Molecular Mechanisms of Insulin Signaling in Insulin-Target Tissues 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 strongly associated with insulin resistance (IR), which leads to a range of PCOS-associated cardiometabolic complications, such as obesity and type 2 diabetes. Glucose transporter type 4 (GLUT4) is a crucial glucose transporter that facilitates insulin-stimulated glucose uptake in white adipose tissue and muscle. Impaired GLUT4 translocation or expression is a hallmark of insulin resistance. In this study, we investigated the effects of the adiponectin receptor agonist AdipoRon, an insulin-sensitizing agent, on cardiometabolic dysfunction and insulin signaling in a PCOS model. Hypothesis: We tested the hypothesis that AdipoRon attenuates metabolic complications via modifications in GLUT4 expression in insulin target tissues in a PCOS model. 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=7-12/group). During the final six weeks of DHT treatment, rats received AdipoRon (50 mg/kg/day) orally in food. Fat and lean mass were determined by Echo-MRI. Food intake was measured weekly. Fasting serum insulin, leptin, and adiponectin were measured by ELISA. Retroperitoneal fat (RPF), subcutaneous fat (SCF), and soleus muscle (SM) ADIPOQ (adiponectin) and SLC2A4 (GLUT4) mRNAs were quantified by digital PCR. Results: DHT significantly (p<0.05) increased BW (315.38 ± 4.02 vs 241.67 ± 3.05 g), fat mass (14.80 ± 0.99 vs 10.94 ± 0.80 g), lean mass (289.91 ± 4.04 vs 222.07 ± 2.80 g), and cumulative food intake (24.26 %) compared to PBO group. DHT significantly increased fasting serum insulin and leptin by 21.41% and 23.90%, respectively, while decreasing fasting serum adiponectin by 27.92% compared to the PBO group. DHT had no impact on ADIPOQ and GLUT4 mRNAs expression in RPF and SM while upregulating SCF ADIPOQ and GLUT4 mRNAs expression by 3.07- and 2.13- fold respectively, compared to the PBO group. AdipoRon significantly decreased BW, fat and lean mass, and cumulative food intake. AdipoRon significantly decreased fasting serum insulin and leptin levels by 26.63% and 47.52% respectively, with no impact on adiponectin levels in PCOS rats. Interestingly, AdipoRon significantly (p<0.05) downregulated SCF GLUT4 mRNA expression by 44.40% with no impact on ADIPOQ compared to the vehicle-treated group. AdipoRon had no effect on the mRNA expression of both genes in RPF and SM in PCOS rats. Conclusion: Obesity and decreased circulating adiponectin levels are present in the PCOS model. The upregulation of the GLUT4 mRNA expression in SCF in PCOS rats may indicate different insulin sensitivity in the different insulin target tissues in the PCOS model. On the other hand, activating adiponectin receptors with AdipoRon attenuated PCOS-associated obesity and hyperinsulinemia. Significance: Targeting adiponectin signaling could be a novel and effective therapeutic approach to mitigate metabolic dysfunction in women with PCOS. Supported by NIH grants R01HL171494 (LLYC), P50MD017338 (LLYC), R01HL144847 (DGR), P20GM121334 (DGR), P20GM104357, and P01HL51971, AHA fellowship 24PRE1198302 (AA). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.