Liver adenosine monophosphate-activated kinase-alpha2 catalytic subunit is a key target for the control of hepatic glucose production by adiponectin and leptin but not insulin.
The AMP-activated kinase (AMPK) is a serine threonine kinase that functions as a fuel sensor to regulate energy balance at both cellular and whole-body levels. Here we studied how hepatic AMPKalpha2 isoform affects hepatic glucose production and peripheral glucose uptake in vivo. We generated mice deleted for the AMPKalpha2 gene specifically in the liver (liveralpha2KO). Liveralpha2KO mice were glucose intolerant and hyperglycemic in the fasted state. Hyperglycemia was associated with a 50% higher endogenous glucose production than in controls as assessed in vivo. We then investigated whether this increased glucose production was sensitive to insulin. Insulin, when infused at a rate inducing physiological hyperinsulinemia, totally inhibited endogenous glucose production in liveralpha2KO mice, showing that they had normal insulin sensitivity. This was confirmed in vivo by normal insulin-induced phosphorylation of Akt and transcriptional regulation of the phosphoenolpyruvate carboxykinase, glucose-6 phosphatase, and pyruvate kinase in liver during the fasted/fed transition. Leptin and adiponectin regulate hepatic glucose production, so we then infused these adipokines into liveralpha2KO mice. Neither of these adipokines regulated hepatic glucose production in mice lacking hepatic AMPKalpha2, whereas both did so in control mice. In conclusion, we show that the hepatic AMPKalpha2 isoform is essential for suppressing hepatic glucose production and maintaining fasting blood glucose levels in the physiological range. We also demonstrate that regulation of hepatic glucose production by leptin and adiponectin, but not insulin, requires hepatic AMPKalpha2 activity.
Andreelli
Fabrizio
F
Institut National de la Santé et de la Recherche Médicale Unité 567, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Université René Descartes Paris 5, France.
Foretz
Marc
M
Knauf
Claude
C
Cani
Patrice D
PD
Perrin
Christophe
C
Iglesias
Miguel A
MA
Pillot
Bruno
B
Bado
André
A
Tronche
François
F
Mithieux
Gilles
G
Vaulont
Sophie
S
Burcelin
Rémy
R
Viollet
Benoit
B
D055372:AMP-Activated Protein Kinases; D052242:Adiponectin / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002384:Catalysis; D004195:Disease Models, Animal; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism; D007301:Insect Hormones / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D020738:Leptin / Q000737:chemistry* / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D015233:Models, Statistical; D009097:Multienzyme Complexes / Q000378:metabolism / Q000502:physiology*; D009842:Oligopeptides / Q000378:metabolism; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D052242:Adiponectin; D001786:Blood Glucose; D007301:Insect Hormones; D007328:Insulin; D020738:Leptin; D009097:Multienzyme Complexes; D009842:Oligopeptides; D020033:Protein Isoforms; C044833:adipokinetic hormone; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005952:Glucose-6-Phosphatase; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D005947:Glucose; D011761:Pyrrolidonecarboxylic Acid