Cocaine- and amphetamine-regulated transcript (CART) is one of the two known mediators of the leptin regulation of bone mass. Cart is expressed in both the brain and peripheral tissues such as the pituitary gland and the pancreatic islets. Cart(-/-) mice present a low bone mass phenotype due to an isolated increase in osteoclast number. In an effort to rescue their bone phenotype, we delivered recombinant CART in the third ventricle of the mutant mice but never recorded any improvement of the low bone mass, although this procedure could affect fat pad mass. In contrast, transgenic mice harboring a 2-fold increase in CART circulating level display a high bone mass due to an isolated decrease in osteoclast number and could rescue the low bone mass phenotype of the Cart(-/-) mice. Thus, our results suggest that in its capacity of a regulator of bone remodeling, CART may act more as a circulating molecule than a neuropeptide.