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PPARdelta regulates glucose metabolism and insulin sensitivity.


ABSTRACT: The metabolic syndrome is a collection of obesity-related disorders. The peroxisome proliferator-activated receptors (PPARs) regulate transcription in response to fatty acids and, as such, are potential therapeutic targets for these diseases. We show that PPARdelta (NR1C2) knockout mice are metabolically less active and glucose-intolerant, whereas receptor activation in db/db mice improves insulin sensitivity. Euglycemic-hyperinsulinemic-clamp experiments further demonstrate that a PPARdelta-specific agonist suppresses hepatic glucose output, increases glucose disposal, and inhibits free fatty acid release from adipocytes. Unexpectedly, gene array and functional analyses suggest that PPARdelta ameliorates hyperglycemia by increasing glucose flux through the pentose phosphate pathway and enhancing fatty acid synthesis. Coupling increased hepatic carbohydrate catabolism with its ability to promote beta-oxidation in muscle allows PPARdelta to regulate metabolic homeostasis and enhance insulin action by complementary effects in distinct tissues. The combined hepatic and peripheral actions of PPARdelta suggest new therapeutic approaches to treat type II diabetes.

SUBMITTER: Lee CH 

PROVIDER: S-EPMC1413918 | biostudies-literature | 2006 Feb

REPOSITORIES: biostudies-literature

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PPARdelta regulates glucose metabolism and insulin sensitivity.

Lee Chih-Hao CH   Olson Peter P   Hevener Andrea A   Mehl Isaac I   Chong Ling-Wa LW   Olefsky Jerrold M JM   Gonzalez Frank J FJ   Ham Jungyeob J   Kang Heonjoong H   Peters Jeffrey M JM   Evans Ronald M RM  

Proceedings of the National Academy of Sciences of the United States of America 20060221 9


The metabolic syndrome is a collection of obesity-related disorders. The peroxisome proliferator-activated receptors (PPARs) regulate transcription in response to fatty acids and, as such, are potential therapeutic targets for these diseases. We show that PPARdelta (NR1C2) knockout mice are metabolically less active and glucose-intolerant, whereas receptor activation in db/db mice improves insulin sensitivity. Euglycemic-hyperinsulinemic-clamp experiments further demonstrate that a PPARdelta-spe  ...[more]

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