Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production.
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.
Könner
A Christine
AC
Department of Mouse Genetics and Metabolism, Institute for Genetics, Center for Molecular Medicine, University of Cologne, D-50674 Cologne, Germany.
Janoschek
Ruth
R
Plum
Leona
L
Jordan
Sabine D
SD
Rother
Eva
E
Ma
Xiaosong
X
Xu
Chun
C
Enriori
Pablo
P
Hampel
Brigitte
B
Barsh
Gregory S
GS
Kahn
C Ronald
CR
Cowley
Michael A
MA
Ashcroft
Frances M
FM
Brüning
Jens C
JC
D054369:Agouti-Related Protein / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight; D004594:Electrophysiology; D005260:Female; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006706:Homeostasis; D006946:Hyperinsulinism / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D007124:Immunoenzyme Techniques; D007328:Insulin / Q000494:pharmacology*; D019426:Integrases / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics
D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D007328:Insulin; D015850:Interleukin-6; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D011333:Pro-Opiomelanocortin; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; C045073:Cre recombinase; D019426:Integrases; D005952:Glucose-6-Phosphatase; D005947:Glucose