title: PPARβ/δ activation induces enteroendocrine L cell GLP-1 production.
abstract: OBJECTIVE
  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.
authors.affiliation: Université Lille Nord de France, Lille, France.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Daoudi
authors.forename: Nathalie
authors.initials: N
authors.lastname: Hennuyer
authors.forename: Michael G
authors.initials: MG
authors.lastname: Borland
authors.forename: Veronique
authors.initials: V
authors.lastname: Touche
authors.forename: Christian
authors.initials: C
authors.lastname: Duhem
authors.forename: Barbara
authors.initials: B
authors.lastname: Gross
authors.forename: Robert
authors.initials: R
authors.lastname: Caiazzo
authors.forename: Julie
authors.initials: J
authors.lastname: Kerr-Conte
authors.forename: François
authors.initials: F
authors.lastname: Pattou
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Peters
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Sophie
authors.initials: S
authors.lastname: Lestavel
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D019858:Enteroendocrine Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D052216:Glucagon-Like Peptide 1 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D048068:PPAR-beta / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats
chemical_list: D001786:Blood Glucose; D048068:PPAR-beta; D012333:RNA, Messenger; D052216:Glucagon-Like Peptide 1