The results of this study indicate that muscle‐specific SIRT3 overexpression does not attenuate the pathological effects of HFHS feeding in mice, since mice overexpressing SIRT3 in cardiac and skeletal muscle that were fed a HFHS diet displayed similar levels of obesity, glucose intolerance, impaired cardiac function, and adverse cardiac remodeling as WT mice also fed a HFHS diet. This evidence concerns the gene SIRT3 and obesity due to melanocortin 4 receptor deficiency.