In this study, an investigation on Mc3r KO, Mc4r KO, and DKO rats was carried out and data were compared systematically regarding their metabolic phenotypes in a single genetic background, in order to provide an overall understanding of these two receptors in energy metabolism, and to evaluate the possibility of using these KO rats as suitable animal models for obesity or type 2 diabetes. This evidence concerns the gene MC3R and type 2 diabetes mellitus.