Adiponectin Receptor Agonist AdipoRon Ameliorates the Metabolic Complications in a Hyperandrogenic Rat Model of PCOS

Abstract Polycystic ovary syndrome (PCOS) is associated with a high prevalence of insulin resistance (IR) and obesity. Adiponectin, an insulin-sensitizing hormone, is reduced in PCOS and inversely correlated with IR and obesity. This study tested whether androgens reduce adiponectin, and if the adiponectin receptor agonist AdipoRon improves IR and obesity in a PCOS model. Four-week-old female Sprague Dawley rats were implanted with dihydrotestosterone (DHT) or control Silastic tubes for 12 weeks. After six weeks of DHT treatment, rats received AdipoRon or vehicle in their food for six weeks. DHT increased body weight, fat and lean mass, food intake, serum leptin, adipose mitochondrial oxidative stress, inflammatory markers, HOMA-IR, adipocyte size, and decreased serum adiponectin levels. DHT upregulated GLUT4, PPARγ, and adiponectin mRNA expression in subcutaneous adipose tissue (SAT), while PPARγ was downregulated in visceral adipose tissue (VAT). DHT also reduced Akt protein expression in SAT and p(S473)-Akt phosphorylation in VAT, and caused a depot-specific effect on androgen receptor expression. AdipoRon reduced body weight, fat, and lean mass, food intake, serum leptin, adipocyte size, and IR markers in DHT-treated rats. AdipoRon upregulated Akt, AMPK, and AdipoR1 mRNA expression in SAT and increased p(S473)-Akt phosphorylation in both WAT depots. AdipoRon also reduced mitochondrial oxidative stress in both WAT depots and decreased AR expression in VAT. AdipoRon attenuates hyperandrogenemia-induced adiposity and IR in a PCOS model by improving adipose insulin and adiponectin signaling, reducing mitochondrial oxidative stress and food intake, supporting its therapeutic potential in managing IR and obesity in PCOS women.