LEP and obesity due to melanocortin 4 receptor deficiency: The longest isoform, HLR-274, is responsible for the effects of leptin on energy homeostasis, with expression in the ARC, VMN, LHA, dorsomedial nucleus (DMN), and paraventricular nucleus (PVN) of the hypothalamus (55, 56), but it is also the most rapidly downregulated and transported to lysosomes for degradation, thus causing the syndrome of functional leptin resistance seen in obesity (53).