Alpha calcitonin gene-related peptide (CGRP) is released mainly from sensory and motor nerves in response to physiological stimuli. Despite well-documented pharmacological effects its primary physiological role has thus far remained obscure. Increased lipid content, particularly in skeletal muscle and liver, is strongly implicated in the pathogenesis of insulin resistance, but the physiological regulation of organ lipid is imperfectly understood. Here, we report our systematic investigations of the effects of CGRP on in vitro and in vivo indices of lipid metabolism. In rodents, levels of CGRP similar to those in the blood markedly stimulated fatty acid -oxidation and evoked concomitant mobilization of muscle lipid via receptor-mediated activation of muscle lipolysis. CGRP exerted potent in vivo effects on lipid metabolism in muscle, liver and the blood, via receptor-mediated pathways. Studies with receptor antagonists were consistent with tonic regulation of lipid metabolism by an endogenous CGRP agonist. These data reveal that CGRP is a newly recognized regulator of lipid availability and utilization in key tissues and that it may elevate the availability of intramyocellular FFA to meet muscle energy requirements generated by contraction by evoking their release from endogenous TG.