1. Peptide Biology Laboratories Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037-1002, USA
2. Laboratory of Genetics, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037-1002, USA

Correspondence to: Marc Montminy¹ Email: montminy@salk.edu

Abstract

Fasting triggers a series of hormonal cues that promote energy balance by inducing glucose output and lipid breakdown in the liver¹. In response to pancreatic glucagon and adrenal cortisol, the cAMP-responsive transcription factor CREB activates gluconeogenic and fatty acid oxidation programmes by stimulating expression of the nuclear hormone receptor coactivator PGC-1 (refs 2–5). In parallel, fasting also suppresses lipid storage and synthesis (lipogenic) pathways¹, but the underlying mechanism is unknown. Here we show that mice deficient in CREB activity have a fatty liver phenotype and display elevated expression of the nuclear hormone receptor PPAR-, a key regulator of lipogenic genes^{6, 7}. CREB inhibits hepatic PPAR- expression in the fasted state by stimulating the expression of the Hairy Enhancer of Split (HES-1) gene, a transcriptional repressor that is shown here to be a mediator of fasting lipid metabolism in vivo. The coordinate induction of PGC-1 and repression of PPAR- by CREB during fasting provides a molecular rationale for the antagonism between insulin and counter-regulatory hormones, and indicates a potential role for CREB antagonists as therapeutic agents in enhancing insulin sensitivity in the liver.