The role of osteocalcin in the endocrine cross-talk between bone remodelling and energy metabolism

Bone remodelling, which maintains bone mass constant during adulthood, is an energy-demanding process. This, together with the observation that the adipocyte-derived hormone leptin is a major inhibitor of bone remodelling, led to the hypothesis that bone cells regulate energy metabolism through an endocrine mechanism. Studies to test this hypothesis identified osteocalcin, a hormone secreted by osteoblasts, as a positive regulator of insulin secretion, insulin resistance and energy expenditure. Remarkably, insulin signalling in osteoblasts is a positive regulator of osteocalcin production and activation via its ability to indirectly enhance bone resorption by osteoclasts. In contrast, leptin is a potent inhibitor of osteocalcin function through its effect on the sympathetic tone. Hence, osteocalcin is part of a complex signalling network between bone and the organs more classically associated with the regulation of energy homeostasis, such as the pancreas and adipose tissue. This review summarises the molecular and cellular bases of the present knowledge on osteocalcin biology and discusses the potential relevance of osteocalcin to human metabolism and pathology.