The osteoblast-specific secreted molecule osteocalcin behaves as a hormone regulating glucose metabolism and fat mass in two mutant mouse strains. Here, we ask two questions: is the action of osteocalcin on beta cells and adipocytes elicited by the same concentrations of the molecule, and more importantly, does osteocalcin regulate energy metabolism in WT mice? Cell-based assays using isolated pancreatic islets, a beta cell line, and primary adipocytes showed that picomolar amounts of osteocalcin are sufficient to regulate the expression of the insulin genes and beta cell proliferation markers, whereas nanomolar amounts affect adiponectin and Pgc1alpha expression in white and brown adipocytes, respectively. In vivo the same difference exists in osteocalcin's ability to regulate glucose metabolism on the one hand and affect insulin sensitivity and fat mass on the other hand. Furthermore, we show that long-term treatment of WT mice with osteocalcin can significantly weaken the deleterious effect on body mass and glucose metabolism of gold thioglucose-induced hyperphagia and high-fat diet. These results establish in WT mice the importance of this novel molecular player in the regulation of glucose metabolism and fat mass and suggest that osteocalcin may be of value in the treatment of metabolic diseases.