The skeleton is an endocrine organ participating in energy metabolism and glucose homeostasis via the undercarboxylated form of the bone-derived protein, osteocalcin. Skeletal muscle is a major site of glucose uptake and disposal in response to both insulin and exercise. It was previously shown that osteocalcin may enhance whole body insulin sensitivity and glucose control via its action on the pancreatic beta cells by increasing beta cell proliferation and insulin secretion, as well as affecting adipocytes by enhancing adiponectin secretion. Both the increase in insulin and adiponectin levels can increase skeletal muscle glucose uptake. However, whether osteocalcin can enhance skeletal muscle insulin sensitivity and glucose uptake at rest and following muscle contraction/exercise via a direct pathway is not clear. Our recent evidence suggests that a direct pathway is plausible. In order to better understand the pathway by which osteocalcin may affect glucose uptake in skeletal muscle, a receptor for osteocalcin should be identified. The class C G protein-coupled receptor 6A (GPRC6A) is the postulated receptor for osteocalcin in several tissues including skeletal muscle. We now have evidence demonstrating a direct role of osteocalcin in enhancing skeletal muscle insulin sensitivity and that that GPRC6A may not be the only receptor for osteocalcin in this tissue.