Evidence that α-Calcitonin Gene-Related Peptide Is a Neurohormone that Controls Systemic Lipid Availability and Utilization

Abstract

α-Calcitonin gene-related peptide (αCGRP) 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 αCGRP on in vitro and in vivo indices of lipid metabolism. In rodents, levels of αCGRP similar to those in the blood markedly stimulated fatty acid β-oxidation and evoked concomitant mobilization of muscle lipid via receptor-mediated activation of muscle lipolysis. αCGRP 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 αCGRP is a newly recognized regulator of lipid availability and utilization in key tissues and that it may elevate the availability of intramyocellular free fatty acids to meet muscle energy requirements generated by contraction by evoking their release from endogenous triglyceride.