Regulation of Glucose Handling by the Skeleton: Insights From Mouse and Human Studies

The skeleton is now recognized as an endocrine organ regulating a growing number of physiological processes. Its endocrine function came to light when it was realized that osteoblasts, the bone-forming cells, contribute to the regulation of energy homeostasis by favoring glucose metabolism, insulin sensitivity, and energy expenditure. Accumulating evidence from mouse studies demonstrated that the traditional bone formation marker osteocalcin secreted by osteoblasts, when undercarboxylated through a resorptionand insulin-dependent mechanism, is an active hormone that promotes insulin secretion and improves insulin sensitivity. This metabolic process is counterbalanced by sympathetic nervous system signaling in osteoblasts that under the control of leptin favors carboxylation and therefore inactivation of osteocalcin. These observations in mice triggered extensive studies exploring the cross talk between bone, pancreas, and fat and showed that, in turn, osteoblasts receive signals from endocrine organs during chronic hyperglycemia and insulin resistance that impact their fuel utilization and substrate availability. Clinical studies also have added support to the notion that bone regulates glucose metabolism in humans. This review highlights recent advances in our understanding of the endocrine functions of bone and explores their relationship to clinical observations.