Estrogen and voluntary exercise attenuate cardiometabolic syndrome and hepatic steatosis in ovariectomized rats fed a high-fat high-fructose diet.

The prevalence of cardiometabolic syndrome (CMS) is increased in women after menopause. While hormone replacement therapy has been prescribed to relieve several components of CMS in postmenopausal women, some aspects of cardiometabolic dysfunction cannot be completely restored. The present study examined the effectiveness of estrogen replacement alone and in combination with exercise by voluntary wheel running (VWR) for alleviating the risks of CMS, insulin-mediated skeletal muscle glucose transport, and hepatic fat accumulation in ovariectomized Sprague-Dawley rats fed a high-fat high-fructose diet (OHFFD). We compared a sham-operated group with OHFFD rats that were subdivided into a sedentary, estradiol replacement (E ₂ ), and E ₂ plus VWR for 12 wk. E ₂ prevented the development of insulin resistance in skeletal muscle glucose transport and decreased hepatic fat accumulation in OHFFD rats. Furthermore, E ₂ treatment decreased visceral fat mass and low-density lipoprotein (LDL)-cholesterol in OHFFD rats, while VWR further decreased LDL-cholesterol and increased the ratio of high-density lipoprotein-cholesterol to total cholesterol to a greater extent. Although E ₂ treatment alone did not reduce serum triglyceride levels in OHFFD rats, the combined intervention of E ₂ and VWR lowered serum triglycerides in E ₂ -treated OHFFD rats. The addition of VWR to E ₂ -treated OHFFD rats led to AMPK activation and upregulation of peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1α and PPARδ in skeletal muscle along with increased fatty acid oxidation and suppressed fatty acid synthesis in the liver. Collectively, our findings indicate that, to achieve greater health benefits, physical exercise is required for E ₂ -treated individuals under ovarian hormone deprivation with high-energy consumption.