Insulin activates PI3-kinase (PI3K)/AKT to regulate glucose homeostasis in the peripheral tissues and the mediobasal hypothalamus (MBH) of rodents. We report that insulin infusion into the MBH or dorsal vagal complex (DVC) activated insulin receptors. The same dose of insulin that activated MBH PI3K/AKT did not in the DVC. DVC insulin instead activated Erk1/2 and lowered glucose production in rats and mice. Molecular and chemical inhibition of DVC Erk1/2 negated, while activation of DVC Erk1/2 recapitulated, the effects of DVC insulin. Circulating insulin failed to inhibit glucose production when DVC Erk1/2 was inhibited in normal rodents, while DVC insulin action was disrupted in high-fat-fed rodents. Activation of DVC ATP-sensitive potassium channels was necessary for insulin-Erk1/2 and sufficient to inhibit glucose production in normal and high-fat-fed rodents. DVC is a site of insulin action where insulin triggers Erk1/2 signaling to inhibit glucose production and of insulin resistance in high-fat feeding.