LEP and obesity due to melanocortin 4 receptor deficiency: In conclusion, the possibility that combined low insulin and low leptin, secondary to hepatic glycogen depletion, are necessary to trigger increased NEFA secretion and uptake by hepatocytes is attractive in the context of the LEM because this would help explain: (i) the potential “threshold” effect (depletion of glycogen triggers hypoleptinemia) and also (ii) why the metabolic phenotype associated with the model presents preferentially in lean persons (leptin is elevated in obesity).