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PMID: 19082571 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Transcriptional co-activator peroxisome proliferator-activated receptor (PPAR)gamma co-activator-1beta is involved in the regulation of glucose-stimulated insulin secretion in INS-1E cells.

Journal of molecular medicine (Berlin, Germany) ·Vol. 87 ·No. 3 ·2009-03-00 ·Pages 299-306

Oberkofler H, Hafner M, Felder T, Krempler F, Patsch W

Abstract

Peroxisome proliferator-activated receptor-gamma co-activator-1 (PGC-1) alpha and -beta play pivotal roles in the regulation of intermediary metabolism. We have previously shown that PGC-1alpha-mediated upregulation of beta-cell sterol element binding protein (SREBP) gene expression impairs insulin secretion via increased transcription of uncoupling protein 2 (UCP2). PGC-1beta, in contrast to PGC-1alpha, directly binds to and acts as a co-activator of SREBPs and the forkhead transcription factor 2A (FOXA2) involved in pancreas development and function. To address a possible role of PGC-1beta in beta-cell function, we determined islet gene expression levels of PGC-1alpha, PGC-1beta, SREBPs, FOXA2, FOXO1, UCP2 as well as granuphilin, a critical component of the insulin secretory machinery, in Zucker diabetic fatty rats (ZDF). In comparison to controls, mRNA levels of all genes studied except for FOXA2 and FOXO1 were increased in islets of obese, fa/fa ZDF rats. The transcriptional activities of the UCP2 and granuphilin promoters were assessed in INS-1E cells in response to PGC-1beta overexpression and small interference RNA (siRNA)-mediated gene silencing. PGC-1beta as well as SREBP-1c and -2 increased transcription from the UCP2 promoter in INS-1E cells. Transient transfection of PGC-1beta-specific siRNAs significantly decreased SREBP-2-mediated transcriptional activation of the UCP2 gene. Furthermore PGC-1beta, SREBP-1c, and FOXA2 overexpression augmented granuphilin promoter activity, whereas siRNA-mediated gene knockdown of PGC-1beta reduced the effects of SREBP-1c and FOXA2 on granuphilin gene transcription and significantly increased glucose-stimulated insulin release from INS-1E cells. Our results support a role of PGC-1beta in the regulation of insulin secretion via upregulation of UCP2 and granuphilin gene expression.

