Prolonged obesity frequently leads to insulin resistance and, eventually, to diabetes. This relationship reflects the integration of fat stores and carbohydrate metabolism and the coordination of central nervous system functions, e.g. appetite, and peripheral metabolism. Recent work suggests that the melanocortin system is involved in this integration; specifically, central administration of melanocyte-stimulating hormone (MSH) decreases, whereas lack of central MSH signaling increases, peripheral insulin resistance. Here we asked whether MSH acting in the periphery has a complementary role in insulin resistance. We tested this in a mouse model where the proopiomelanocortin (POMC) gene encoding all of the melanocortins has been genetically deleted. The homozygous POMC-null mouse lacks central as well as peripheral MSH signaling; in addition, it lacks adrenal glands and thus is devoid of corticosterone and epinephrine. Here we report that homozygous POMC mutants have normal serum levels of insulin, normal fasting levels of glucose, and normal clearance of glucose in glucose tolerance tests. Thus, insulin production and sensitivity and glucose uptake in peripheral tissues are functioning normally. However, we found a striking inability of the homozygous POMC mutants to recover from insulin-induced hypoglycemia. This defect was in the glucagon-mediated counterregulatory response. Both peripheral administration of an MSH analog and supplementation with corticosterone alleviated the hypoglycemia after insulin challenge, but did not make the obese POMC mutant mice diabetic. We conclude that, similar to the regulation of body weight homeostasis, the regulation of glucose homeostasis requires the integration of both central and peripheral melanocortin signaling systems.