PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3.
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)-gamma 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-alpha, 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-alpha. 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.
Koo
Seung-Hoi
SH
Peptide Biology Laboratories, Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, California 92037-1002, USA.
Satoh
Hiroaki
H
Herzig
Stephan
S
Lee
Chih-Hao
CH
Hedrick
Susan
S
Kulkarni
Rohit
R
Evans
Ronald M
RM
Olefsky
Jerrold
J
Montminy
Marc
M
D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D004247:DNA / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D018160:Receptors, Cytoplasmic and Nuclear; C474830:TRB3 protein, mouse; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D004247:DNA