This is in sharp contrast to the anorexigenic endocrine hormones leptin and insulin, whose serum concentrations rise in DIO, leading to chronic overstimulation and cognate receptor desensitization, resulting in loss of efficacy of these hormone receptor axes.42, 43 Indeed, obesity is pathognomonically associated with chronic hyperleptinemia and hyperinsulinemia and hormone overexpression with receptor desensitization has challenged efforts to employ these impaired satiety circuits as therapeutic targets. This evidence concerns the gene INS and obesity due to melanocortin 4 receptor deficiency.