AMPK activation regulates apoptosis, adipogenesis, and lipolysis by eIF2alpha in adipocytes.
AMP-activated protein kinase (AMPK) is a metabolic master switch regulating glucose and lipid metabolism. Recently, AMPK has been implicated in the control of adipose tissue content. Yet, the nature of this action is controversial. We examined the effect on F442a adipocytes of the AMPK activator-AICAR. Activation of AMPK induced dose-dependent apoptotic cell death, inhibition of lipolysis, and downregulatation key adipogenic genes, such as peroxisome proliferator-activated receptor (PPARgamma) and CCAAT/enhancer-binding protein alpha (C/EBPalpha). We have identified the alpha-subunit of the eukaryotic initiation factor-2 (eIF2alpha) as a target gene which is phosphorylated following AICAR treatment. Such phosphorylation is one of the best-characterized mechanisms for downregulating protein synthesis. 2-Aminopurine (2-AP), an inhibitor of eIF2alpha kinases, could overcome the apoptotic effect of AICAR, abolishing the reduction of PPARgamma and C/EBPalpha and the lipolytic properties of AMPK. Thus, AMPK may diminish adiposity via reduction of fat cell number through eIF2alpha-dependent translation shutdown.
Dagon
Yossi
Y
Department of Human Nutrition and Metabolism, Braun School of Public Health, Faculty of Medicine, Hebrew University, Hadassah Medical School, Israel.
Avraham
Yosefa
Y
Berry
Elliot M
EM
D055372:AMP-Activated Protein Kinases; D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D050156:Adipogenesis / Q000187:drug effects / Q000502:physiology*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D008066:Lipolysis / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012265:Ribonucleotides / Q000494:pharmacology
D015852:Eukaryotic Initiation Factor-2; D009097:Multienzyme Complexes; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide