During the last 20 years, the emergence of sophisticated genetic tools has extraordinarily improved our understanding of a large number of physiological functions, among which the physiology of the skeleton. Bone, recently described as an endocrine organ, has the ability to constantly renew itself through bone remodeling, which requires a constant supply of energy. Hence, we hypothesized that there must be a coregulation of bone mass and energy metabolism, and focused on leptin, an adipocyte-derived hormone, which regulates both energy metabolism and bone remodeling through a central relay. Through a careful analysis of leptin neuronal targets, we unraveled that leptin regulation of bone mass occurs indirectly by inhibiting serotonin release and synthesis in neurons of the brainstem. Surprisingly, we observed that the other pool of serotonin, produced in enterochromaffin cells of the duodenum, negatively regulates bone mass accrual. Thus, serotonin is a molecule with two distinct functional identities depending on its site of synthesis. Finally, a recent study provides a proof of principle that inhibiting gut-derived serotonin (GDS) biosynthesis could become a new anabolic treatment for osteoporosis. double dagger.