Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

PGC-1 promotes insulin resistance in liver through PPAR-α-dependent induction of TRB-3

An Erratum to this article was published on 01 July 2004

Abstract

Insulin resistance is a major hallmark in the development of type 2 diabetes, which is characterized by an impaired ability of insulin to inhibit glucose output from the liver and to promote glucose uptake in muscle1,2. The nuclear hormone receptor coactivator PGC-1 (peroxisome proliferator-activated (PPAR)-γ coactivator-1) has been implicated in the onset of type 2 diabetes. Hepatic PGC-1 expression is elevated in mouse models of this disease, where it promotes constitutive activation of gluconeogenesis and fatty acid oxidation through its association with the nuclear hormone receptors HNF-4 and PPAR-α, respectively3,4,5. Here we show that PGC-1-deficient mice, generated by adenoviral delivery of PGC-1 RNA interference (RNAi) to the liver, experience fasting hypoglycemia. Hepatic insulin sensitivity was enhanced in PGC-1-deficient mice, reflecting in part the reduced expression of the mammalian tribbles homolog TRB-3, a fasting-inducible inhibitor of the serine-threonine kinase Akt/PKB (ref. 6). We show here that, in the liver, TRB-3 is a target for PPAR-α. Knockdown of hepatic TRB-3 expression improved glucose tolerance, whereas hepatic overexpression of TRB-3 reversed the insulin-sensitive phenotype of PGC-1-deficient mice. These results indicate a link between nuclear hormone receptor and insulin signaling pathways, and suggest a potential role for TRB-3 inhibitors in the treatment of type 2 diabetes.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: PGC-1 deficiency promotes fasting hypoglycemia and altered hepatic lipid metabolism.
Figure 2: Acute PGC-1 deficiency improves insulin sensitivity in liver.
Figure 3: PGC-1 promotes expression of TRB-3 through PPAR‐α.
Figure 4: PGC-1 promotes insulin resistance by inducing TRB-3 expression in liver.

Similar content being viewed by others

References

  1. Saltiel, A. & Kahn, C.R. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799–806 (2001).

    Article  CAS  Google Scholar 

  2. Hribal, M., Oriente, F. & Accili, D. Mouse models of insulin resistance. Am. J. Physiol. Endocrinol. Metab. 282, E977–E981 (2002).

    Article  CAS  Google Scholar 

  3. Yoon, J. et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413, 131–138 (2001).

    Article  CAS  Google Scholar 

  4. Herzig, S. et al. CREB regulates hepatic gluconeogenesis via the co-activator PGC-1. Nature 413, 179–183 (2001).

    Article  CAS  Google Scholar 

  5. Rhee, J. et al. Regulation of hepatic fasting response by PPARγ coactivator-1α (PGC-1): requirement for hepatocyte nuclear factor 4α in gluconeogenesis. Proc. Natl. Acad. Sci. USA 100, 4012–4017 (2003).

    Article  CAS  Google Scholar 

  6. Du, K., Herzig, S., Kulkarni, R.N. & Montminy, M. TRB-3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science 300, 1574–1577 (2003).

    Article  CAS  Google Scholar 

  7. Saltiel, A.R. New perspectives into the molecular pathogenesis and treatment of type 2 diabetes. Cell 104, 517–529 (2001).

    Article  CAS  Google Scholar 

  8. Hanson, R.W. & Reshef, L. Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression. Annu. Rev. Biochem. 66, 581–611 (1997).

    Article  CAS  Google Scholar 

  9. Imai, E., Miner, J.N., Mitchell, J.A., Yamamoto, K.R. & Granner, D.K. Glucocorticoid receptor-cAMP response element-binding protein interaction and the response of the phosphoenolpyruvate carboxykinase gene to glucocorticoids. J. Biol. Chem. 268, 5353–5356 (1993).

    CAS  PubMed  Google Scholar 

  10. Kliewer, S., Xu, H., Lambert, M. & Willson, T. Peroxisome proliferator-activated receptors: from genes to physiology. Recent Prog. Horm. Res. 56, 239–263 (2001).

