In summary, the identification of fundamental roles for RAGE in energy conservation mechanisms, which go awry in nutrient excess, thereby contributing to the development of obesity in high-fat feeding in mice; and in the propagation of chronic tissue-damaging pro-inflammatory mechanisms, lay the framework for the potential benefits for RAGE antagonism both in the causes and consequences of diabetes and its complications, particularly in CVD. The gene discussed is AGER; the disease is obesity due to melanocortin 4 receptor deficiency.