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 (PPAR gamma) and CCAAT/enhancer-binding protein alpha (C/EBP alpha). We have identified the a-subunit of the eukaryotic initiation factor-2 (eIF2 alpha) 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 eIF2 alpha kinases, could overcome the apoptotic effect of AICAR, abolishing the reduction of PPAR gamma and C/EBP alpha and the lipolytic properties of AMPK. Thus, AMPK may diminish adiposity via reduction of fat cell number through eIF2 alpha-dependent translation shutdown. (c) 2005 Elsevier Inc. All rights reserved.