Role of Adiponectin in the Androgen-Mediated Cardiometabolic Complications in a Rat Model of Polycystic Ovary Syndrome

Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women and is associated with a high prevalence of obesity, adipose insulin resistance (adipose IR), and insulin resistance (IR). Adipose IR is an early metabolic defect in the development of whole-body IR. Specific evaluation of adipose IR and its consequences on the whole-body metabolic state in women with PCOS has not been thoroughly investigated. Adiponectin is a peptide secreted by adipocytes that increases insulin sensitivity. PEG-BHD1028 is a novel potent peptide adiponectin receptor agonist. Despite that PEG-BHD1028 modulates insulin sensitivity in different models of diabetes, the potential of PEG-BHD1028 to attenuate androgen-mediated adipose IR and obesity remains unknown. Hypothesis: We tested the hypothesis that PEG-BHD1028 attenuates adipose IR and obesity in a rat model of PCOS. Methods: To induce PCOS, four-week-old female Sprague Dawley rats were implanted with dihydrotestosterone (DHT) silastic tubes (7.5 mg) or placebo (PBO) for 90 days (n=4-8/group). During the final three weeks of DHT treatment, rats received PEG-BHD1028 (25 μg/kg/day) subcutaneously. Body weight (BW) by gravimetry, fat and lean mass were measured by Echo-MRI. Fasting plasma insulin was measured by ELISA. Fasting plasma glucose and non-esterified fatty acids (NEFA) were measured with a clinical chemistry analyzer. HOMA-IR, an index of systemic IR, and adipose IR (fasting insulin x fasting NEFA) were calculated. Protein levels of insulin signaling markers including IRS1, p-IRS1 (Ser1101), PI3 kinase p110, Akt, p-Akt (SER473), GLUT4, mTOR, p-mTOR (Ser2481) were quantified in the retroperitoneal fat by Western-blot. Results: DHT significantly (p<0.05) increased BW (352.67± 6.93 vs 250.88 ± 5.26 g), fat mass (20.82 ± 1.48 vs 9.44 ± 1.81 g), and lean mass (316.92 ± 4.15 vs 224.45 ± 4.79 g), compared to PBO group. DHT significantly (p<0.05) increased HOMA-IR and adipose IR by 75% and 80%, respectively, compared to PBO group. DHT downregulated retroperitoneal fat p-IRS-1, IRS-1, p-mTOR, mTOR, GLUT4, PI3 kinase and Akt protein expression by 50% to 70% while upregulating p-Akt by 1.8- fold compared to the PBO group. PEG-BHD1028 significantly decreased BW, fat mass and lean mass while attenuating IR by 34.7% reduction in HOMA-IR and significantly (p<0.05) decreased adipose IR by 51.6% in PCOS rats. Interestingly, PEG-BHD1028 significantly (p<0.05) upregulated p-IRS-1, IRS-1, p-mTOR, mTOR and p-AKT levels by 2.6-, 3-, 2.2-, 4-, 2.6- fold, respectively with no impact on the other insulin signaling markers compared to vehicle-treated group. Conclusion: PCOS rats exhibit obesity and lower adiponectin levels that are associated with both adipose and whole-body insulin resistance. Activating adiponectin receptors with PEG-BHD1028 attenuated PCOS-associated obesity and adipose IR. Significance: Targeting adiponectin signaling could be a novel and effective therapeutic approach to mitigate metabolic dysfunction in females with excess androgens. Supported by NIH-NIGMS grant P20GM121334 (L.L.Y.C. and D.G.R.), NIH-NIGMS grant P20GM121334, P20GM104357, NIH-NHLBI grant P01HL51971, NIH-NIMHD-P50MD017338 and University of Mississippi Medical Center Medical Student Research Program (R.C.) and the Robert M. Hearin Foundation (R.C.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.