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Insulin action in the central nervous system regulates energy homeostasis and glucose metabolism. To define the insulin-responsive neurons that mediate these effects, we generated mice with selective inactivation of the insulin receptor (IR) in either pro-opiomelanocortin (POMC)- or agouti-related peptide (AgRP)-expressing neurons of the arcuate nucleus of the hypothalamus. While neither POMC- nor AgRP-restricted IR knockout mice exhibited altered energy homeostasis, insulin failed to normally suppress hepatic glucose production during euglycemic-hyperinsulinemic clamps in AgRP-IR knockout (IR(DeltaAgRP)) mice. These mice also exhibited reduced insulin-stimulated hepatic interleukin-6 expression and increased hepatic expression of glucose-6-phosphatase. These results directly demonstrate that insulin action in POMC and AgRP cells is not required for steady-state regulation of food intake and body weight. However, insulin action specifically in AgRP-expressing neurons does play a critical role in controlling hepatic glucose production and may provide a target for the treatment of insulin resistance in type 2 diabetes.

Original publication




Journal article


Cell Metab

Publication Date





438 - 449


Agouti-Related Protein, Animals, Blotting, Western, Body Weight, Electrophysiology, Female, Glucose, Glucose Tolerance Test, Glucose-6-Phosphatase, Homeostasis, Hyperinsulinism, Hypothalamus, Immunoenzyme Techniques, Insulin, Integrases, Interleukin-6, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurons, Phosphatidylinositol 3-Kinases, Phosphatidylinositol Phosphates, Pro-Opiomelanocortin, Receptor, Insulin