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

@article{citeulike:893662, 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)-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.}, address = {Peptide Biology Laboratories, Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, California 92037-1002, USA.}, author = {Koo, S. H. and Satoh, H. and Herzig, S. and Lee, C. H. and Hedrick, S. and Kulkarni, R. and Evans, R. M. and Olefsky, J. and Montminy, M. }, citeulike-article-id = {893662}, doi = {http://dx.doi.org/10.1038/nm1044}, issn = {1078-8956}, journal = {Nat Med}, keywords = {diabetes, ox\_stress, pgc1-alpha}, month = {May}, number = {5}, pages = {530--534}, posted-at = {2006-10-12 00:42:51}, priority = {3}, title = {PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3.}, url = {http://dx.doi.org/10.1038/nm1044}, volume = {10}, year = {2004} }

TY - JOUR ID - citeulike:893662 L3 - citeulike-article-id:893662 N2 - 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. IS - 5 JF - Nat Med SN - 1078-8956 AD - Peptide Biology Laboratories, Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, California 92037-1002, USA. EP - 534 TI - PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3. VL - 10 SP - 530 KW - diabetes KW - ox_stress KW - pgc1-alpha AU - Koo, SH AU - Satoh, H AU - Herzig, S AU - Lee, CH AU - Hedrick, S AU - Kulkarni, R AU - Evans, RM AU - Olefsky, J AU - Montminy, M PY - 2004/05// UR - http://dx.doi.org/10.1038/nm1044 ER -