Vdr-Pparα-Plin5-regulated lipid droplet dynamics mediates exercise protection against HFD-induced skeletal muscle ectopic lipid deposition and insulin resistance in mice.

Aerobic exercise serves as an effective non-pharmacological strategy for alleviating high-fat diet (HFD)-induced ectopic lipid deposition and insulin resistance (IR) in skeletal muscle. Vitamin D receptor (Vdr) is involved in the alleviation of ectopic lipid deposition in skeletal muscle by exercise, yet the underlying mechanisms remain to be further elucidated. In our study, twenty-four C57BL/6 J male mice were fed with vitamin D (VD) - deficient diet to establish a VD deficiency model and conduct aerobic exercise; lentivirus transfection was used to knockdown Vdr in C2C12 cells; skeletal muscle-specific knockout of Vdr (Vdr-MKO) male mice were fed a HFD to establish a model of ectopic lipid deposition in skeletal muscle and IR, followed by aerobic exercise intervention. We evaluated the blood, energy metabolism of mice, and conducted histological analysis, immunofluorescence staining, RT-qPCR, Western blotting and Co-Immunoprecipitation on the muscle of mice. We found that the decrease in Vdr weakened the beneficial effects of exercise on lipid metabolism in skeletal muscles. Vdr-MKO aggravates HFD-induced ectopic lipid deposition and IR in skeletal muscle, and impairs the protective effects of aerobic exercise on lipid metabolism and insulin sensitivity. Mechanistically, Vdr ablation leads to downregulated of Pparα and Plin5, reduced interaction between Plin5 and Cgi-58, as well as impaired lipid droplet protection and mitochondrial oxidative capacity in myocytes. The lipid droplet dynamics regulated by Vdr exerts a protective effect in aerobic exercise-mediate alleviation of HFD-induced ectopic lipid deposition and IR in skeletal muscle of mice.