Skeletal research is currently undergoing a period of marked expansion. One aspect in particular is the relationship between bone, fat and glucose metabolism.  Emerging evidence indicates that bone, adipose and pancreatic activity are co-regulated and interdependent. Bone and fat are known insulin targets. Signals from fat cells are known to regulate bone mass and insulin action, with prominent adipokines such as leptin and adiponectin. Interestingly, signals produced by bone cells are now being identified that are capable of regulating fat and bate cells, both directly and through central hypothalamic signalling.

Osteocalcin, a protein secreted by osteoblasts, has emerged as a bone-specific endocrine signal, capable of regulating of energy and glucose homeostasis. Increasing osteocalcin levels reduced fat mass and improved insulin sensitivity in wild type mice, through secretion of the undercarboxylated form of osteocalcin, acting to increase the insulin sensitising adipokines adiponectin, and directly increasing insulin production in the beta cell. Recently, our laboratory has produced data suggesting a novel central loop for osteocalcin signalling, also capable of regulating adipose and glucose homeostasis, as well as providing feedback to central bone regulatory pathways. One such central, bone/ fat/glucose-active pathway is controlled by neuropeptide Y, most prominently in the hypothalamus. Recent data has also implicated neuropeptide signalling in the osteoblastic regulation of glucose homeostasis, with loss of osteoblastic neuropeptide Y receptors, markedly reducing insulin production.

In conclusion, the link between energy and bone and glucose homeostasis is far more complex than previously appreciated, with multiple axes of control, involving both central and direct signalling pathways. These signalling axes reveal a classic, hypothalamic pattern of feedback and efferent neural/endocrine control. But they also reveal novel intra-organ endocrine signals with powerful effects on target tissues. In this manner, a new level of organ to organ endocrine signalling is emerging.