In summary, our results show for the first time that the nonpeptide Mas agonist—AVE0991—improved the obesity-induced metabolic alterations in the skeletal muscle, which was reflected by improvement of the whole-body glucose tolerance accompanied by elevated IRβ and IRS total protein content and tyrosine phosphorylation and decreased serine phosphorylation. This evidence concerns the gene MAS1 and obesity due to melanocortin 4 receptor deficiency.