    Article  CAS  Google Scholar 

  11. Wu, Z. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115–124 (1999).

    Article  CAS  Google Scholar 

  12. Brazil, D.P. & Hemmings, B.A. Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem. Sci. 26, 657–664 (2001).

    Article  CAS  Google Scholar 

  13. Cho, H. et al. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB β). Science 292, 1728–1731 (2001).

    Article  CAS  Google Scholar 

  14. Klingenspor, M., Xu, P., Cohen, R., Welch, C. & Reue, K. Altered gene expression pattern in the fatty liver dystrophy mouse reveals impaired insulin-mediated cytoskeleton dynamics. J. Biol. Chem. 274, 23078–23084 (1999).

    Article  CAS  Google Scholar 

  15. Brown, P.J. et al. Identification of a subtype selective human PPARα agonist through parallel-array synthesis. Bioorg. Med. Chem. Lett. 11, 1225–1227 (2001).

    Article  CAS  Google Scholar 

  16. Michael, M.D. et al. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol. Cell 6, 87–97 (2000).

    Article  CAS  Google Scholar 

  17. Kliewer, S. et al. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc. Natl. Acad. Sci. USA 91, 7355–7359 (1994).

    Article  CAS  Google Scholar 

  18. Kersten, S. et al. Peroxisome proliferator-activated receptor α mediates the adaptive response to fasting. J. Clin. Invest. 103, 1489–1498 (1999).

    Article  CAS  Google Scholar 

  19. Leone, T.C., Weinheimer, C.J. & Kelly, D.P. A critical role for the peroxisome proliferator-activated receptor α (PPARα) in the cellular fasting response: the PPARα-null mouse as a model of fatty acid oxidation disorders. Proc. Natl. Acad. Sci. USA 96, 7473–7478 (1999).

    Article  CAS  Google Scholar 

  20. Bernal-Mizrachi, C. et al. Dexamethasone induction of hypertension and diabetes is PPAR-α dependent in LDL receptor-null mice. Nat. Med. 9, 1069–1075 (2003).

    Article  CAS  Google Scholar 

  21. Tordjman, K. et al. PPARα deficiency reduces insulin resistance and atherosclerosis in apoE-null mice. J. Clin. Invest. 107, 1025–1034 (2001).

    Article  CAS  Google Scholar 

  22. Dresner, A. et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J. Clin. Invest. 103, 253–259 (1999).

    Article  CAS  Google Scholar 

  23. Shimomura, I. et al. Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Mol. Cell 6, 77–86 (2000).

    Article  CAS  Google Scholar 

  24. Kruszynska, Y. et al. Fatty acid-induced insulin resistance: decreased muscle PI3K activation but unchanged Akt phosphorylation. J. Clin. Endocrinol. Metab. 87, 226–234 (2002).

    Article  CAS  Google Scholar 

  25. Peterfy, M., Phan, J., Xu, P. & Reue, K. Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin. Nat. Genet. 27, 121–124 (2001).

    Article  CAS  Google Scholar 

  26. Koo, S.H. & Towle, H. Glucose regulation of mouse S(14) gene expression in hepatocytes. Involvement of a novel transcription factor complex. J. Biol. Chem. 275, 5200–5207 (2000).

    Article  CAS  Google Scholar 

  27. Hevener, A.L. et al. Muscle-specific Pparg deletion causes insulin resistance. Nat. Med. 9, 1491–1497 (2003).

    Article  CAS  Google Scholar 

  28. Hevener, A.L., Reichart, D., Janez, A. & Olefsky, J. Thiazolidinedione treatment prevents free fatty acid-induced insulin resistance in male Wistar rats. Diabetes 50, 2316–2322 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank K. Suter and L. Vera for performing injections, and C.R. Kahn (Joslin Diabetes Center) for LIRKO mice. This work was supported by National Institutes of Health grant GM RO1 37828 (M.M.), the American Diabetes Association, the Hillblom Foundation and Deutsche Forschungsgemeinschaft grant He3260/1-1 (S.H.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marc Montminy.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Koo, SH., Satoh, H., Herzig, S. et al. PGC-1 promotes insulin resistance in liver through PPAR-α-dependent induction of TRB-3. Nat Med 10, 530–534 (2004). https://doi.org/10.1038/nm1044

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1044

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing