Benefits of administering GLP-1 analogs to patients with polycystic ovary syndrome, considering their effect on adipose tissue metabolism

Małgorzata Król, Justyna Żychowska, Ryszard Łagowski, Patrycja Kupnicka, Donata Simińska, Dariusz Chlubek


Mammals have 2 primary types of adipose tissue: brown adipose tissue (BAT) and white adipose tissue (WAT). White adipose tissue, one of the largest organs, spans the entire body and persists throughout an individual’s life, with the highest concentrations found in the abdominal cavity or subcutaneously. In obese individuals, the amount of WAT can reach up to 70% of total body weight. Today, glucagon-like peptide-1 (GLP-1) analogs have gained popularity in the treatment of obesity, insulin resistance, and related metabolic disorders. Patients using glucagon-like peptide-1 receptor agonists (GLP-1RAs) have improved lipid profiles, reduced visceral fat accumulation, and improved glucose tolerance. Polycystic ovarian syndrome (PCOS) is a disorder strongly associated with insulin resistance and obesity. It is the most common heterogeneous endocrine disorder, affecting an estimated 1 in 5 women of reproductive age. The introduction of GLP-1 analog treatment in women with PCOS could help to manage the disease, improve the quality of life of PCOS patients, increase their chances of conception, and maintain pregnancy until delivery. This review presents the latest reports on the use of GLP-1RAs and the treatment of PCOS.


glucagon-like peptide-1 agonists; adipose tissue; obesity; polycystic ovary syndrome

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Rosenwald M, Wolfrum C. The origin and definition of brite versus white and classical brown adipocytes. Adipocyte 2014;3(1):4-9.

Loyd C, Obici S. Brown fat fuel use and regulation of energy homeostasis. Curr Opin Clin Nutr Metab Care 2014;17(4):368-72.

Neumann E, Junker S, Schett G, Frommer K, Müller-Ladner U. Adipokines in bone disease. Nat Rev Rheumatol 2016;12(5):296-302.

Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev Immunol 2011;11(2):85-97.

Rosen ED, Spiegelman BM. What we talk about when we talk about fat. Cell 2014;156(1-2):20-44.

Shen W, Wang Z, Punyanita M, Lei J, Sinav A, Kral JG, et al. Adipose tissue quantification by imaging methods: a proposed classification. Obes Res 2003;11(1):5-16.

Aherne W, Hull D. Brown adipose tissue and heat production in the newborn infant. J Pathol Bacteriol 1966;91(1):223-34.

Heaton JM. The distribution of brown adipose tissue in the human. J Anat 1972;112(Pt 1):35-9.

Hocking S, Samocha-Bonet D, Milner KL, Greenfield JR, Chisholm DJ. Adiposity and insulin resistance in humans: the role of the different tissue and cellular lipid depots. Endocr Rev 2013;34(4):463-500.

Longo M, Zatterale F, Naderi J, Parrillo L, Formisano P, Raciti GA, et al. Adipose tissue dysfunction as determinant of obesity-associated met-abolic complications. Int J Mol Sci 2019;20(9):2358.

Kawai T, Autieri MV, Scalia R. Adipose tissue inflammation and metabolic dysfunction in obesity. Am J Physiol Cell Physiol 2021;320(3):C375-91.

Rohm TV, Meier DT, Olefsky JM, Donath MY. Inflammation in obesity, diabetes, and related disorders. Immunity 2022;55(1):31-55.

Hall JE, do Carmo JM, da Silva AA, Wang Z, Hall ME. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ Res 2015;116(6):991-1006.

Van Gaal LF, Mertens IL, De Block CE. Mechanisms linking obesity with cardiovascular disease. Nature 2006;444(7121):875-80.

Muls E, Kolanowski J, Scheen A, Van Gaal L. The effects of orlistat on weight and on serum lipids in obese patients with hypercholesterole-mia: a randomized, double-blind, placebo-controlled, multicentre study. Int J Obes Relat Metab Disord 2001;25(11):1713-21.

