetics in whole white adipose tissues. Redox Biol 2: 656-660. doi: 10.1016/j.redox.2014.04.005.
  • Færch K, Torekov SS, Vistisen D, Johansen NB, Witte DR, Jonsson A, Pedersen O, Hansen T, Lauritzen T, Sandbæk A, Holst JJ, Jørgensen ME (2015) GLP-1 response to oral glucose is reduced in prediabetes, screen-detected type 2 diabetes, and obesity and influenced by sex: The ADDITION-PRO Study. Diabetes 64: 2513-2525. doi: 10.2337/db14-1751.
  • Feher M, Vega-Hernandez G, Mocevic E, Buysse B, Myland M, Power GS, Nystrup Husemoen LL, Kim J, Witte DR (2017) Effectiveness of liraglutide and lixisenatide in the treatment of type 2 diabetes: Real-World Evidence from The Health Improvement Network (THIN) Database in the United Kingdom. Diabetes Ther [Epub ahead of print]. doi: 10.1007/s13300-017-0241-z.
  • Fehmann HC, Habener JF (1992) Insulinotropic hormone glucagon-like peptide-I(7-37) stimulation of proinsulin gene expression and proinsulin biosynthesis in insulinoma beta TC-1 cells. Endocrinology 130: 159-166.
  • Frye RA (2000) Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun 273: 793-798.
  • Giralt A, Villarroya F (2012) SIRT3, a pivotal actor in mitochondrial functions: metabolism, cell death and aging. Biochem J 444: 1-10. doi: 10.1042/BJ20120030.
  • Heppner KM, Marks S, Holland J, Ottaway N, Smiley D, Dimarchi R, Perez-Tilve D (2015) Contribution of brown adipose tissue activity to the control of energy balance by GLP-1 receptor signalling in mice. Diabetologia 58: 2124-2132. doi: 10.1007/s00125-015-3651-3.
  • Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, Grueter CA, Harris C, Biddinger S, Ilkayeva OR, Stevens RD, Li Y, Saha AK, Ruderman NB, Bain JR, Newgard CB, Farese RV Jr, Alt FW, Kahn CR, Verdin E (2010) SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464: 121-125. doi: 10.1038/nature08778.
  • Imai S, Guarente L (2010) Ten years of NAD-dependent SIR2 family deacetylases: implications for metabolic diseases. Trends Pharmacol Sci 31: 212-220.
  • Jarmuszkiewicz W, Navet R, Alberici LC, Douette P, Sluse-Goffart CM, Sluse FE, Vercesi AE (2004) Redox state of endogenous coenzyme q modulates the inhibition of linoleic acid-induced uncoupling by guanosine triphosphatein isolated skeletal muscle mitochondria. J Bioenerg Biomembr 36: 493-502.
  • Kang MY, Oh TJ, Cho YM (2015) Glucagon-Like Peptide-1 Increases Mitochondrial Biogenesis and Function in INS-1 Rat Insulinoma Cells. Endocrinol Metab Seoul 30: 216-220. doi: 10.3803/EnM.2015.30.2.216.
  • le Roux CW, Astrup A, Fujioka K, Greenway F, Lau DC, Van Gaal L, Ortiz RV, Wilding JP, Skjøth TV, Manning LS, Pi-Sunyer, X SCALE Obesity; Prediabetes NN8022-1839 Study Group (2017) 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet 389: 1399-1409. doi: 10.1016/S0140-6736(17)30069-7. [Epub ahead of print].
  • Lee J, Hong SW, Park SE, Rhee EJ, Park CY, Oh KW, Park SW, Lee WY (2014) Exendin-4 attenuates endoplasmic reticulum stress through a SIRT1-dependent mechanism. Cell Stress Chaperones 19: 649-656. doi: 10.1007/s12192-013-0490-3.
  • Li Y, Hansotia T, Yusta B, Ris F, Halban PA, Drucker DJ (2003) Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis. J Biol Chem 278: 471-478.
  • Lockie SH, Heppner KM, Chaudhary N, Chabenne JR, Morgan DA, Veyrat-Durebex C, Ananthakrishnan G, Rohner-Jeanrenaud F, Drucker DJ, DiMarchi R, Rahmouni K, Oldfield BJ, Tschöp MH, Perez-Tilve D (2012) Direct control of brown adipose tissue thermogenesis by central nervous system glucagon-like peptide-1 receptor signaling. Diabetes 61: 2753-2762. doi: 10.2337/db11-1556.
  • Loyd C, Obici S (2014) Brown fat fuel use and regulation of energy homeostasis. Curr Opin Clin Nutr Metab Care 17: 368-372. doi: 10.1097/MCO.0000000000000063.
  • Lundkvist P, Sjöström CD, Amini S, Pereira MJ, Johnsson E, Eriksson JW (2017) Dapagliflozin once-daily and exenatide once-weekly dual therapy: A 24-week randomized, placebo-controlled, phase II study examining effects on body weight and prediabetes in obese adults without diabetes. Diabetes Obes Metab 19: 49-60. doi: 10.1111/dom.12779.
