FOXO1 Mediates Vitamin D Deficiency–Induced Insulin Resistance in Skeletal Muscle

ABSTRACT Prospective epidemiological studies have consistently shown a relationship between vitamin D deficiency, insulin resistance, and type 2 diabetes mellitus (DM2). This is supported by recent trials showing that vitamin D supplementation in prediabetic or insulin‐resistant patients with inadequate vitamin D levels improves insulin sensitivity. However, the molecular mechanisms underlying vitamin D deficiency–induced insulin resistance and DM2 remain unknown. Skeletal muscle insulin resistance is a primary defect in the majority of patients with DM2. Although sustained activation of forkhead box O1 (FOXO1) in skeletal muscle causes insulin resistance, a relationship between vitamin D deficiency and FOXO1 activation in muscle is unknown. We generated skeletal muscle‐specific vitamin D receptor (VDR)‐null mice and discovered that these mice developed insulin resistance and glucose intolerance accompanied by increased expression and activity of FOXO1. We also found sustained FOXO1 activation in the skeletal muscle of global VDR‐null mice. Treatment of C2C12 muscle cells with 1,25‐dihydroxyvitamin D (VD3) reduced FOXO1 expression, nuclear translocation, and activity. The VD3‐dependent suppression of FOXO1 activation disappeared by knockdown of VDR, indicating that it is VDR‐dependent. Taken together, these results suggest that FOXO1 is a critical target mediating VDR‐null signaling in skeletal muscle. The novel findings provide the conceptual support that persistent FOXO1 activation may be responsible for insulin resistance and impaired glucose metabolism in vitamin D signaling‐deficient mice, as well as evidence for the utility of vitamin D supplementation for intervention in DM2. © 2015 American Society for Bone and Mineral Research.