Peroxisome Proliferator-activated Receptor (PPAR)-2 Controls Adipocyte Differentiation and Adipose Tissue Function through the Regulation of the Activity of the Retinoid X Receptor/PPARγ Heterodimer
The peroxisome proliferator-activated receptor-γ (PPARγ, NR1C3) in complex with the retinoid X receptor (RXR) plays a central role in white adipose tissue (WAT) differentiation and function, regulating the expression of key WAT proteins. In this report we show that poly(ADP-ribose) polymerase-2 (PARP-2), also known as an enzyme participating in the surveillance of the genome integrity, is a member of the PPARγ/RXR transcription machinery. PARP-2-/- mice accumulate less WAT, characterized by smaller adipocytes. In the WAT of PARP-2-/- mice the expression of a number of PPARγ target genes is reduced despite the fact that PPARγ1 and -γ2 are expressed at normal levels. Consistent with this, PARP-2-/- mouse embryonic fibroblasts fail to differentiate to adipocytes. In transient transfection assays, PARP-2 small interference RNA decreases basal activity and ligand-dependent activation of PPARγ, whereas PARP-2 overexpression enhances the basal activity of PPARγ, although it does not change the maximal ligand-dependent activation. In addition, we show a DNA-dependent interaction of PARP-2 and PPARγ/RXR heterodimer by chromatin immunoprecipitation. In combination, our results suggest that PARP-2 is a novel cofactor of PPARγ activity. The peroxisome proliferator-activated receptor-γ (PPARγ, NR1C3) in complex with the retinoid X receptor (RXR) plays a central role in white adipose tissue (WAT) differentiation and function, regulating the expression of key WAT proteins. In this report we show that poly(ADP-ribose) polymerase-2 (PARP-2), also known as an enzyme participating in the surveillance of the genome integrity, is a member of the PPARγ/RXR transcription machinery. PARP-2-/- mice accumulate less WAT, characterized by smaller adipocytes. In the WAT of PARP-2-/- mice the expression of a number of PPARγ target genes is reduced despite the fact that PPARγ1 and -γ2 are expressed at normal levels. Consistent with this, PARP-2-/- mouse embryonic fibroblasts fail to differentiate to adipocytes. In transient transfection assays, PARP-2 small interference RNA decreases basal activity and ligand-dependent activation of PPARγ, whereas PARP-2 overexpression enhances the basal activity of PPARγ, although it does not change the maximal ligand-dependent activation. In addition, we show a DNA-dependent interaction of PARP-2 and PPARγ/RXR heterodimer by chromatin immunoprecipitation. In combination, our results suggest that PARP-2 is a novel cofactor of PPARγ activity. Adipose tissue is composed of adipocytes that store energy in the form of triglycerides. Excessive accumulation of white adipose tissue (WAT) 2The abbreviations used are: WATwhite adipose tissuePPARperoxisome proliferator-activated receptorPARP-1 and -2poly(ADP-ribose) polymerase-1 and -2TTF1thyroid transcription factor-1WTwild typeRT-qPCRreverse transcription-coupled quantitative PCRaP2adipocyte fatty acid-binding protein 2ERβestrogen receptor βK19keratin-19ChIPchromatin immunoprecipitationRXRretinoid X receptorHEK 293human embryonic kidney 293TNFαtumor necrosis factor αCREBcAMP-response element-binding proteinDMEMDulbecco's modified Eagle's mediumMEFmouse embryonic fibroblastsiRNAsmall interference RNABES2[bis(2-hydroxyethyl)amino]ethanesulfonic acid leads to obesity, whereas its absence leads to lipodystrophic syndromes. The peroxisome proliferator-activated receptor-γ (PPARγ, NR1C3) is the main protein orchestrating the differentiation and function of WAT, as evidenced by the combination of in vitro studies, the analysis of mouse models, and the characterization of patients with mutations in the human PPARγ gene (1Gurnell M. Best Pract. Res. Clin. Endocrinol. Metab. 