Insulin Action in AgRP-expressing Neurons Is Required for Suppression of Hepatic Glucose Production

Cell Metab. 2007 Jun;5(6):438-49. doi: 10.1016/j.cmet.2007.05.004.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Agouti-Related Protein
  • Agrp protein, mouse
  • Insulin
  • Interleukin-6
  • Phosphatidylinositol Phosphates
  • phosphatidylinositol 3,4,5-triphosphate
  • Pro-Opiomelanocortin
  • Phosphatidylinositol 3-Kinases
  • Receptor, Insulin
  • Cre recombinase
  • Integrases
  • Glucose-6-Phosphatase
  • Glucose