Vitamin D signaling orchestrates skeletal muscle metabolic flexibility by regulating its fuel choice.

Vitamin D deficiency is associated with skeletal muscle pathologies. However, the role of vitamin D signaling in maintenance of muscle function is not well understood. Mice lacking vitamin D receptor (VDR) exhibit severe muscle wasting after weaning and this is associated with accumulation of muscle glycogen and energy deprivation. Here we show that the skeletal muscles of vdr-/- mice exhibit upregulation of fatty acid oxidation pathway and PPAR pathway and are predisposed to utilize fatty acids as the energy source even in a carbohydrate-enriched diet. As a result, fat-enriched diets could alleviate energy deprivation and atrophy of vdr-/- skeletal muscles. However, the complete restoration of muscle mass and systemic metabolism of vdr-/- mice depended on the quality of diets. Despite increasing muscle energy levels, a lard-based high-fat diet (HFD) disrupted glucose homeostasis by specifically inhibiting the insulin synthesis in pancreatic islets. Surprisingly, milk-based high-fat diets (MBD) could restore both muscle mass and pancreatic insulin response. This study reveals a micronutrient-macronutrient interaction network that connects vitamin D signaling with muscle fuel selection and pancreatic insulin response to enable energy homeostasis under different metabolic landscapes.