CREB regulates hepatic gluconeogenesis through the coactivator PGC-1

Stephan Herzig, Fanxin Long, Ulupi S. Jhala, Susan Hedrick, Rebecca Quinn, Anton Bauer, Dorothea Rudolph, Gunther Schutz, Cliff Yoon, Pere Puigserver, Bruce Spiegelman, Marc Montminy

Research output: Contribution to journalArticle

Abstract

When mammals fast, glucose homeostasis is achieved by triggering expression of gluconeogenic genes in response to glucagon and glucocorticoids. The pathways act synergistically to induce gluconeogenesis (glucose synthesis), although the underlying mechanism has not been determined1-4. Here we show that mice carrying a targeted disruption of the cyclic AMP (cAMP) response element binding (CREB) protein gene, or overexpressing a dominant-negative CREB inhibitor, exhibit fasting hyperglycaemia and reduced expression of gluconeogenic enzymes. CREB was found to induce expression of the gluconeogenic programme through the nuclear receptor coactivator PGC-1, which is shown here to be a direct target for CREB regulation in vivo. Overexpression of PGC-1 in CREB-deficient mice restored glucose homeostasis and rescued expression of gluconeogenic genes. In transient assays, PGC-1 potentiated glucocorticoid induction of the gene for phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme in gluconeogenesis. PGC-1 promotes cooperativity between cyclic AMP and glucocorticoid signalling pathways during hepatic gluconeogenesis. Fasting hyperglycaemia is strongly correlated with type II diabetes, so our results suggest that the activation of PGC-1 by CREB in liver contributes importantly to the pathogenesis of this disease.

Original languageEnglish (US)
Pages (from-to)179-183
Number of pages5
JournalNature
Volume413
Issue number6852
DOIs
StatePublished - Sep 13 2001
Externally publishedYes

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Gluconeogenesis
Response Elements
Liver
Glucocorticoids
Glucose
Hyperglycemia
Fasting
Homeostasis
Nuclear Receptor Coactivator 1
Gene Expression
Cyclic AMP Response Element-Binding Protein
Phosphoenolpyruvate
Enzymes
Glucagon
Cyclic AMP
Type 2 Diabetes Mellitus
Genes
Mammals

ASJC Scopus subject areas

  • General

Cite this

Herzig, S., Long, F., Jhala, U. S., Hedrick, S., Quinn, R., Bauer, A., ... Montminy, M. (2001). CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature, 413(6852), 179-183. https://doi.org/10.1038/35093131

CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. / Herzig, Stephan; Long, Fanxin; Jhala, Ulupi S.; Hedrick, Susan; Quinn, Rebecca; Bauer, Anton; Rudolph, Dorothea; Schutz, Gunther; Yoon, Cliff; Puigserver, Pere; Spiegelman, Bruce; Montminy, Marc.

In: Nature, Vol. 413, No. 6852, 13.09.2001, p. 179-183.

Research output: Contribution to journalArticle

Herzig, S, Long, F, Jhala, US, Hedrick, S, Quinn, R, Bauer, A, Rudolph, D, Schutz, G, Yoon, C, Puigserver, P, Spiegelman, B & Montminy, M 2001, 'CREB regulates hepatic gluconeogenesis through the coactivator PGC-1', Nature, vol. 413, no. 6852, pp. 179-183. https://doi.org/10.1038/35093131
Herzig S, Long F, Jhala US, Hedrick S, Quinn R, Bauer A et al. CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature. 2001 Sep 13;413(6852):179-183. https://doi.org/10.1038/35093131
Herzig, Stephan ; Long, Fanxin ; Jhala, Ulupi S. ; Hedrick, Susan ; Quinn, Rebecca ; Bauer, Anton ; Rudolph, Dorothea ; Schutz, Gunther ; Yoon, Cliff ; Puigserver, Pere ; Spiegelman, Bruce ; Montminy, Marc. / CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. In: Nature. 2001 ; Vol. 413, No. 6852. pp. 179-183.
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