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.
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References
Saltiel, A. & Kahn, C.R. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799–806 (2001).
Hribal, M., Oriente, F. & Accili, D. Mouse models of insulin resistance. Am. J. Physiol. Endocrinol. Metab. 282, E977–E981 (2002).
Yoon, J. et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413, 131–138 (2001).
Herzig, S. et al. CREB regulates hepatic gluconeogenesis via the co-activator PGC-1. Nature 413, 179–183 (2001).
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).
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).
Saltiel, A.R. New perspectives into the molecular pathogenesis and treatment of type 2 diabetes. Cell 104, 517–529 (2001).
Hanson, R.W. & Reshef, L. Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression. Annu. Rev. Biochem. 66, 581–611 (1997).
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).
Kliewer, S., Xu, H., Lambert, M. & Willson, T. Peroxisome proliferator-activated receptors: from genes to physiology. Recent Prog. Horm. Res. 56, 239–263 (2001).
Wu, Z. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115–124 (1999).
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).
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).
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).
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).
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).
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).
Kersten, S. et al. Peroxisome proliferator-activated receptor α mediates the adaptive response to fasting. J. Clin. Invest. 103, 1489–1498 (1999).
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).
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).
Tordjman, K. et al. PPARα deficiency reduces insulin resistance and atherosclerosis in apoE-null mice. J. Clin. Invest. 107, 1025–1034 (2001).
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).
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).
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).
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).
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).
Hevener, A.L. et al. Muscle-specific Pparg deletion causes insulin resistance. Nat. Med. 9, 1491–1497 (2003).
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).
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.).
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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
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DOI: https://doi.org/10.1038/nm1044
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