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 determined1,2,3,4. 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 hypoglycaemia 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.
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Notes
* Correction: In the printed version, "hypoglycaemia" incorrectly appeared as "hyperglycaemia". A Correction will shortly be published.
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Acknowledgements
We thank J. Frangioni for help with adenovirus constructs, C. Arias for help with histology, and K. Suter for performing injections. This work was supported by grants from the National Institutes for Health to M.M. and from the DFG to S.H.
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Figure S1
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Plasma insulin levels in fed and fasted C57Bl6 (top) and db/db (bottom) mice injected with control (GFP) or A-CREB adenoviruses.
Figure S2
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(left). Dose-response curve of insulin effects on PGC-1 mRNA levels in FAO hepatoma cells. Cells were treated with indicated concentrations of insulin for 4 hours, and PGC-1 mRNA levels were measured by quantitative PCR analysis.
(right). Time course analysis of insulin effects on PGC-1 mRNA levels in FAO hepatoma cells. Cells were treated with maximal (100nM) dose of insulin for various times, and PGC-1 mRNA levels were measured by quantitative PCR analysis. Average of two independent experiments ± SEM.
Figure S3
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PGC-1 has no effect on expression of A-CREB in mice co-infected with PGC-1 plus A-CREB adenoviruses. Western blot analysis of liver extracts from mice infected with GFP, A-CREB plus GFP, or A-CREB plus PGC-1 adenoviruses. Equal numbers of adenovirus particles were infected in each set. A-CREB protein was detected with anti-FLAG tag antiserum.
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Herzig, S., Long, F., Jhala, U. et al. CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature 413, 179–183 (2001). https://doi.org/10.1038/35093131
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DOI: https://doi.org/10.1038/35093131
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