Vettor R, Serra R, Fabris R, Pagano C, Federspil G. Effect of sibutramine on weight management and metabolic control in type 2 diabetes: a meta-analysis of clinical studies. Diabetes Care 2005;28(4):942-9.

Singh J, Kumar R. Phentermine-topiramate: First combination drug for obesity. Int J Appl Basic Med Res 2015;5(2):157-8.

Apovian CM, Aronne L, Rubino D, Still C, Wyatt H, Burns C, et al. A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk Factors (COR-II). Obesity (Silver Spring) 2013;21(5):935.

Gołacki J, Matuszek M, Matyjaszek-Matuszek B. Link between insulin resistance and obesity-from diagnosis to treatment. Diagnostics (Ba-sel) 2022;12(7):1681.

Trzaskalski NA, Fadzeyeva E, Mulvihill EE. Dipeptidyl peptidase-4 at the interface between inflammation and metabolism. Clin Med In-sights Endocrinol Diabetes 2020;13:1179551420912972.

Ustinova M, Ansone L, Silamikelis I, Rovite V, Elbere I, Silamikele L, et al. Whole-blood transcriptome profiling reveals signatures of metfor-min and its therapeutic response. PLoS One 2020;15(8): e0237400.

Chen X, Huang L, Cui L, Xiao Z, Xiong X, Chen C. Sodium-glucose cotransporter 2 inhibitor ameliorates high fat diet-induced hypothalamic-pituitary-ovarian axis disorders. J Physiol 2022;600(21):4549-68.

Nanjan MJ, Mohammed M, Prashantha Kumar BR, Chandrasekar MJN. Thiazolidinediones as antidiabetic agents: A critical review. Bioorg Chem 2018;77:548-67.

Thornberry NA, Gallwitz B. Mechanism of action of inhibitors of dipeptidyl-peptidase-4 (DPP-4). Best Pract Res Clin Endocrinol Metab 2009;23(4):479-86.

Vendrell J, El Bekay R, Peral B, García-Fuentes E, Megia A, Macias-Gonzalez M, et al. Study of the potential association of adipose tissue GLP-1 receptor with obesity and insulin resistance. Endocrinology 2011;152(11):4072-9.

Wang Y, Kole HK, Montrose-Rafizadeh C, Perfetti R, Bernier M, Egan JM. Regulation of glucose transporters and hexose uptake in 3T3-L1 adipocytes: glucagon-like peptide-1 and insulin interactions. J Mol Endocrinol 1997;19(3):241-8.

Sancho V, Trigo MV, González N, Valverde I, Malaisse WJ, Villanueva-Peñacarrillo ML. Effects of glucagon-like peptide-1 and exendins on kinase activity, glucose transport and lipid metabolism in adipocytes from normal and type-2 diabetic rats. J Mol Endocrinol 2005;35(1):27-38.

Han SH, Safeek R, Ockerman K, Trieu N, Mars P, Klenke A, et al. Public interest in the off-label use of glucagon-like peptide 1 agonists (Ozempic) for cosmetic weight loss: a google trends analysis. Aesthet Surg J 2023:sjad211.

Łabuzek K, Kozłowski M, Szkudłapski D, Sikorska P, Kozłowska M, Okopień B. Incretin-based therapies in the treatment of type 2 diabetes – more than meets the eye? Eur J Intern Med 2013;24(3):207-12.

Yoshida Y, Joshi P, Barri S, Wang J, Corder AL, O’Connell SS, et al. Progression of retinopathy with glucagon-like peptide-1 receptor agonists with cardiovascular benefits in type 2 diabetes – A systematic review and meta-analysis. J Diabetes Complications 2022;36(8):108255.

Del Prato S, Kahn SE, Pavo I, Weerakkody GJ, Yang Z, Doupis J, et al. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet 2021;398(10313):1811-24.

