PPARβ/δ Activation Induces Enteroendocrine L Cell GLP-1 Production

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) beta/delta is a nuclear receptor that improves glucose homeostasis and pancreas islet function in diabetic animal models. Here, we investigated whether PPAR beta/delta 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, PPAR beta/delta-null, and ob/ob C57Bl/6 mice treated with the PPAR beta/delta synthetic agonists GW501516 or GW0742. RESULTS: PPAR beta/delta 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 PPAR beta/delta -deficient mice. Treatment of wildtype 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, PPAR beta/delta agonists activate the proglucagon gene transcription by interfering with the beta-catenin/TCF-4 pathway. CONCLUSIONS: Our data show that PPAR beta/delta activation potentiates GLP-1 production by the small intestine. Pharmacologic targeting of PPAR beta/delta is a promising approach in the treatment of patients with type 2 diabetes mellitus, especially in combination with dipeptidyl peptidase IV inhibitors.