Short-term overexpression of a constitutively active form of AMP-activated protein kinase in the liver leads to mild hypoglycemia and fatty liver.
AMP-activated protein kinase (AMPK) is a major therapeutic target for the treatment of diabetes. We investigated the effect of a short-term overexpression of AMPK specifically in the liver by adenovirus-mediated transfer of a gene encoding a constitutively active form of AMPKalpha2 (AMPKalpha2-CA). Hepatic AMPKalpha2-CA expression significantly decreased blood glucose levels and gluconeogenic gene expression. Hepatic expression of AMPKalpha2-CA in streptozotocin-induced and ob/ob diabetic mice abolished hyperglycemia and decreased gluconeogenic gene expression. In normal mouse liver, AMPKalpha2-CA considerably decreased the refeeding-induced transcriptional activation of genes encoding proteins involved in glycolysis and lipogenesis and their upstream regulators, SREBP-1 (sterol regulatory element-binding protein-1) and ChREBP (carbohydrate response element-binding protein). This resulted in decreases in hepatic glycogen synthesis and circulating lipid levels. Surprisingly, despite the inhibition of hepatic lipogenesis, expression of AMPKalpha2-CA led to fatty liver due to the accumulation of lipids released from adipose tissue. The relative scarcity of glucose due to AMPKalpha2-CA expression led to an increase in hepatic fatty acid oxidation and ketone bodies production as an alternative source of energy for peripheral tissues. Thus, short-term AMPK activation in the liver reduces blood glucose levels and results in a switch from glucose to fatty acid utilization to supply energy needs.
Foretz
Marc
M
Institut Cochin, Département de Génétique, Développement et Pathologie Moléculaire, Université René Descartes Paris 5, Institut National de la Santé et de la Recherche Medicale U567, Centre National de la Recherche Scientifique UMR8104, Paris, France.
Ancellin
Nicolas
N
Andreelli
Fabrizio
F
Saintillan
Yannick
Y
Grondin
Pascal
P
Kahn
Axel
A
Thorens
Bernard
B
Vaulont
Sophie
S
Viollet
Benoît
B
D055372:AMP-Activated Protein Kinases; D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D003001:Cloning, Molecular; D017931:DNA Primers; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000201:enzymology*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D007003:Hypoglycemia / Q000201:enzymology*; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009097:Multienzyme Complexes / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D001786:Blood Glucose; D017931:DNA Primers; D005227:Fatty Acids; D009097:Multienzyme Complexes; D011994:Recombinant Proteins; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases