α-Calcitonin gene-related peptide (αCGRP) is a neuropeptide that is expressed inmotorandsensory neurons. It is a powerful vasodilator and has been implicated in diverse metabolic roles. However, its precise physiological function remains unclear. In this study, we investigated the role of αCGRP in lipid metabolism by chronically challenging αCGRP-specific knockout (αCGRP-/-) and control mice with high-fat diet regimens. At the start of the study, both animal groups displayed similar body weights, serum lipid markers, and insulin sensitivity. However, αCGRP-/- mice displayed higher core temperatures, increased energy expenditures, and a relative daytime (nonactive) depression in respiratory quotients, which indicated increased β-oxidation. In response to fat feeding, αCGRP-/- mice were comparatively protected against diet-induced obesity with an attenuated body weight gain and an overall reduction in adiposity across all the three diets examined. αCGRP -/- mice also displayed improved glucose handling and insulin sensitivity, lower im and hepatic lipid accumulation, and improved overall metabolic health. These findings define a new role for αCGRP as a mediator of energy metabolism and opens up therapeutic opportunities to target CGRP action in obesity.