LEP and obesity due to melanocortin 4 receptor deficiency: Although leptin appears to bind to its receptor in mutant homozygous db/db mice (38), defective intracellular signal transduction attenuates leptin function, leading to a characteristic phenotype of severe obesity and diabetes, similar to what is observed in most human T2DM patients (39, 40), and replicated in the present study as demonstrated by low-bone mass and severe diabetes.