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The objective of this study was to investigate the glucose handling, adipose and cardiac effects of voluntary exercise in male and female mice in a cardiometabolic disease setting induced by a high\u2010fat diet (HFD). The extent of exercise tolerance improvement was similar between HFD male and HFD female mice with running wheel access, despite greater daily running distances in female HFD mice. Exercise attenuated HFD\u2010induced increased body and fat mass in females but had no effect in males. A slight improvement in insulin tolerance was observed in HFD males only. The anti\u2010inflammatory effects of exercise were evident in both HFD males and HFD females, but the inflammatory cell types and tissue depots involved were sex\u2010specific. Cardiac diastolic function was improved with exercise in HFD females but not HFD males. Surprisingly, cardiomyocyte dimensions increased with exercise in HFD females and decreased with exercise in HFD males. This study provides the first evidence that the cardiometabolic effects of exercise are differentially elicited in males and females in a metabolic disease setting.<\/jats:p>","DOI":"10.14814\/phy2.70656","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T10:31:23Z","timestamp":1769596283000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Exercise has differential cardiometabolic effects in male and female mice on a high\u2010fat diet"],"prefix":"10.14814","volume":"14","author":[{"given":"L. 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