1. PPARβ/δ activation induces enteroendocrine L cell GLP-1 production.
- Author
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Daoudi M, Hennuyer N, Borland MG, Touche V, Duhem C, Gross B, Caiazzo R, Kerr-Conte J, Pattou F, Peters JM, Staels B, and Lestavel S
- Subjects
- Animals, Blood Glucose metabolism, Blotting, Western, Cells, Cultured, Diabetes Mellitus, Experimental pathology, Disease Models, Animal, Enteroendocrine Cells pathology, Glucagon-Like Peptide 1 genetics, Humans, Male, Mice, Polymerase Chain Reaction, RNA, Messenger biosynthesis, Rats, Diabetes Mellitus, Experimental metabolism, Enteroendocrine Cells metabolism, Gene Expression Regulation, Glucagon-Like Peptide 1 biosynthesis, PPAR-beta metabolism, RNA, Messenger genetics
- 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., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
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