Pandemic vitamin D deficiency is associated with insulin resistance and type 2 diabetes (T2D). Vitamin D supplementation has been reported to have improved glucose homeostasis. However, its mechanism to improve insulin sensitivity remains unclear.Male C57BL/6J mice were fed with/without vitamin D control (CD) or Western (WD) diets for 15 weeks. The Vitamin D deficient lean (CDVDD) and obese (WDVDD) mice were further subdivided into two groups. One group was re-supplemented with vitamin D for 6 weeks and hepatic insulin signaling was examined. Both CD and WD mice with vitamin D deficiency developed insulin resistance. Vitamin D supplementation in CDVDD mice significantly improved insulin sensitivity, hepatic inflammation and antioxidative capacity. The hepatic insulin signals like pAKT, pFOXO1 and pGSK3β were increased and the downstream Pepck, G6pase and Pgc1α were reduced. Furthermore, the lipogenic genes Srebp1c, Acc and Fasn were decreased, indicating that hepatic lipid accumulation was inhibited.Our results demonstrate that vitamin D deficiency induces insulin resistance. Its supplementation has significant beneficial effects on pathophysiological mechanisms in T2D but only in lean and not in the obese phenotype. The increased subacute inflammation and insulin resistance in obesity could not be significantly alleviated by vitamin D supplementation. This needs to be taken consideration in the design of new clinical trials. This article is protected by copyright. All rights reserved.