2005; 19: 501-523Crossref PubMed Scopus (71) Google Scholar, 2Knouff C. Auwerx J. Endocr. Rev. 2004; 25: 899-918Crossref PubMed Scopus (244) Google Scholar). PPARγ acts as heterodimer with the retinoid X receptor (RXR) (3Fajas L. Auboeuf D. Raspe E. Schoonjans K. Lefebvre A.M. Saladin R. Najib J. Laville M. Fruchart J.C. Deeb S. Vidal-Puig A. Flier J. Briggs M.R. Staels B. Vidal H. Auwerx J. J. Biol. Chem. 1997; 272: 18779-18789Abstract Full Text Full Text PDF PubMed Scopus (1087) Google Scholar). The PPARγ/RXR receptor dimer is involved in the transcriptional control of energy, lipid, and glucose homeostasis (4Evans R.M. Barish G.D. Wang Y.X. Nat. Med. 2004; 10: 355-361Crossref PubMed Scopus (1293) Google Scholar, 5Cock T.A. Houten S.M. Auwerx J. EMBO Rep. 2004; 5: 142-147Crossref PubMed Scopus (127) Google Scholar). The actions of PPARγ are mediated by two protein isoforms, the widely expressed PPARγ1 and adipose tissue-restricted PPARγ2, both produced from a single gene by alternative splicing and differing only by an additional 28 amino acids in the N terminus of PPARγ2 (3Fajas L. Auboeuf D. Raspe E. Schoonjans K. Lefebvre A.M. Saladin R. Najib J. Laville M. Fruchart J.C. Deeb S. Vidal-Puig A. Flier J. Briggs M.R. Staels B. Vidal H. Auwerx J. J. Biol. Chem. 1997; 272: 18779-18789Abstract Full Text Full Text PDF PubMed Scopus (1087) Google Scholar, 6Tontonoz P. Hu E. Graves R.A. Budavari A.I. Spiegelman B.M. Genes Dev. 1994; 8: 1224-1234Crossref PubMed Scopus (2005) Google Scholar). white adipose tissue peroxisome proliferator-activated receptor poly(ADP-ribose) polymerase-1 and -2 thyroid transcription factor-1 wild type reverse transcription-coupled quantitative PCR adipocyte fatty acid-binding protein 2 estrogen receptor β keratin-19 chromatin immunoprecipitation retinoid X receptor human embryonic kidney 293 tumor necrosis factor α cAMP-response element-binding protein Dulbecco's modified Eagle's medium mouse embryonic fibroblast small interference RNA 2[bis(2-hydroxyethyl)amino]ethanesulfonic acid PPARγ is activated by binding of small lipophilic ligands, mainly fatty acids, derived from nutrition or metabolic pathways, or synthetic agonists, like the anti-diabetic thiazoli-denediones (2Knouff C. Auwerx J. Endocr. Rev. 2004; 25: 899-918Crossref PubMed Scopus (244) Google Scholar, 7Rosen E.D. Spiegelman B.M. J. Biol. 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These corepressors and coactivators determine transcriptional activity by altering chromatin structure via enzyme such as histone deacetylases and histone acetyltransferases (CREB-binding protein/p300). Other mechanisms include DNA methylation, ATP-dependent remodeling, protein phosphorylation, sumoylation, ubiquitinylation, and poly(ADP-ribosyl)ation. Poly(ADP-ribose) polymerase-2 (PARP-2) was described by Ame et al. (12Ame J.C. Rolli V. Schreiber V. Niedergang C. Apiou F. Decker P. Muller S. Hoger T. Menissier-de Murcia J. de Murcia G. J. Biol. Chem. 1999; 274: 17860-17868Abstract Full Text Full Text PDF PubMed Scopus (616) Google Scholar) in 1999 as a 66.2-kDa nuclear protein with poly-(ADP-ribosyl)ating activity. Through its DNA-binding domain in the N terminus (amino acids 1-62), PARP-2 can bind to DNase I-treated DNA and to aberrant DNA forms, and its subsequent activation results in poly(ADP-ribose) polymer formation (12Ame J.C. Rolli V. Schreiber V. Niedergang C. Apiou F. Decker P. Muller S. Hoger T. Menissier-de Murcia J. de Murcia G. J. Biol. Chem. 1999; 274: 17860-17868Abstract Full Text Full Text PDF PubMed Scopus (616) Google Scholar). According to the general scheme of PARP activation, the active enzyme catalyzes the polymerization of poly(ADP-ribose) polymer onto different acceptor proteins and itself using NAD+ as a substrate (13Schreiber V. Dantzer F. Ame J.C. de Murcia G. Nat. Rev. Mol. Cell. Biol. 2006; 7: 517-528Crossref PubMed Scopus (1589) Google Scholar). PARP-2 shares a similar catalytic domain (amino acid 202-593) as poly(ADP-ribose) polymerase-1 (PARP-1) (14Oliver A.W. Ame J.C. Roe S.M. Good V. de Murcia G. Pearl L.H. Nucleic Acids Res. 2004; 32: 456-464Crossref PubMed Scopus (93) Google Scholar), the founding member of the PARP family, though PARP-2 has a smaller reaction velocity compared with PARP-1 (12Ame J.C. Rolli V. Schreiber V. Niedergang C. Apiou F. Decker P. Muller S. Hoger T. Menissier-de Murcia J. de Murcia G. J. Biol. Chem. 1999; 274: 17860-17868Abstract Full Text Full Text PDF PubMed Scopus (616) Google Scholar). PARP-2 has multiple in vivo functions comprising DNA surveillance and DNA repair processes (reviewed in Ref. 15Huber A. Bai P. Menissier-de Murcia J. de Murcia G. DNA Repair (Amst.). 