The neural regulation of bone remodeling has proven to be increasingly complex at the molecular level since it involves both positive and negative mediators of bone formation and resorption. One of the mediator expressed in hypothalamic neurons that leptin uses to inhibit osteoclast differentiation and thereby bone resorption is cocaine amphetamine regulated transcript (CART). CART expression in hypothalamus is increased in mice lacking melanocortin 4 receptor (Mc4r -/- mice). Moreover, we show here that human or mice lacking only one allele of Mc4r display a decrease in bone resorption parameters, high bone mass and an increase in CART serum levels and/or hypothalamic expression. To demonstrate that the Cart overexpression is the only identifiable cause for the high bone mass observed upon Mc4r inactivation we removed one allele of Cart from mice either heterozygous or homozygous for Mc4r inactivation. This manipulation sufficed to either significantly improve or normalize bone resorption parameters, without improving the energy metabolism disturbance that characterize Mc4r deficient mice. These results identify CART signaling as the main if not only molecular pathway accounting for the decrease in bone resorption leading to high bone mass in mice and humans deficient in Mc4r. As importantly, they also indicate that CART regulates bone resorption independently of the role it may exert in energy metabolism suggesting that the neural control of appetite and bone remodeling are independent of each others.