Given the intrinsic negative side effects associated with excessive motivation for food and lack of sleep, including anxiety, obesity, diabetes, and low self-esteem, our experiments suggest that the REV-ERB regulation of the orexin pathway may hold utility in ameliorating the detrimental effects of imbalanced circadian behavior via orexinergic pathways. Here, HCRT is linked to obesity due to melanocortin 4 receptor deficiency.