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

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 acid-induced 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.
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Contributor : Marie-Hélène Derudas <>
Submitted on : Monday, February 14, 2011 - 4:11:40 PM
Last modification on : Friday, July 17, 2020 - 10:54:02 AM
Long-term archiving on: : Sunday, May 15, 2011 - 3:18:48 AM

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Mehdi Daoudi, Nathalie Hennuyer, Michael Borland, Véronique Touche, Christian Duhem, et al.. PPARβ/δ activation induces enteroendocrine L cell GLP-1 production.. Gastroenterology, WB Saunders, 2011, 140 (5), pp.1564-74. ⟨10.1053/j.gastro.2011.01.045⟩. ⟨inserm-00565808⟩

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