Overall, our results confirm that CRTC1 is critical for the maintenance of energy balance and show, for the first time, the presence of a clear sexual dimorphism in the obesity of Crtc1−/− mice, because males develop a more severe obesity than females, and are more active and hyperphagic during the resting (diurnal) phase of the light/dark cycle. This evidence concerns the gene CRTC1 and obesity due to melanocortin 4 receptor deficiency.