MeSH Terms
Animals Blotting, Western Cell Line, Tumor Forkhead Transcription Factors/genetics,metabolism Gene Expression Glucose/pharmacology Hepatocyte Nuclear Factor 3-alpha/genetics,metabolism Insulin/metabolism Insulin Secretion Insulinoma/genetics,metabolism,pathology Ion Channels/genetics,metabolism Islets of Langerhans/metabolism Mitochondrial Proteins/genetics,metabolism Models, Biological Nerve Tissue Proteins/genetics,metabolism Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha RNA, Small Interfering/genetics RNA-Binding Proteins/genetics,metabolism Rats Rats, Zucker Reverse Transcriptase Polymerase Chain Reaction Sterol Regulatory Element Binding Protein 1/genetics,metabolism Transcription Factors/genetics,metabolism Transfection Uncoupling Protein 2 Vesicular Transport Proteins/genetics,metabolism
Chemicals
Forkhead Transcription Factors Foxa1 protein, rat Hepatocyte Nuclear Factor 3-alpha Insulin Ion Channels Mitochondrial Proteins Nerve Tissue Proteins Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Ppargc1a protein, rat RNA, Small Interfering RNA-Binding Proteins Sterol Regulatory Element Binding Protein 1 Sytl4 protein, rat Transcription Factors Ucp2 protein, rat Uncoupling Protein 2 Vesicular Transport Proteins Foxo1 protein, rat Glucose
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Oberkofler Hannes
Department of Laboratory Medicine, Landeskliniken and Paracelsus Private Medical University Salzburg, Müllner Hauptstr., Austria. h.oberkofler@salk.at
Hafner Michael
Felder Thomas
Krempler Franz
Patsch Wolfgang
References (37)
37 references, click to expand
  1. Complex haplotypes of the PGC-1alpha gene are associated with carbohydrate metabolism and type 2 diabetes.
    Diabetes. 2004 May;53(5):1385-93 PMID: 15111510
  2. Characterization of the human, mouse and rat PGC1 beta (peroxisome-proliferator-activated receptor-gamma co-activator 1 beta) gene in vitro and in vivo.
    Biochem J. 2003 Jul 1;373(Pt 1):155-65 PMID: 12678921
  3. Method for the isolation of intact islets of Langerhans from the rat pancreas.
    Diabetes. 1967 Jan;16(1):35-9 PMID: 5333500
  4. Selective association of sterol regulatory element-binding protein isoforms with target promoters in vivo.
    J Biol Chem. 2004 Sep 3;279(36):37360-7 PMID: 15220339
  5. Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes.
    Cell. 2001 Jun 15;105(6):745-55 PMID: 11440717
  6. Genipin inhibits UCP2-mediated proton leak and acutely reverses obesity- and high glucose-induced beta cell dysfunction in isolated pancreatic islets.
    Cell Metab. 2006 Jun;3(6):417-27 PMID: 16753577
  7. Multiple environmental and genetic factors influence skeletal muscle PGC-1alpha and PGC-1beta gene expression in twins.
    J Clin Invest. 2004 Nov;114(10):1518-26 PMID: 15546003
  8. Uncoupling protein 2 and islet function.
    Diabetes. 2004 Feb;53 Suppl 1:S136-42 PMID: 14749279
  9. A quantitative trait locus influencing type 2 diabetes susceptibility maps to a region on 5q in an extended French family.
    Diabetes. 2002 Dec;51(12):3568-72 PMID: 12453915
  10. PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity.
    Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12378-83 PMID: 14530391
  11. Overexpression of uncoupling protein 2 inhibits glucose-stimulated insulin secretion from rat islets.
    Diabetes. 1999 Jul;48(7):1482-6 PMID: 10389858
  12. Mutation analysis of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) and relationships of identified amino acid polymorphisms to Type II diabetes mellitus.
    Diabetologia. 2001 Dec;44(12):2220-6 PMID: 11793024
  13. Granuphilin molecularly docks insulin granules to the fusion machinery.
    J Cell Biol. 2005 Oct 10;171(1):99-109 PMID: 16216924
  14. Coactivation of Foxa2 through Pgc-1beta promotes liver fatty acid oxidation and triglyceride/VLDL secretion.
    Cell Metab. 2006 Feb;3(2):99-110 PMID: 16459311
  15. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1.
    Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8466-71 PMID: 12832613
  16. Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism.
    Endocr Rev. 2006 Dec;27(7):728-35 PMID: 17018837
  17. A genomewide scan for loci predisposing to type 2 diabetes in a U.K. population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q.
    Am J Hum Genet. 2001 Sep;69(3):553-69 PMID: 11484155
  18. A functional polymorphism in the promoter of UCP2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans.
    Diabetes. 2002 Nov;51(11):3331-5 PMID: 12401727
  19. The diabetic Zucker fatty rat.
    Proc Soc Exp Biol Med. 1983 May;173(1):68-75 PMID: 6344096
  20. Imaging analysis reveals mechanistic differences between first- and second-phase insulin exocytosis.
    J Cell Biol. 2007 May 21;177(4):695-705 PMID: 17502420
  21. The Rab27a/granuphilin complex regulates the exocytosis of insulin-containing dense-core granules.
    Mol Cell Biol. 2002 Mar;22(6):1858-67 PMID: 11865063
  22. Role of peroxisome proliferator-activated receptor-gamma coactivator-1alpha in the transcriptional regulation of the human uncoupling protein 2 gene in INS-1E cells.
    Endocrinology. 2006 Feb;147(2):966-76 PMID: 16282353
  23. PGC-1alpha: a potent transcriptional cofactor involved in the pathogenesis of type 2 diabetes.
    Diabetologia. 2006 Jul;49(7):1477-88 PMID: 16752166
  24. Foxa2 regulates multiple pathways of insulin secretion.
    J Clin Invest. 2004 Aug;114(4):512-20 PMID: 15314688
  25. Inhibition of UCP2 expression reverses diet-induced diabetes mellitus by effects on both insulin secretion and action.
    FASEB J. 2007 Apr;21(4):1153-63 PMID: 17209127
  26. A common polymorphism in the promoter of UCP2 contributes to the variation in insulin secretion in glucose-tolerant subjects.
    Diabetes. 2003 May;52(5):1280-3 PMID: 12716765
  27. Suppression of beta cell energy metabolism and insulin release by PGC-1alpha.
    Dev Cell. 2003 Jul;5(1):73-83 PMID: 12852853
  28. Superoxide-mediated activation of uncoupling protein 2 causes pancreatic beta cell dysfunction.
    J Clin Invest. 2003 Dec;112(12):1831-42 PMID: 14679178
  29. On the role of uncoupling protein-2 in pancreatic beta cells.
    Biochim Biophys Acta. 2008 Jul-Aug;1777(7-8):973-9 PMID: 18433713
  30. Hyperlipidemic effects of dietary saturated fats mediated through PGC-1beta coactivation of SREBP.
    Cell. 2005 Jan 28;120(2):261-73 PMID: 15680331
  31. The -866A/A genotype in the promoter of the human uncoupling protein 2 gene is associated with insulin resistance and increased risk of type 2 diabetes.
    Diabetes. 2004 Jul;53(7):1905-10 PMID: 15220218
  32. Granuphilin is activated by SREBP-1c and involved in impaired insulin secretion in diabetic mice.
    Cell Metab. 2006 Aug;4(2):143-54 PMID: 16890542
  33. PGC-1beta in the regulation of hepatic glucose and energy metabolism.
    J Biol Chem. 2003 Aug 15;278(33):30843-8 PMID: 12807885
  34. Evidence of an association between genetic variation of the coactivator PGC-1beta and obesity.
    J Med Genet. 2005 May;42(5):402-7 PMID: 15863669
  35. Pancreatic beta-cell protein granuphilin binds Rab3 and Munc-18 and controls exocytosis.
    Mol Biol Cell. 2002 Jun;13(6):1906-15 PMID: 12058058
  36. Impact of the peroxisome proliferator activated receptor-gamma coactivator-1beta (PGC-1beta) Ala203Pro polymorphism on in vivo metabolism, PGC-1beta expression and fibre type composition in human skeletal muscle.
    Diabetologia. 2007 Aug;50(8):1615-20 PMID: 17579828
  37. Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells.
    PLoS Biol. 2006 Feb;4(2):e31 PMID: 16366736
Article Info
Journal
Journal of molecular medicine (Berlin, Germany)
Abbr.
J Mol Med (Berl)
ISSN
1432-1440
DOI
10.1007/s00109-008-0425-0
Email
h.oberkofler@salk.at
Published
2009-03-00
Epub
2008-00-11
Pages
299-306
Language
English
Region
Germany
NLM ID
9504370
Subset
IM
Grants
Austrian Science Fund FWF · P 19893 · Austria
External Links
PubMed source DOI: 10.1007/s00109-008-0425-0 View journal details
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