  • Majumdar ID, Weber HC (2010) Gastrointestinal regulatory peptides and their effects on fat tissue. Curr Opin Endocrinol Diabetes Obes 17: 51-56.
  • Mariani S, Di Rocco G, Toietta G, Russo MA, Petrangeli E, Salvatori L (2016) Sirtuins 1-7 expression in human adipose-derived stem cells from subcutaneous and visceral fat depots: influence of obesity and hypoxia. Endocrine [Epub ahead of print].
  • McAdam-Marx C, Nguyen H, Schauerhamer MB, Singhal M, Unni S, Ye X, Cobden D (2016) Glycemic control and weight outcomes for exenatide once weekly versus liraglutide in patients with type 2 diabetes: a 1-year retrospective cohort analysis. Clin Ther 38: 2642-2651. doi: 10.1016/j.clinthera.2016.11.003.
  • Morano S, Romagnoli E, Filardi T, Nieddu L, Mandosi E, Fallarino M, Turinese I, Dagostino MP, Lenzi A, Carnevale V (2015) Short-term effects of glucagon-like peptide 1 (GLP-1) receptor agonists on fat distribution in patients with type 2 diabetes mellitus: an ultrasonography study. Acta Diabetol 52: 727-732. doi: 10.1007/s00592-014-0710-z.
  • Mostafa AM, Hamdy NM, El-Mesallamy HO, Abdel-Rahman SZ (2015) Glucagon-like peptide 1 (GLP-1)-based therapy upregulates LXR-ABCA1/ABCG1 cascade in adipocytes. Biochem Biophys Res Commun 468: 900-905. doi: 10.1016/j.bbrc.2015.11.054.
  • Muoio DM, Newgard CB (2008) Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes. Nat Rev Mol Cell Biol 9: 193-205. doi: 10.1038/nrm2327.
  • Østergaard L, Frandsen CS, Madsbad S (2016) Treatment potential of the GLP-1 receptor agonists in type 2 diabetes mellitus: a review. Expert Rev Clin Pharmacol 9: 241-265. doi: 10.1586/17512433.2016.1121808.
  • Pastel E, Joshi S, Knight B, Liversedge N, Ward R, Kos K (2016) Effects of Exendin-4 on human adipose tissue inflammation and ECM remodelling. Nutr Diabetes 6: e235. doi: 10.1038/nutd.2016.44.
  • Sluse FE, Jarmuszkiewicz W, Navet R, Douette P, Mathy G, Sluse-Goffart CM (2006) Mitochondrial UCPs: new insights into regulation and impact. Biochim Biophys Acta 1757: 480-485.
  • Szendroedi J, Phielix E, Roden M (2011) The role of mitochondria in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol 8: 92-103 doi: 10.1038/nrendo.2011.138.
  • Takada S, Masaki Y, Kinugawa S, Matsumoto J, Furihata T, Mizushima W, Kadoguchi T, Fukushima A, Homma T, Takahashi M, Harashima S, Matsushima S, Yokota T, Tanaka S, Okita K, Tsutsui H (2016) Dipeptidyl peptidase-4 inhibitor improved exercise capacity and mitochondrial biogenesis in mice with heart failure via activation of glucagon-like peptide-1 receptor signalling. Cardiovasc Res 111: 338-347. doi: 10.1093/cvr/cvw182.
  • Tews D, Lehr S, Hartwig S, Osmers A, Paslack W, Eckel J (2009) Anti-apoptotic action of exendin-4 in INS-1 beta cells: comparative protein pattern analysis of isolated mitochondria. Horm Metab Res 41: 294-301. doi: 10.1055/s-0028-1105911.
  • Wadden TA, Hollander P, Klein S, Niswender K, Woo V, Hale PM, Aronne L; NN8022-1923 Investigators (2013) Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes Lond 37: 1443-1451. doi: 10.1038/ijo.2013.120.
  • Wang A, Li T, An P, Yan W, Zheng H, Wang B, Mu Y (2017) Exendin-4 upregulates adiponectin level in adipocytes via Sirt1/Foxo-1 signaling pathway. PLoS One 12: e0169469. doi: 10.1371/journal.pone.0169469.
  • Xu F, Lin B, Zheng X, Chen Z, Cao H, Xu H, Liang H, Weng J (2016) GLP-1 receptor agonist promotes brown remodelling in mouse white adipose tissue through SIRT1. Diabetologia 59: 1059-1069. doi: 10.1007/s00125-016-3896-5.
  • Zeng Y, Yang K, Wang F, Zhou L, Hu Y, Tang M, Zhang S, Jin S, Zhang J, Wang J, Li W, Lu L, Xu GT (2016) The glucagon like peptide 1 analogue, exendin-4, attenuates oxidative stress-induced retinal cell death in early diabetic rats through promoting Sirt1 and Sirt3 expression. Exp Eye Res 151: 203-211. doi: 10.1016/j.exer.2016.05.002.
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