High-fat diet–induced obesity is associated with hyperinsulinemia and ovarian lipid remodeling without overt inflammation

Obesity is characterized by a chronic low-grade pro-inflammatory state that contributes to the development of multiple comorbidities, including type 2 diabetes, dyslipidemia, non-alcoholic fatty liver disease, and asthma. However, the contribution of this inflammatory milieu to the pathophysiology of polyendocrine metabolic ovarian syndrome (PCOS) remains poorly defined. Here, we investigated whether a high-fat (HF) diet induces PCOS-like features in an obesity-prone mouse model. Female Swiss mice were fed an HF diet for 16 weeks and compared with lean controls (CT) receiving a standard diet. Metabolic parameters, estrous cyclicity, and ovarian molecular and histological features were assessed using RT-qPCR, Western blotting, mass spectrometry, and histological analysis. HF feeding increased food intake, body weight, and perigonadal adipose tissue compared with CT animals. Obese females maintained normal glucose levels and insulin sensitivity, accompanied by compensatory hyperinsulinemia. The total number of ovarian follicles was not altered, although estrous cyclicity was disrupted in HF-fed mice. High-resolution mass spectrometry revealed subtle but consistent changes in the ovarian fatty acid profile, with increased levels of C17:1, C18:0, C20:1, and C20:2 species. Despite these lipidomic alterations, the expression of inflammatory genes and proteins, as well as inflammasome-related components, remained unchanged. Together, these findings indicate that, in obesity-prone Swiss mice, HF diet–induced reproductive dysfunction is primarily associated with hyperinsulinemia-driven metabolic dysregulation rather than with ovarian low-grade inflammation.