AgRP signalling negatively regulates bone mass

Abstract The central nervous system is an active and major regulator of bone structure and remodelling. Specifically, signalling within the hypothalamus has been shown to be critical to ensuring that skeletal functions align with whole body metabolic supply and demand. Here, we identify agouti‐related peptide (AgRP), an orexigenic peptide exclusively co‐expressed with neuropeptide Y (NPY) in the arcuate nucleus (ARC) of the hypothalamus, as another critical player in the central control of bone homeostasis. Using novel mouse models, we show that AgRP deletion leads to an increase in cortical and trabecular bone mass as a result of an increase in bone thickness despite a lean phenotype, particularly in male mice. Interestingly, male AgRP deficient mice display a significant decrease in pro‐opiomelanocortin (POMC) expression in the ARC, but no change in NPY or CART expression, suggesting that the increase in bone mass in AgRP‐deficient mice is unlikely to be a result of altered NPY signalling. This is consistent with the observation that bone mass is unchanged in response to the specific deletion of NPY from AgRP expressing neurones. By contrast, POMC expression in the ARC is significantly increased in female AgRP deficient mice, although AgRP deletion results in altered respiratory exchange ratio regulation in response to re‐feeding after a fast in both sexes. Taken together, the present study identifies AgRP as being directly involved in the regulation of bone mass and highlights the complexity intrinsic to the neuropeptide regulation of the skeleton.