The role of bone in whole-body energy metabolism.

The skeleton is one of the largest organs in the body and is integrated with systemic energy metabolism. This integration is mediated in part through the process of skeletal remodelling, which is fundamental for maintenance of bone mass and quality. Remodelling is an energetically expensive process that contributes to energy balance owing to constant substrate flow to the skeleton in the form of glucose, lipids and amino acids, as well as output of hormonal factors regulating peripheral metabolism. Bone remodelling is orchestrated by osteocytes, the most abundant cells in bone. Hence, it stands to reason that osteocytes must also regulate substrate availability and utilization not only for their own function but also for those of other skeletal cells (namely, osteoblasts and osteoclasts). Osteocytes also secrete factors (such as osteokines) that are engaged in complex molecular signalling networks that influence glucose metabolism, insulin sensitivity and energy homeostasis. Importantly, whole-body metabolism and bone homeostasis share similar regulatory mechanisms, including the RANKL and parathyroid hormone signalling pathways. This Review summarizes our current understanding of how the skeleton regulates whole-body energy metabolism and leads to the conclusion that bone might not be the core regulator of systemic energy metabolism but rather acts as an organ that instead regulates these complex processes.