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) 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.

[1]  F. Pattou,et al.  The nuclear receptor FXR is expressed in pancreatic β‐cells and protects human islets from lipotoxicity , 2010, FEBS letters.

[2]  Guangji Wang,et al.  Modulation of glucagon-like peptide-1 release by berberine: in vivo and in vitro studies. , 2010, Biochemical pharmacology.

[3]  B. Ahrén,et al.  Improved insulin sensitivity and islet function after PPARdelta activation in diabetic db/db mice. , 2010, European journal of pharmacology.

[4]  N. Tong,et al.  Activation of PPARdelta up-regulates fatty acid oxidation and energy uncoupling genes of mitochondria and reduces palmitate-induced apoptosis in pancreatic beta-cells. , 2010, Biochemical and biophysical research communications.

[5]  J. Auwerx,et al.  TGR5-mediated bile acid sensing controls glucose homeostasis. , 2009, Cell metabolism.

[6]  K. Lim,et al.  Regulation of Wnt/β‐catenin pathway by cPLA2α and PPARδ , 2008, Journal of cellular biochemistry.

[7]  M. Tzvetkov,et al.  A Peroxisome Proliferator-Activated Receptor γ-Retinoid X Receptor Heterodimer Physically Interacts with the Transcriptional Activator PAX6 to Inhibit Glucagon Gene Transcription , 2008, Molecular Pharmacology.

[8]  B. Staels,et al.  PPAR agonists: multimodal drugs for the treatment of type-2 diabetes. , 2007, Best practice & research. Clinical endocrinology & metabolism.

[9]  J. Auwerx,et al.  Anti-hyperglycemic activity of a TGR5 agonist isolated from Olea europaea. , 2007, Biochemical and biophysical research communications.

[10]  D. Drucker,et al.  Biology of incretins: GLP-1 and GIP. , 2007, Gastroenterology.

[11]  Michael Schuler,et al.  PGC1α expression is controlled in skeletal muscles by PPARβ, whose ablation results in fiber-type switching, obesity, and type 2 diabetes , 2006 .

[12]  F. Pattou,et al.  Peroxisome Proliferator–Activated Receptor α Improves Pancreatic Adaptation to Insulin Resistance in Obese Mice and Reduces Lipotoxicity in Human Islets , 2006, Diabetes.

[13]  Jerrold M. Olefsky,et al.  PPARδ regulates glucose metabolism and insulin sensitivity , 2006 .

[14]  G. Tsujimoto,et al.  Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. , 2005, Biochemical and biophysical research communications.

[15]  P. Scherer,et al.  Erratum: Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes (Diabetes (2004) 53 (1621-1629)) , 2005 .

[16]  R. Evans,et al.  Regulation of Muscle Fiber Type and Running Endurance by PPARδ , 2004, PLoS biology.

[17]  P. Scherer,et al.  Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes. , 2004, Diabetes.

[18]  M. Prentki,et al.  Glucagon-like peptide-1 prevents beta cell glucolipotoxicity , 2004, Diabetologia.

[19]  J. Holst,et al.  Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes. , 2003, The Journal of clinical endocrinology and metabolism.

[20]  R. Evans,et al.  Peroxisome-Proliferator-Activated Receptor δ Activates Fat Metabolism to Prevent Obesity , 2003, Cell.

[21]  R. Perfetti,et al.  Glucagon-like peptide-1 inhibits apoptosis of insulin-secreting cells via a cyclic 5'-adenosine monophosphate-dependent protein kinase A- and a phosphatidylinositol 3-kinase-dependent pathway. , 2003, Endocrinology.

[22]  Bei B. Zhang,et al.  Glucagon and regulation of glucose metabolism. , 2003, American journal of physiology. Endocrinology and metabolism.

[23]  D. Drucker,et al.  Role of endogenous glucagon-like peptide-1 in islet regeneration after partial pancreatectomy. , 2003, Diabetes.

[24]  R. Evans,et al.  PPARδ is a very low-density lipoprotein sensor in macrophages , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[25]  G. Mills,et al.  Transcriptional Activation of the Proglucagon Gene by Lithium and β-Catenin in Intestinal Endocrine L Cells* , 2003, The Journal of Biological Chemistry.

[26]  C. Heinlein,et al.  Repression of Glucagon Gene Transcription by Peroxisome Proliferator-activated Receptor γ through Inhibition of Pax6 Transcriptional Activity* , 2002, The Journal of Biological Chemistry.

[27]  J. Holst,et al.  Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. , 2001, The Journal of clinical endocrinology and metabolism.

[28]  S. Kliewer,et al.  A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[29]  J. Holst,et al.  Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. , 2001, Diabetes.

[30]  E. Mannucci,et al.  Glucagon‐like peptide (GLP)‐1 and leptin concentrations in obese patients with Type 2 diabetes mellitus , 2000, Diabetic medicine : a journal of the British Diabetic Association.

[31]  J. Habener,et al.  Glucagon stimulates expression of the inducible cAMP early repressor and suppresses insulin gene expression in pancreatic beta-cells. , 2000, Diabetes.

[32]  J. Ward,et al.  Growth, Adipose, Brain, and Skin Alterations Resulting from Targeted Disruption of the Mouse Peroxisome Proliferator-Activated Receptor β(δ) , 2000, Molecular and Cellular Biology.

[33]  D. Drucker,et al.  Essential requirement for Pax6 in control of enteroendocrine proglucagon gene transcription. , 1999, Molecular endocrinology.

[34]  D. Drucker,et al.  Regulation of Glucagon-Like Peptide-1 Synthesis and Secretion in the GLUTag Enteroendocrine Cell Line* * This work was supported by grants from the Canadian Diabetes Association (Margaret A. Mollet grant, to P.L.B.) and Eli Lilly. , 1998, Endocrinology.

[35]  R. Pederson,et al.  Enhanced glucose-dependent insulinotropic polypeptide secretion and insulinotropic action in glucagon-like peptide 1 receptor -/- mice. , 1998, Diabetes.

[36]  H Clevers,et al.  Two Members of the Tcf Family Implicated in Wnt/β-Catenin Signaling during Embryogenesis in the Mouse , 1998, Molecular and Cellular Biology.

[37]  A. Joyner,et al.  Glucose intolerance but normal satiety in mice with a null mutation in the glucagon–like peptide 1 receptor gene , 1996, Nature Medicine.

[38]  D. Drucker,et al.  The proglucagon gene upstream enhancer contains positive and negative domains important for tissue-specific proglucagon gene transcription. , 1995, Molecular endocrinology.

[39]  J. Philippe,et al.  Islet-specific Proteins Interact with the Insulin-response Element of the Glucagon Gene (*) , 1995, The Journal of Biological Chemistry.

[40]  J. Philippe,et al.  The Upstream Promoter Element of the Glucagon Gene, G1, Confers Pancreatic Alpha Cell-specific Expression (*) , 1995, The Journal of Biological Chemistry.

[41]  D. Drucker,et al.  Activation of proglucagon gene transcription by protein kinase-A in a novel mouse enteroendocrine cell line. , 1994, Molecular endocrinology.

[42]  K. Minaker,et al.  The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7–37) in normal and diabetic subjects , 1994, Regulatory Peptides.

[43]  D. Drucker,et al.  Proglucagon gene expression is regulated by a cyclic AMP-dependent pathway in rat intestine. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[44]  A. Wilks,et al.  Identical mRNA for preproglucagon in pancreas and gut. , 1987, European journal of biochemistry.

[45]  D. Drucker,et al.  Glucagon gene transcription in an islet cell line is regulated via a protein kinase C-activated pathway. , 1987, The Journal of biological chemistry.

[46]  D. Drucker,et al.  Proglucagon processing in a rat islet cell line resembles phenotype of intestine rather than pancreas. , 1986, Endocrinology.

[47]  L. Orci,et al.  Preproglucagon gene expression in pancreas and intestine diversifies at the level of post-translational processing. , 1986, The Journal of biological chemistry.

[48]  D. Drucker,et al.  Cell-specific post-translational processing of preproglucagon expressed from a metallothionein-glucagon fusion gene. , 1986, The Journal of biological chemistry.

[49]  J. Holst.  Glucagon and glucagon-like peptides 1 and 2. , 2010, Results and problems in cell differentiation.

[50]  E. Barroso,et al.  Peroxisome proliferator-activated receptor (PPAR) beta/delta: a new potential therapeutic target for the treatment of metabolic syndrome. , 2009, Current molecular pharmacology.

[51]  E. Barroso,et al.  Peroxisome Proliferator-Activated Receptor (PPAR)β /δ: A New Potential Therapeutic Target for the Treatment of Metabolic Syndrome , 2009 .

[52]  D. Klonoff,et al.  Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. , 2008, Current medical research and opinion.

[53]  A. Hevener,et al.  PPARdelta regulates glucose metabolism and insulin sensitivity. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[54]  Michael Schuler,et al.  PGC1alpha expression is controlled in skeletal muscles by PPARbeta, whose ablation results in fiber-type switching, obesity, and type 2 diabetes. , 2006, Cell metabolism.

[55]  M. Nauck,et al.  Reduced incretin effect in Type 2 (non-insulin-dependent) diabetes , 2006, Diabetologia.

[56]  T. Willson,et al.  PPARbeta/delta selectively induces differentiation and inhibits cell proliferation. , 2006, Cell death and differentiation.

[57]  T. Willson,et al.  PPARβ/δ selectively induces differentiation and inhibits cell proliferation , 2006, Cell Death and Differentiation.

[58]  T. Jin,et al.  TCF-4 mediates cell type-specific regulation of proglucagon gene expression by beta-catenin and glycogen synthase kinase-3beta. , 2005, The Journal of biological chemistry.

[59]  T. Willson,et al.  Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PPARdelta)--synthesis and biological activity. , 2003, Bioorganic & medicinal chemistry letters.

[60]  R. Evans,et al.  Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. , 2003, Cell.

[61]  R. Evans,et al.  PPARdelta is a very low-density lipoprotein sensor in macrophages. , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[62]  S. Bloom,et al.  Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39. , 1999, Diabetes.