Selective OX2R agonists inhibited diet-induced obesity, and leptin overexpression enhanced this effect, but obese mice deficient in leptin- completely lost the inhibitory effect, suggesting that leptin-OX2R signaling can exert a diet-induced MetS by improving leptin sensitivity and energy homeostasis. This evidence concerns the gene HCRTR2 and obesity due to melanocortin 4 receptor deficiency.