Metabolic Syndrome and the Role of GLP‐1 Receptor Agonists in a Model of Postmenopausal PCOS

Abstract

IntroductionPolycystic Ovary Syndrome (PCOS), the most common endocrine disorder in women, is characterized by androgen excess and ovarian dysfunction. PCOS is often associated with components of metabolic syndrome (MS) such as visceral obesity, dyslipidemia, insulin resistance (IR) and increased blood pressure (BP). Liraglutide, a glucagon‐like peptide‐1 receptor agonist (GLP‐1RA), has been found to cause weight loss in several small clinical trials on young women with PCOS. Moreover, it has been reported that Liraglutide decreases IR and BP in reproductive age‐PCOS rats. Postmenopausal women who have had PCOS and chronic androgen excess may be at a greater risk for MS and cardiovascular disease than normo‐androgenemic postmenopausal women. We have previously characterized a rat model of chronic androgen excess that resembles many components of MS in postmenopausal PCOS women: increased body weight, fat mass, dyslipidemia, IR and BP. In the present study, we tested the hypothesis that Liraglutide administration improves the MS found in the rat model of postmenopausal PCOS.MethodsFemale Sprague Dawley rats, 4 week‐old, were randomized to chronically receive DHT (dihydrotestosterone, 7.5 mg/90 days) or placebo (n=18/group). At 17 months of age, postmenopausal PCOS and aged‐matched placebo rats were randomized to receive liraglutide (0.3 mg/kg/day) or vehicle subcutaneously for 3 weeks. During liraglutide treatment, food intake, body weight and mean arterial blood pressure (MAP), measured by radiotelemetry, were recorded. Before and after liraglutide treatment body composition (by Echo‐MRI) and insulin resistance (using HOMA‐IR index) were measured. At the end of the study, circulating insulin, leptin, cholesterol and triglycerides levels were quantified.ResultsPostmenopausal PCOS rats exhibit significantly higher food intake, body weight, fat mass, total cholesterol, triglycerides, leptin and MAP compared to aged‐matched placebo. After 3 weeks of treatment, liraglutide caused significant greater reduction in cumulative food intake (−65.7 ± 9.6 vs −46 ± 10 g, p<0.01), body weight (−38.4 ± 4.7 vs −28.8 ± 2.4 g, p<0.05), fat mass/body weight (−7.7 ± 0.6 vs −4.8 ± 0.7, p<0.01), HOMA‐IR index (−4.5 ± 0.6 vs −1.4 ± 1.1, p<0.05), leptin, cholesterol, and triglycerides levels in postmenopausal PCOS compared to aged‐matched placebo. In contrast, liraglutide decreased MAP in aged‐matched placebo (108 ± 1 vs 101 ± 1 mmHg, p<0.0001), however, did not lowered MAP in postmenopausal PCOS (123 ± 2 vs 126 ± 3 mmHg, p=0.56). In summary, the GLP‐1 receptor agonist liraglutide exhibit beneficial effects in several components of the MS: body weight, cumulative food intake, fat mass/body weight, HOMA‐IR index, leptin, cholesterol and triglycerides levels found in the rat model postmenopausal PCOS. In contrast, liraglutide treatment failed to lower MAP in postmenopausal PCOS. Liraglutide treatment is a promising therapeutic agent to treat obesity and dyslipidemia in postmenopausal PCOS; however, these women will need additional treatments to maintain their MAP under control.Support or Funding InformationAmerican Heart Association Grants 0830239N (L.L.Y.C.) and 12SDG8980032 (D.G.R.), Endocrine Fellows Foundation Endocrine Research Grant (L.L.Y.C.), and National Institutes of Health grants R21 DK‐113500 (D.G.R.), and P20 GM‐121334 (L.L.Y.C.)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.