AMP-activated protein kinase (AMPK) acts as an intracellular sensor to maintain the energy balance by phosphorylation of several downstream metabolic enzymes and certain transcription factors. We have identified a transcription factor named AREBP which is phosphorylated by AMPK in vitro. AREBP binds to the promoter element of PEPCK, a key enzyme of gluconeogenesis. Transient transfection experiments indicated AREBP repressed transcription of PEPCK gene in a phosphorylation dependent manner. To investigate the in vivo function of AREBP, we overexpressed AREBP in mice. Fasting-induced up-regulation of PEPCK gene expression was reduced by AICAR injection in AREBP mice. AICAR treatment repressed PEPCK gene expression in cultured hepatocytes derived from AREBP mice. Glucose output was reduced in AREBP mice after AICAR injection. Our results suggest AREBP is a key modulator of hepatic glucose production regulated by AMPK in vivo. (C) 2011 Elsevier Inc. All rights reserved.