PPARβ/δ activation induces enteroendocrine L cell GLP-1 production

Mehdi Daoudi, Nathalie Hennuyer, Michael G. Borland, Veronique Touche, Christian Duhem, Barbara Gross, Robert Caiazzo, Julie Kerrconte, Franois Pattou, Jeffrey M. Peters, Bart Staels, Sophie Lestavel

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Background & Aims: Glucagon-like peptide (GLP)-1, an intestinal incretin produced by L cells through proglucagon processing, is secreted after nutrient ingestion and acts on endocrine pancreas beta cells to enhance insulin secretion. Peroxisome proliferator-activated receptor (PPAR) β/δ is a nuclear receptor that improves glucose homeostasis and pancreas islet function in diabetic animal models. Here, we investigated whether PPARβ/δ activation regulates L cell GLP-1 production. Methods: Proglucagon regulation and GLP-1 release were evaluated in murine GLUTag and human NCI-H716 L cells and in vivo using wild-type, PPARβ/δ-null, and ob/ob C57Bl/6 mice treated with the PPARβ/δ synthetic agonists GW501516 or GW0742. Results: PPARβ/δ activation increased proglucagon expression and enhanced glucose- and bile acidinduced GLP-1 release by intestinal L cells in vitro and ex vivo in human jejunum. In vivo treatment with GW0742 increased proglucagon messenger RNA levels in the small intestine in wild-type but not in PPARβ/δ-deficient mice. Treatment of wild-type and ob/ob mice with GW501516 enhanced the increase in plasma GLP-1 level after an oral glucose load and improved glucose tolerance. Concomitantly, proglucagon and GLP-1 receptor messenger RNA levels increased in the small intestine and pancreas, respectively. Finally, PPARβ/δ agonists activate the proglucagon gene transcription by interfering with the β-catenin/TCF-4 pathway. Conclusions: Our data show that PPARβ/δ activation potentiates GLP-1 production by the small intestine. Pharmacologic targeting of PPARβ/δ is a promising approach in the treatment of patients with type 2 diabetes mellitus, especially in combination with dipeptidyl peptidase IV inhibitors.

Original languageEnglish (US)
Pages (from-to)1564-1574
Number of pages11
JournalGastroenterology
Volume140
Issue number5
DOIs
StatePublished - May 2011

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

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