Endocrine regulation of energy metabolism by the skeleton
That obesity protects mammals from osteoporosis led us to show in the past that bone remodeling, and thereby bone mass, is regulated by the adipocyte-derived hormone leptin via a central relay and the sympathetic nervous system. To test whether in response to this regulation bone could exert a feedback control of energy homeostasis we performed a functional genetic screen in mice designed to identify genes expressed specifically in osteoblasts, encoding signaling molecules and affecting energy metabolism. Through this effort we identified two genes, Osteocalcin and Esp, whose products are both involved in the regulation of glucose metabolism and of pancreas biology. Indeed, mice lacking the product of Esp are hypoglycemic and protected from obesity and glucose intolerance because of an increase in β-cell proliferation, insulin secretion and insulin sensitivity. In contrast, mice lacking the osteoblast-secreted molecule osteocalcin display decreased β-cell proliferation, glucose intolerance and insulin resistance. Genetic and biochemical analyses revealed that Esp and Osteocalcin lie in the same molecular cascade and that the Esp−/− mice are a model of osteocalcins gain-of-activity. Highlighting the importance of this novel regulation of energy metablism Esp−/− mice are protected from diet-induced obesity and diabetes. These studies establish that the skeleton, via its secretion of osteocalcin, exerts an endocrine regulation of sugar homeostasis thus expanding the biological importance of this organ as well as our understanding of the regulation of energy metabolism.
In a new set of studies, we have tested the effect of recombinant osteocalcin on energy metabolism in WT mice as well as in a model of diet-induced obesity. Results of these experiments will be presented at the meeting.