Cellular, molecular and endocrine mechanisms contributing to the functioning of the skeleton in whole-body glucose homeostasis

Metabolic disorders such as osteoporosis, obesity and diabetes represent a growing global epidemic. Ample links exist between these conditions, particularly underscoring the regular association of diseases of energy metabolism with skeletal complications. Conversely, the skeleton itself represents an endocrine organ integrated in the regulation of whole-body energy homeostasis. Understanding the cellular and molecular mechanisms involved in the endocrine function of bone is consequently of high clinical relevance. Preliminary data obtained in our lab using mutant mice indicate that intracellular signaling by specific catenin family members in skeletal progenitors may contribute to the complex interactions between bone and other metabolic tissues. This project is designed to address the underlying mechanisms, exploring two aspects. First, we will study how these molecules function in the local control of cell fate specification and differentiation, and regulate bone homeostasis and marrow fat accumulation. Second, we will investigate the impact of these effects in bone on systemic energy metabolism and the susceptibility to develop obesity and diabetes. Moreover, we hope to identify novel glucose-regulatory endocrine signals derived from the skeleton. These studies will bring new insights in the mechanisms controlling bone health and their significance in the regulation of glucose homeostasis, which could impact on the future management of widespread metabolic disorders.