Drucker DJ, Habener JF, Holst JJ. Discovery, characterization, and clinical development of the glucagon-like peptides. J Clin Invest 2017;127(12):4217-27.

Williams EK, Chang RB, Strochlic DE, Umans BD, Lowell BB, Liberles SD. Sensory neurons that detect stretch and nutrients in the digestive system. Cell 2016;166(1):209-21.

Koliaki C, Doupis J. Incretin-based therapy: a powerful and promising weapon in the treatment of type 2 diabetes mellitus. Diabetes Ther 2011;2(2):101-21.

Knudsen LB, Lau J. The discovery and development of liraglutide and semaglutide. Front Endocrinol (Lausanne) 2019;10:155.

Baggio LL, Yusta B, Mulvihill EE, Cao X, Streutker CJ, Butany J, et al. GLP-1 receptor expression within the human heart. Endocrinology 2018;159(4):1570-84.

MacLusky NJ, Cook S, Scrocchi L, Shin J, Kim J, Vaccarino F, et al. Neuroendocrine function and response to stress in mice with complete dis-ruption of glucagon-like peptide-1 receptor signaling. Endocrinology 2000;141(2):752-62.

Toft-Nielsen MB, Damholt MB, Madsbad S, Hilsted LM, Hughes TE, Michelsen BK, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab 2001;86(8):3717-23.

Meier JJ. Treatment of type 2 diabetes. Internist (Berl) 2016;57(2):153-65.

Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 2012;8(12):728-42.

Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art. Mol Metab 2021;46:101102.

Pedrosa MR, Franco DR, Gieremek HW, Vidal CM, Bronzeri F, de Cassia Rocha A, et al. GLP-1 agonist to treat obesity and prevent cardiovas-cular disease: what have we achieved so far? Curr Atheroscler Rep 2022;24(11):867-84.

Kadouh H, Chedid V, Halawi H, Burton DD, Clark MM, Khemani D, et al. GLP-1 analog modulates appetite, taste preference, gut hormones, and regional body fat stores in adults with obesity. J Clin Endocrinol Metab 2020;105(5):1552-63.

Berg G, Barchuk M, Lobo M, Nogueira JP. Effect of glucagon-like peptide-1 (GLP-1) analogues on epicardial adipose tissue: A meta-analysis. Diabetes Metab Syndr 2022;16(7):102562.

Rodrigues T, Borges P, Mar L, Marques D, Albano M, Eickhoff H, et al. GLP-1 improves adipose tissue glyoxalase activity and capillarization improving insulin sensitivity in type 2 diabetes. Pharmacol Res 2020;161:105198.

Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med 2022;387(3):205-16.

Thomas MK, Nikooienejad A, Bray R, Cui X, Wilson J, Duffin K, et al. Dual GIP and GLP-1 receptor agonist tirzepatide improves beta-cell function and insulin sensitivity in type 2 diabetes. J Clin Endocrinol Metab 2021;106(2):388-96.

Rosenstock J, Wysham C, Frías JP, Kaneko S, Lee CJ, Fernández Landó L, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor ago-nist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet 2021;398(10295):143-55.

Holeček M. Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements. Nutr Metab (Lond) 2018;15:33.

White PJ, McGarrah RW, Herman MA, Bain JR, Shah SH, Newgard CB. Insulin action, type 2 diabetes, and branched-chain amino acids: A two-way street. Mol Metab 2021;52:101261.

Samms RJ, Zhang G, He W, Ilkayeva O, Droz BA, Bauer SM, et al. Tirzepatide induces a thermogenic-like amino acid signature in brown adi-pose tissue. Mol Metab 2022;64:101550.

Martins FF, Marinho TS, Cardoso LEM, Barbosa-da-Silva S, Souza-Mello V, Aguila MB, et al. Semaglutide (GLP-1 receptor agonist) stimulates browning on subcutaneous fat adipocytes and mitigates inflammation and endoplasmic reticulum stress in visceral fat adipocytes of obese mice. Cell Biochem Funct 2022;40(8):903-13.

