The regulation of bone remodeling by an adipocyte-derived hormone implies that bone may exert a feedback control of energy homeostasis. To test this hypothesis we looked for genes expressed in osteoblasts, encoding signaling molecules and affecting energy metabolism. We show here that mice lacking the protein tyrosine phosphatase OST-PTP are hypoglycemic and are protected from obesity and glucose intolerance because of an increase in beta-cell proliferation, insulin secretion, and insulin sensitivity. In contrast, mice lacking the osteoblast-secreted molecule osteocalcin display decreased beta-cell proliferation, glucose intolerance, and insulin resistance. Removing one Osteocalcin allele from OST-PTP-deficient mice corrects their metabolic phenotype. Ex vivo, osteocalcin can stimulate CyclinD1 and Insulin expression in beta-cells and Adiponectin, an insulin-sensitizing adipokine, in adipocytes; in vivo osteocalcin can improve glucose tolerance. By revealing that the skeleton exerts an endocrine regulation of sugar homeostasis this study expands the biological importance of this organ and our understanding of energy metabolism.

A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEBUnder basal conditions TFEB, a master regulator of lysosomal biogenesis, is sequestered in the cytosol due to mTORC1-dependent phosphorylation at the lysosomal membrane. Nutrient starvation or lysosomal dysfunction inhibit mTORC1 activity and induce nuclear translocation of TFEB inducing target gene expression.

The broad expression of the insulin receptor suggests that the spectrum of insulin function has not been fully described. A cell type expressing this receptor is the osteoblast, a bone-specific cell favoring glucose metabolism through a hormone, osteocalcin, that becomes active once uncarboxylated. We show here that insulin signaling in osteoblasts is necessary for whole-body glucose homeostasis because it increases osteocalcin activity. To achieve this function insulin signaling in osteoblasts takes advantage of the regulation of osteoclastic bone resorption exerted by osteoblasts. Indeed, since bone resorption occurs at a pH acid enough to decarboxylate proteins, osteoclasts determine the carboxylation status and function of osteocalcin. Accordingly, increasing or decreasing insulin signaling in osteoblasts promotes or hampers glucose metabolism in a bone resorption-dependent manner in mice and humans. Hence, in a feed-forward loop, insulin signals in osteoblasts to activate a hormone, osteocalcin, that promotes glucose metabolism.

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 ␤ 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 ␤ cell line, and primary adipocytes showed that picomolar amounts of osteocalcin are sufficient to regulate the expression of the insulin genes and ␤ cell proliferation markers, whereas nanomolar amounts affect adiponectin and Pgc1␣ 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.fat ͉ insulin ͉ diet-induced obesity ͉ diet-induced diabetes ͉ adiponectin W e recently showed that the uncarboxylated form of the osteoblast-specific secreted molecule osteocalcin functions as a hormone regulating glucose metabolism and fat mass (1). However, this unexpected role for osteocalcin had not previously been exclusively demonstrated in genetically modified animals such as the Osteocalcin Ϫ/Ϫ and Esp Ϫ/Ϫ mice (1, 2). The latter mouse model exhibits an osteocalcin gain of bioactivity. Data generated in these two animal models and cell-based assays showed that osteocalcin can increase ␤ cell proliferation, stimulate insulin expression and secretion by pancreatic ␤ cells, enhance energy expenditure, and increase expression of adiponectin, an insulin-sensitizing hormone produced by adipocytes (3, 4).The next critical question to answer is whether the functions of osteocalcin on energy metabolism extend to WT animals. Moreover, if it is the case, one needs to know whether identical or different concentrations of osteocalcin are required to affect glucose metabolism and fat mass. Answers to these questions are of critical importance for two reasons. First, if osteocalcin has an effect in WT mice it would firmly establish the notion that it is a physiologically important hormone; second, it would start addressing the therapeutic potential of this new player in the regulation of energy metabolism.Thus, we embarked on a systematic analysis of osteocalcin relevance in regulating energy metabolism in WT mice. We performed in vitro and in vivo assays to determine the doses of osteocalcin able to affect various aspects of energy metabolism and tested different doses of osteocalcin in WT mice fed either a normal diet or a diet favo...

Although the endocrine capacity of bone is widely recognized, interactions between bone and the reproductive system have until now focused on the gonads as a regulator of bone remodeling. We now show that in males, bone acts as a regulator of fertility. Using co-culture assays, we demonstrate that osteoblasts are able to induce testosterone production by the testes, while they fail to influence estrogen production by the ovaries. Analyses of cell-specific loss- and gain-of-function models reveal that the osteoblast-derived hormone osteocalcin performs this endocrine function. By binding to a G-protein coupled receptor expressed in the Leydig cells of the testes, osteocalcin regulates in a CREB-dependent manner the expression of enzymes required for testosterone synthesis, promoting germ cell survival. This study expands the physiological repertoire of osteocalcin, and provides the first evidence that the skeleton is an endocrine regulator of reproduction.