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Letter
Nature Medicine 10, 530 - 534 (2004)
Published online: 25 April 2004 | doi:10.1038/nm1044
There is an Erratum (July 2004) associated with this Letter.
PGC-1 promotes insulin resistance in liver through PPAR-
-dependent induction of TRB-3
Seung-Hoi Koo1, Hiroaki Satoh2, Stephan Herzig1, Chih-Hao Lee3, Susan Hedrick1, Rohit Kulkarni4, Ronald M Evans3, Jerrold Olefsky2 & Marc Montminy1
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)-
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-
, 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-. 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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