Although fully functional adipose tissue is required for the maintenance of insulin sensitivity, the presence of systemic IR may reflect different degrees of dysfunction of the adipose tissue and other tissues involved in insulin signaling pathways, depending on the level of chronic low-grade inflammation and/or the concurrent presence of hyperglycemia, hypertriglyceridemia, and other metabolic disturbances typically associated with obesity, type-2 diabetes, and MetS. The gene discussed is INS; the disease is obesity due to melanocortin 4 receptor deficiency.