Zhu R, Chen S. Proteomic analysis reveals semaglutide impacts lipogenic protein expression in epididymal adipose tissue of obese mice. Front Endocrinol (Lausanne) 2023;14:1095432.

Yoon HS, Cho CH, Yun MS, Jang SJ, You HJ, Kim JH, et al. Akkermansia muciniphila secretes a glucagon-like peptide-1-inducing protein that improves glucose homeostasis and ameliorates metabolic disease in mice. Nat Microbiol 2021;6(5):563-73.

Chakrabarti P, English T, Karki S, Qiang L, Tao R, Kim J, et al. SIRT1 controls lipolysis in adipocytes via FOXO1-mediated expression of ATGL. J Lipid Res 2011;52(9):1693-701.

Xu F, Lin B, Zheng X, Chen Z, Cao H, Xu H, et al. GLP-1 receptor agonist promotes brown remodelling in mouse white adipose tissue through SIRT1. Diabetologia 2016;59(5):1059-69.

Laisk-Podar T, Lindgren CM, Peters M, Tapanainen JS, Lambalk CB, Salumets A, et al. Ovarian physiology and GWAS: biobanks, biology, and beyond. Trends Endocrinol Metab 2016;27(7):516-28.

Lew R. Natural history of ovarian function including assessment of ovarian reserve and premature ovarian failure. Best Pract Res Clin Ob-stet Gynaecol 2019;55:2-13.

Munoz E, Bosch E, Fernandez I, Portela S, Ortiz G, Remohi J, et al. The role of LH in ovarian stimulation. Curr Pharm Biotechnol 2012;13(3):409-16.

March WA, Moore VM, Willson KJ, Phillips DIW, Norman RJ, Davies MJ. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod 2010;25(2):544-51.

Teede H, Deeks A, Moran L. Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan. BMC Med 2010;8:41.

Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004;19(1):41-7.

Ajmal N, Khan SZ, Shaikh R. Polycystic ovary syndrome (PCOS) and genetic predisposition: A review article. Eur J Obstet Gynecol Reprod Biol X 2019;3:100060.

Escobar-Morreale HF. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol 2018;14(5):270-84.

Diamanti-Kandarakis E. Insulin resistance in PCOS. Endocrine 2006;30(1):13-7.

Carmina E, Oberfield SE, Lobo RA. The diagnosis of polycystic ovary syndrome in adolescents. Am J Obstet Gynecol 2010;203(3):201.e1-5.

Lim SS, Davies MJ, Norman RJ, Moran LJ. Overweight, obesity and central obesity in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 2012;18(6):618-37.

Zore T, Joshi NV, Lizneva D, Azziz R. Polycystic ovarian syndrome: long-term health consequences. Semin Reprod Med 2017;35(3):271-81.

Somagutta MR, Jain M, Uday U, Pendyala SK, Mahadevaiah A, Mahmutaj G, et al. Novel antidiabetic medications in polycystic ovary syn-drome. Discov (Craiova) 2022;10(1):e145.

Wu LM, Wang YX, Zhan Y, Liu AH, Wang YX, Shen HF, et al. Dulaglutide, a long-acting GLP-1 receptor agonist, can improve hyperandro-genemia and ovarian function in DHEA-induced PCOS rats. Peptides 2021;145:170624.

Sun L, Ji C, Jin L, Bi Y, Feng W, Li P, et al. Effects of exenatide on metabolic changes, sexual hormones, inflammatory cytokines, adipokines, and weight change in a DHEA-treated rat model. Reprod Sci 2016;23(9):1242-9.

Xing C, Lv B, Zhao H, Wang D, Li X, He B. Metformin and exenatide upregulate hepatocyte nuclear factor-4α, sex hormone binding globulin levels and improve hepatic triglyceride deposition in polycystic ovary syndrome with insulin resistance rats. J Steroid Biochem Mol Biol 2021;214:105992.

