Endocrine Abstracts

JOINT2732

Introduction: Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder affecting women of reproductive age. Early manifestations of the syndrome emerge before puberty, often in conjunction with obesity, which, in the presence of hyperandrogenemia and/or hyperinsulinemia during adolescence, contributes to the full manifestation of PCOS in adulthood. To elucidate the contributions of prepubertal obesity and hyperandrogenemia to the development of metabolic disturbances in PCOS, we analysed lipid and glucose metabolism in the main insulin-responsive tissues (visceral and subcutaneous adipose tissue (VAT and SAT), skeletal muscle) in a well-established PCOS animal model.

Methods: Female Wistar rats were subjected to postnatal overfeeding via litter size reduction and treated with 5α-dihydrotestosterone (DHT) to induce PCOS-like features. Systemic insulin sensitivity was assessed alongside the expression of key markers of glucose and lipid metabolism, and energy sensing, like AMPK activation, in VAT, SAT, and skeletal muscle.

Results: Litter size reduction led to increase in body mass and visceral adiposity, while DHT treatment combined with overfeeding resulted in systemic insulin resistance and hyperinsulinemia. In VAT, both litter size reduction and DHT treatment contributed to adipocyte hypertrophy, along with a suppression of de novo lipogenesis (reduced gene expression of lipogenic enzymes) and lipolysis (decreased hormone-sensitive lipase), while insulin sensitivity was preserved due to AMPK activation. Conversely, SAT exhibited increased expression of lipogenic and lipolytic markers and reduced AMPK activity, suggesting an impaired metabolic profile in this tissue as a result of effect of both factors, litter size reduction and DHT treatment. In skeletal muscle, insulin signalling was disrupted at key nodes (pIRS1-Ser307, AKT) in overfed animals, while DHT treatment reduced glucose transport (decreased GLUT4 expression), leading to diminished glucose uptake and systemic hyperinsulinemia. In this altered energy landscape, as result of effects of both factors, skeletal muscle preferentially utilised fatty acids for energy, indicated by enhanced fatty acid uptake and increased markers of lipolysis and α-oxidation. However, this shift induced oxidative stress and inflammation, and triggered AMPK activation as a compensatory mechanism that maintain metabolic homeostasis.

Conclusion: AMPK emerges as a critical metabolic regulator that acts as a protective mechanism in VAT and skeletal muscle to counteract metabolic stress and maintain tissue functionality. The differential regulation of AMPK in VAT and SAT highlights its tissue-specific role in PCOS-associated metabolic disturbances. Given its pivotal function, targeted activation of AMPK may represent a promising therapeutic strategy to improve metabolic health in women with PCOS.