CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-γ

Stephan Herzig, Susan Hedrick, Ianessa Morantte, Seung-Hoi Koo, Francesco Galimi, Marc Montminy

Research output: Contribution to journalArticle

203 Citations (Scopus)

Abstract

Fasting triggers a series of hormonal cues that promote energy balance by inducing glucose output and lipid breakdown in the liver. 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) pathways, 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-γ, a key regulator of lipogenic genes. CREB inhibits hepatic PPAR-γ 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-γ 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.

Original languageEnglish
Pages (from-to)190-193
Number of pages4
JournalNature
Volume426
Issue number6963
DOIs
Publication statusPublished - 2003 Nov 13
Externally publishedYes

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Peroxisome Proliferator-Activated Receptors
Cytoplasmic and Nuclear Receptors
Lipid Metabolism
Fasting
Liver
Nuclear Receptor Coactivators
Lipids
Fatty Liver
Regulator Genes
Glucagon
Cues
Insulin Resistance
Hydrocortisone
Transcription Factors
Fatty Acids
Hormones
Insulin
Phenotype
Glucose
Genes

ASJC Scopus subject areas

  • General

Cite this

Herzig, S., Hedrick, S., Morantte, I., Koo, S-H., Galimi, F., & Montminy, M. (2003). CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-γ. Nature, 426(6963), 190-193. https://doi.org/10.1038/nature02110

CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-γ. / Herzig, Stephan; Hedrick, Susan; Morantte, Ianessa; Koo, Seung-Hoi; Galimi, Francesco; Montminy, Marc.

In: Nature, Vol. 426, No. 6963, 13.11.2003, p. 190-193.

Research output: Contribution to journalArticle

Herzig, S, Hedrick, S, Morantte, I, Koo, S-H, Galimi, F & Montminy, M 2003, 'CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-γ', Nature, vol. 426, no. 6963, pp. 190-193. https://doi.org/10.1038/nature02110
Herzig S, Hedrick S, Morantte I, Koo S-H, Galimi F, Montminy M. CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-γ. Nature. 2003 Nov 13;426(6963):190-193. https://doi.org/10.1038/nature02110
Herzig, Stephan ; Hedrick, Susan ; Morantte, Ianessa ; Koo, Seung-Hoi ; Galimi, Francesco ; Montminy, Marc. / CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-γ. In: Nature. 2003 ; Vol. 426, No. 6963. pp. 190-193.
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