Orosomucoid 2 improves reproductive phenotypes in a mouse model of PCOS induced by letrozole under high-fat diet conditions

Polycystic ovary syndrome (PCOS) is the most common reproductive endocrine disorder among women of reproductive age. It is characterized by excess androgens, anovulation, and polycystic ovarian morphology, and is often accompanied by obesity, insulin resistance, and glucose metabolism abnormalities. Although PCOS is a complex disease with diverse and uncertain etiologies, metabolic dysfunction and adipose tissue abnormalities are critical components in its pathology. Previous studies have demonstrated that letrozole exposure combined with high-fat diet treatment in female mice produced key endocrine and metabolic features of PCOS, including elevated testosterone levels, anovulation, and adipocyte hypertrophy. Orosomucoid 2 (ORM2), an acute-phase protein predominantly secreted by hepatocytes, plays a regulatory role in metabolic balance and gut microbiota composition. This study aimed to investigate the effects of ORM2 levels on the metabolic and endocrine dysregulations associated with letrozole-induced PCOS in female mice. We established a letrozole-induced PCOS by treating mice with Let+HFD (letrozole and high-fat diet) for 5 weeks. Our findings revealed that compared to control females receiving placebo and high-fat diet treatment, females treated with Let+HFD exhibited significantly reduced hepatic Orm2 expression. Furthermore, Orm2 knockout mice subjected to Let+HFD treatment developed more severe ovarian pathology, higher testosterone levels, hepatocyte hypertrophy, and reduced Ucp1 expression in white adipose tissue compared to wild-type mice. Conversely, supplementation with recombinant ORM2 protein in females under Let+HFD treatment resulted in improved ovarian morphology, reduced hepatocyte cell size, and enhanced Ucp1 expression in white adipose tissue. Overall, this research identifies ORM2 as a promising therapeutic target for PCOS treatment.