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

Seung-Hoi Koo, Hiroaki Satoh, Stephan Herzig, Chih Hao Lee, Susan Hedrick, Rohit Kulkarni, Ronald M. Evans, Jerrold Olefsky, Marc Montminy

Research output: Contribution to journalArticle

424 Citations (Scopus)

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 muscle. 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, respectively. 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.

Original languageEnglish
Pages (from-to)530-534
Number of pages5
JournalNature Medicine
Volume10
Issue number5
DOIs
Publication statusPublished - 2004 May 1
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Koo, S-H., Satoh, H., Herzig, S., Lee, C. H., Hedrick, S., Kulkarni, R., Evans, R. M., Olefsky, J., & Montminy, M. (2004). PGC-1 promotes insulin resistance in liver through PPAR-α-dependent induction of TRB-3. Nature Medicine, 10(5), 530-534. https://doi.org/10.1038/nm1044