PPARδ regulates glucose metabolism and insulin sensitivity

Chih Hao Lee, Peter Olson, Andrea Hevener, Isaac Mehl, Ling Wa Chong, Jerrold M. Olefsky, Frank J. Gonzalez, Jungyeob Ham, Heonjoong Kang, Jeffrey M. Peters, Ronald M. Evans

Research output: Contribution to journalArticlepeer-review

388 Scopus citations

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 PPARδ (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 PPARδ-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 PPARδ 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 β-oxidation in muscle allows PPARδ to regulate metabolic homeostasis and enhance insulin action by complementary effects in distinct tissues. The combined hepatic and peripheral actions of PPARδ suggest new therapeutic approaches to treat type II diabetes.

Original languageEnglish (US)
Pages (from-to)3444-3449
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number9
DOIs
StatePublished - Feb 28 2006

All Science Journal Classification (ASJC) codes

  • General

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