In this report, we demonstrated that p53 plays a critical role in reprogramming adipocyte glucose and lipid metabolisms and that the down-regulation of p53 increases glycolysis capacity and inhibits lipolysis activity simultaneously, which may result in Warburg-like metabolic effects in adipocytes and contribute to increased adipocyte metabolic flexibility and insulin sensitivity in obesity. This evidence concerns the gene TP53 and obesity due to melanocortin 4 receptor deficiency.