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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.

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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.

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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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Correspondence to Marc Montminy.

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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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