Singh A, Fernandes JRD, Chhabra G, Krishna A, Banerjee A. Liraglutide modulates adipokine expression during adipogenesis, ameliorating obesity, and polycystic ovary syndrome in mice. Endocrine 2019;64(2):349-66.

Hoang V, Bi J, Mohankumar SM, Vyas AK. Liraglutide improves hypertension and metabolic perturbation in a rat model of polycystic ovari-an syndrome. PLoS One 2015;10(5):e0126119.

Jensterle Sever M, Kocjan T, Pfeifer M, Kravos NA, Janez A. Short-term combined treatment with liraglutide and metformin leads to signifi-cant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin. Eur J Endocrinol 2014;170(3):451-9.

Jensterle M, Goricar K, Janez A. Metformin as an initial adjunct to low-dose liraglutide enhances the weight-decreasing potential of lirag-lutide in obese polycystic ovary syndrome: Randomized control study. Exp Ther Med 2016;11(4):1194-200.

Jensterle M, Kravos NA, Goričar K, Janez A. Short-term effectiveness of low dose liraglutide in combination with metformin versus high dose liraglutide alone in treatment of obese PCOS: randomized trial. BMC Endocr Disord 2017;17(1):5.

Salamun V, Jensterle M, Janez A, Vrtacnik Bokal E. Liraglutide increases IVF pregnancy rates in obese PCOS women with poor response to first-line reproductive treatments: a pilot randomized study. Eur J Endocrinol 2018;179(1):1-11.

Elkind-Hirsch K, Marrioneaux O, Bhushan M, Vernor D, Bhushan R. Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab 2008;93(7):2670-8.

Tao T, Zhang Y, Zhu YC, Fu JR, Wang YY, Cai J, et al. Exenatide, metformin, or both for prediabetes in PCOS: A randomized, open-label, par-allel-group controlled study. J Clin Endocrinol Metab 2021;106(3):E1420-32.

Jensterle M, Ferjan S, Vovk A, Battelino T, Rizzo M, Janež A. Semaglutide reduces fat accumulation in the tongue: A randomized single-blind, pilot study. Diabetes Res Clin Pract 2021;178:108935.

Elkind-Hirsch KE, Chappell N, Seidemann E, Storment J, Bellanger D. Exenatide, dapagliflozin, or phentermine/topiramate differentially affect metabolic profiles in polycystic ovary syndrome. J Clin Endocrinol Metab 2021;106(10):3019-33.

Kahal H, Aburima A, Ungvari T, Rigby AS, Coady AM, Vince RV, et al. The effects of treatment with liraglutide on atherothrombotic risk in obese young women with polycystic ovary syndrome and controls. BMC Endocr Disord 2015;15:14.

Frøssing S, Nylander M, Chabanova E, Frystyk J, Holst JJ, Kistorp C, et al. Effect of liraglutide on ectopic fat in polycystic ovary syndrome: A randomized clinical trial. Diabetes Obes Metab 2018;20(1):215-8.

Nylander M, Frøssing S, Clausen HV, Kistorp C, Faber J, Skouby SO. Effects of liraglutide on ovarian dysfunction in polycystic ovary syn-drome: a randomized clinical trial. Reprod Biomed Online 2017;35(1):121-7.

Liu X, Zhang Y, Zheng SY, Lin R, Xie YJ, Chen H, et al. Efficacy of exenatide on weight loss, metabolic parameters and pregnancy in over-weight/obese polycystic ovary syndrome. Clin Endocrinol (Oxf) 2017;87(6):767-74.

Elkind-Hirsch KC, Chappell N, Shaler D, Storment J, Bellanger D. A randomized, double-blind, placebo-controlled study of liraglutide 3 mg [LIRA 3 mg] on weight, body composition, hormonal and metabolic parameters in women with obesity and polycystic ovary syndrome (PCOS). Res Sq 2021. doi: 10.21203/


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