The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity.
AMP-activated protein kinase (AMPK) is viewed as a fuel sensor for glucose and lipid metabolism. To better understand the physiological role of AMPK, we generated a knockout mouse model in which the AMPKalpha2 catalytic subunit gene was inactivated. AMPKalpha2(-/-) mice presented high glucose levels in the fed period and during an oral glucose challenge associated with low insulin plasma levels. However, in isolated AMPKalpha2(-/-) pancreatic islets, glucose- and L-arginine-stimulated insulin secretion were not affected. AMPKalpha2(-/-) mice have reduced insulin-stimulated whole-body glucose utilization and muscle glycogen synthesis rates assessed in vivo by the hyperinsulinemic euglycemic clamp technique. Surprisingly, both parameters were not altered in mice expressing a dominant-negative mutant of AMPK in skeletal muscle. Furthermore, glucose transport was normal in incubated isolated AMPKalpha2(-/-) muscles. These data indicate that AMPKalpha2 in tissues other than skeletal muscles regulates insulin action. Concordantly, we found an increased daily urinary catecholamine excretion in AMPKalpha2(-/-) mice, suggesting altered function of the autonomic nervous system that could explain both the impaired insulin secretion and insulin sensitivity observed in vivo. Therefore, extramuscular AMPKalpha2 catalytic subunit is important for whole-body insulin action in vivo, probably through modulation of sympathetic nervous activity.
Viollet
Benoit
B
Department of Genetic, Development, and Molecular Pathology, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), René Descartes University, Paris, France. viollet@cochin.inserm.fr
Andreelli
Fabrizio
F
Jørgensen
Sebastian B
SB
Perrin
Christophe
C
Geloen
Alain
A
Flamez
Daisy
D
Mu
James
J
Lenzner
Claudia
C
Baud
Olivier
O
Bennoun
Myriam
M
Gomas
Emmanuel
E
Nicolas
Gaël
G
Wojtaszewski
Jørgen F P
JF
Kahn
Axel
A
Carling
David
D
Schuit
Frans C
FC
Birnbaum
Morris J
MJ
Richter
Erik A
EA
Burcelin
Rémy
R
Vaulont
Sophie
S
D055372:AMP-Activated Protein Kinases; D000483:Alleles; D000818:Animals; D001692:Biological Transport; D015139:Blotting, Southern; D001835:Body Weight; D020134:Catalytic Domain; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D006003:Glycogen / Q000378:metabolism; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D013997:Time Factors
D007328:Insulin; D009097:Multienzyme Complexes; D006003:Glycogen; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose