Sex-differences in improving metabolic disorders by changing lifestyles

Understanding how exercise training or a healthy diet improves metabolic outcomes is crucial to developing therapeutic targets for obesity-associated diseases. In this study, obesity was induced by a 12-week high-fat diet (HFD) feeding in male and female mice. Then, mice of each sex were divided into 3 groups of lifestyle interventions that followed for 6 weeks: a. HFD; b. chow diet; c. HFD+exercise; d. chow diet +exercise. Age-matched mice continuously fed a chow diet served as controls. An oral glucose tolerance test was performed 48 hours after the final exercise session. HFD increased body weight, fasting blood triacylglycerol (TG) and insulin levels only in male mice, while increased body fat composition, fasting glucose and cholesterol, hepatic steatosis, and impaired glucose tolerance in both sexes. Glucose tolerance was improved in both sexes by all three interventions: the chow diet, exercise training, or the combination of both. However, sex differences were presented in improving certain pathways in the liver or skeletal muscle tissues in response to the chow diet or exercise training. Furthermore, the chow diet reduced body fat composition, hepatic steatosis, and fasting cholesterol in both sexes. Exercise training reduced body fat and fasting lipid levels only in male mice and appeared more beneficial to males than females in improving glucose metabolism. Regarding HDL functions, exercise training improved the antioxidant activity of HDL particles in both lean and obese mice of both sexes, independent of weight-loss or diet. There was no combined effect of diet and exercise training in improving glucose tolerance once body weight is corrected to control levels by either diet or exercise. Further analysis of molecular pathways demonstrated several gene sets modified by HFD were reversed by all three lifestyle interventions, which were tissue specific, either in the liver or skeletal muscles. Results from your studies may provide insight into the metabolic pathways that could be potentially targeted for improving metabolic diseases. L Zhu (K01AG077038); J Stafford (BX002223) (R01DK109102) (R01HL144846). 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.