It is not surprising that the most important genes affecting energy homeostasis, including those first postulated by Coleman, are involved in the leptin-melanocortin pathway [including Lep, Lepr, melanocortin 4 receptor (Mc4r), pro-opiomelanocortin (Pomc)] were all first discovered in rodent models of extreme obesity and only subsequently identified in humans. This evidence concerns the gene LEP and obesity due to melanocortin 4 receptor deficiency.