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Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1α transcription coactivator

Nature volume 447, pages 1012–1016 (2007)Cite this article

Abstract

Type 2 diabetes mellitus, a disease with significant effects on the health and economy of Western societies, involves disturbances in both lipid and carbohydrate metabolism1,2,3. In the insulin-resistant or diabetic state, the liver is unresponsive to the actions of insulin with regard to the suppression of glucose output but continues to produce large amounts of lipid, the latter mimicking the fed, insulin-replete condition4,5. The disordered distribution of lipids contributes to the cardiovascular disease that is the greatest cause of mortality of type 2 diabetes mellitus6,7. Yet the precise signal transduction pathways by which insulin regulates hepatic lipid synthesis and degradation remain largely unknown. Here we describe a mechanism by which insulin, through the intermediary protein kinase Akt2/protein kinase B (PKB)-β, elicits the phosphorylation and inhibition of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1α (PGC-1α), a global regulator of hepatic metabolism during fasting. Phosphorylation prevents the recruitment of PGC-1α to the cognate promoters, impairing its ability to promote gluconeogenesis and fatty acid oxidation. These results define a mechanism by which insulin controls lipid catabolism in the liver and suggest a novel site for therapy in type 2 diabetes mellitus.

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Figure 1: Akt phosphorylates PGC-1α at Ser 570.
Figure 2: Induction of gene expression, glucose production and β-oxidation by PGC-1α S570A is resistant to inhibition by Akt.
Figure 3: Akt inhibits hepatic gene expression and glucose production in vivo by the phosphorylation of PGC-1α at Ser 570.
Figure 4: Phosphorylation of PGC-1α at Ser 570 is required for Akt to inhibit recruitment of PGC-1α to chromatin.

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Acknowledgements

We thank Q. Chu for her help with the animal experiments, and P. Puigserver, M. Accili and B. Finck for providing reagents and advice. This work was supported by NIH grants to M.J.B. and X.L.

Author Contributions X.L. performed all the experiments, which were designed by X.L. and M.J.B. B.M. assisted in experiments with animals, and Q.G. generated the phospho-specific antiserum. The paper was written by X.L. and M.J.B.

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Authors and Affiliations

  1. Institute for Diabetes, Obesity and Metabolism, Cox Institute, University of Pennsylvania School of Medicine and the Howard Hughes Medical Institute, Philadelphia, Pennsylvania 19104, USA,

    Xinghai Li, Bobby Monks & Morris J. Birnbaum

  2. Cell Signaling Technology, Inc., 166B Cummings Center, Danvers, Massachusetts 01923, USA,

    Qingyuan Ge

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Correspondence to Morris J. Birnbaum.

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Li, X., Monks, B., Ge, Q. et al. Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1α transcription coactivator. Nature 447, 1012–1016 (2007). https://doi.org/10.1038/nature05861

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