Obesity and type 2 diabetes (T2D) are metabolic diseases with increasing prevalence worldwide. Obesity often leads to T2D. Insulin resistance and impaired β cell function contribute to the onset of hyperglycemia. Previously, we reported that ablation of Gc, encoding a secreted protein with a primary role in vitamin D transport, improved pancreatic β cell function in models of diet-induced insulin resistance. Here, we show that Gc ablation had systemic insulin-sensitizing effects to prevent weight gain, hyperglycemia, and glucose intolerance; lower nonesterified fatty acids and triglycerides; and augment glucose uptake in skeletal muscle and adipose in male mice fed a high-fat diet. Interestingly, weight loss in Gc-ablated mice resulted from selective fat mass loss with preserved lean mass. Moreover, acute Gc inhibition prevented glucose intolerance caused by high-fat feeding. The data suggest that Gc inhibition can increase insulin production in β cells and insulin action in peripheral tissues, while reducing fat mass.