2004; 3: 1103-1108Crossref PubMed Scopus (191) Google Scholar), spermatogenesis (16Tramontano F. Di M.S. Quesada P. J. Cell. Biochem. 2005; 94: 58-66Crossref PubMed Scopus (19) Google Scholar, 17Dantzer F. Mark M. Quenet D. Scherthan H. Huber A. Liebe B. Monaco L. Chicheportiche A. Sassone-Corsi P. de Murcia G. Menissier-de Murcia J. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 14854-14859Crossref PubMed Scopus (92) Google Scholar), inflammation, and oxidative injury (18Kofler J. Otsuka T. Zhang Z. Noppens R. Grafe M.R. Koh D.W. Dawson V.L. Menisser-de Murcia J. Hurn P.D. Traystman R.J. J. Cereb. Blood Flow Metab. 2006; 26: 135-141Crossref PubMed Scopus (54) Google Scholar, 19Mota R.A. Sanchez-Bueno F. Saenz L. 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L. S. Auwerx J. Briggs M. Cell 1999; 10: Google Scholar). the PPARγ are in the these that PARP-2-/- differentiate less adipocytes. The expression of PPARγ target such as fatty acid and adipocyte fatty acid-binding protein 2 in PARP-2 of in PARP-2 expression we used 293 with a PPARγ2 expression and a In these we the expression of PARP-2 expression by overexpression and the of PARP-2 we used the whereas PARP-2 overexpression we used the The and the as the PARP-2 by using a both the and the PARP-2 protein whereas the PARP-2 not the PARP-2 levels. in PARP-2 protein was of the overexpression PARP-2 the basal PPARγ activity and receptor activation by its synthetic PARP-2 overexpression by the basal PPARγ although it does not change the ligand-dependent activation by this of PARP-2 was PPARγ, we similar the nuclear and and the estrogen receptor β of PARP-2 the basal activity of both and and PARP-2 overexpression not activity. The activation of and with and was not modified by the of PARP-2 In addition, PARP-2 PARP-2 overexpression an the basal or activity of these results of the PARP-2 the of the an interaction PPARγ and PARP-2 we used chromatin from we used PARP-2 and and a as used to the of the P. Hu E. Graves R.A. Budavari A.I. Spiegelman B.M. Genes Dev. 1994; 8: 1224-1234Crossref PubMed Scopus (2005) Google Scholar) and K. P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) as by PPARγ, and keratin-19 as a M. I. C. A. J. R.J. Mol. Biol. Cell. 2004; PubMed Scopus Google Scholar). 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S. 1997; PubMed Google Scholar). expression was not in mice it was its expression was not by the absence of PARP-2, it is less that is a of the in the PARP-2-/- is also that to the in the PARP-2-/- was in the expression of the and PARP-2-/- expression of multiple PPARγ target genes involved in adipocyte of both PPARγ was PPARγ/RXR In the differentiation of the PARP-2-/- adipocytes was compared with the differentiation of the of the differentiation the expression of both PPARγ1 and PPARγ2 was in the PARP-2-/- the of the expression of the PPARγ target genes was In transfection assays, the of PARP-2 results in the whereas PARP-2 overexpression by The of PARP-2 PPARγ, or the and and the PARP-2 these it is of the PPARγ/RXR transcription complex as by assays, that PARP-2 as a PPARγ/RXR receptor of the PPARγ/RXR nuclear receptor dimer be the the of the PARP-2-/- PARP-2 the to the of PARP-2 PPARγ was compared with and that PARP-2 acts report in vitro and in vivo that PARP-2 be a cofactor of nuclear receptor PARP-2 is a protein with multiple These functions DNA repair (reviewed in Ref. 15Huber A. 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