The Orphan Nuclear Receptor Rev-Erbα Is a Peroxisome Proliferator-activated Receptor (PPAR) γ Target Gene and Promotes PPARγ-induced Adipocyte Differentiation

Abstract

Rev-Erbα (NR1D1) is an orphan nuclear receptor encoded on the opposite strand of the thyroid receptor α gene. Rev-Erbα mRNA is induced during adipocyte differentiation of 3T3-L1 cells, and its expression is abundant in rat adipose tissue. Peroxisome proliferator-activated receptor γ (PPARγ) (NR1C3) is a nuclear receptor controlling adipocyte differentiation and insulin sensitivity. Here we show that Rev-Erbα expression is induced by PPARγ activation with rosiglitazone in rat epididymal and perirenal adipose tissues in vivo as well as in 3T3-L1 adipocytes in vitro. Furthermore, activated PPARγ induces Rev-Erbα promoter activity by binding to the direct repeat (DR)-2 response element Rev-DR2. Mutations of the 5′ or 3′ half-sites of the response element totally abrogated PPARγ binding and transcriptional activation, identifying this site as a novel type of functional PPARγ response element. Finally, ectopic expression of Rev-Erbα in 3T3-L1 preadipocytes potentiated adipocyte differentiation induced by the PPARγ ligand rosiglitazone. These results identify Rev-Erbα as a target gene of PPARγ in adipose tissue and demonstrate a role for this nuclear receptor as a promoter of adipocyte differentiation. Rev-Erbα (NR1D1) is an orphan nuclear receptor encoded on the opposite strand of the thyroid receptor α gene. Rev-Erbα mRNA is induced during adipocyte differentiation of 3T3-L1 cells, and its expression is abundant in rat adipose tissue. Peroxisome proliferator-activated receptor γ (PPARγ) (NR1C3) is a nuclear receptor controlling adipocyte differentiation and insulin sensitivity. Here we show that Rev-Erbα expression is induced by PPARγ activation with rosiglitazone in rat epididymal and perirenal adipose tissues in vivo as well as in 3T3-L1 adipocytes in vitro. Furthermore, activated PPARγ induces Rev-Erbα promoter activity by binding to the direct repeat (DR)-2 response element Rev-DR2. Mutations of the 5′ or 3′ half-sites of the response element totally abrogated PPARγ binding and transcriptional activation, identifying this site as a novel type of functional PPARγ response element. Finally, ectopic expression of Rev-Erbα in 3T3-L1 preadipocytes potentiated adipocyte differentiation induced by the PPARγ ligand rosiglitazone. These results identify Rev-Erbα as a target gene of PPARγ in adipose tissue and demonstrate a role for this nuclear receptor as a promoter of adipocyte differentiation. Adipocyte differentiation is a complex biological process, which is reflected at the molecular level by the transcriptional activation of a number of adipocyte-specific genes and by the acquisition of the ability to accumulate cytoplasmic lipid droplets (1Cornelius P. MacDougald O.A. Lane M.D. Annu. Rev. Nutr. 1994; 14: 99-129Crossref PubMed Scopus (575) Google Scholar, 2Spiegelman B.M. Flier J.S. Cell. 1996; 87: 377-389Abstract Full Text Full Text PDF PubMed Scopus (1162) Google Scholar, 3Rosen E.D. Walkey C.J. Puigserver P. Spiegelman B.M. Genes Dev. 2000; 14: 1293-1307Crossref PubMed Google Scholar). The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ, 1The abbreviations used are: PPAR, peroxisome proliferator-activated receptor; DMEM, Dulbecco's modified Eagle's medium; EMSA, electrophoretic mobility shift assay; RSG, rosiglitazone; DR, direct repeat; IBMX, 3-methyl-1-isobutylxanthine. NR1C3) (4Tontonoz P. Hu E. Spiegelman B.M. Cell. 1994; 79: 1147-1156Abstract Full Text PDF PubMed Scopus (3133) Google Scholar, 5Tontonoz P. Hu E. Graves R.A. Budavari A.I. Spiegelman B.M. Genes Dev. 1994; 8: 1224-1234Crossref PubMed Scopus (2005) Google Scholar) and members of the CCAAT enhancer-binding protein (C/EBP) family (6Christy R.J. Yang V.W. Ntambi J.M. Geiman D.E. Landschulz W.H. Friedman A.D. Nakabeppu Y. Kelly T.J. Lane M.D. Genes Dev. 1989; 3: 1323-1335Crossref PubMed Scopus (467) Google Scholar, 7Freytag S.O. Geddes T.J. Science. 1992; 256: 379-382Crossref PubMed Scopus (251) Google Scholar, 8Freytag S.O. Paielli D.L. Gilbert J.D. Genes Dev. 1994; 8: 1654-1663Crossref PubMed Scopus (393) Google Scholar, 9Wu Z. Xie Y. Bucher N.L. Farmer S.R. Genes Dev. 1995; 9: 2350-2363Crossref PubMed Scopus (481) Google Scholar, 10Wu Z. Bucher N.L. Farmer S.R. Mol. Cell. Biol. 1996; 16: 4128-4136Crossref PubMed Google Scholar, 11Yeh W.C. Cao Z. Classon M. McKnight S.L. Genes Dev. 1995; 9: 168-181Crossref PubMed Scopus (813) Google Scholar, 12Holst D. Grimaldi P.A. Curr. Opin. Lipidol. 2002; 13: 241-245Crossref PubMed Scopus (79) Google Scholar) play key roles in this adipogenic process. In addition, the adipocyte differentiation and determination factor-1 (SREBP-1/ADD1) appears to promote adipocyte differentiation by activating the expression of PPARγ and increasing the synthesis of endogenous PPARγ ligands (13Kim J.B. Spiegelman B.M. Genes Dev. 1996; 10: 1096-1107Crossref PubMed Scopus (850) Google Scholar, 14Tontonoz P. Kim J.B. Graves R.A. Spiegelman B.M. Mol. Cell. Biol. 1993; 13: 4753-4759Crossref PubMed Scopus (536) Google Scholar, 15Kim J.B. Wright H.M. Wright M. Spiegelman B.M. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 4333-4337Crossref PubMed Scopus (562) Google Scholar). Members of the PPAR family bind as heterodimers with the retinoid X receptors (RXR) to specific response elements termed peroxisome proliferator response elements (PPRE) (for review see Ref. 16Barbier O. Torra I.P. Duguay Y. Blanquart C. Fruchart J.C. Glineur C. Staels B. Arterioscler. Thromb. Vasc. Biol. 2002; 22: 717-726Crossref PubMed Scopus (383) Google Scholar). These PPREs usually consist of a direct repeat of the PuGGTCA motif spaced by one nucleotide (DR1). The transcriptional activity of the PPARs is activated by a number of different fatty acid metabolites, most notably products of the cycloxygenase and lipoxygenase pathways. In addition, a large number of synthetic compounds are known to be potent and subtype specific PPAR ligands. For example, thiazolidinedione compounds used as insulin sensitizers in the treatment of type II diabetes are high affinity PPARγ ligands (17Willson T.M. Lambert M.H. Kliewer S.A. Annu. Rev. Biochem. 2001; 70: 341-367Crossref PubMed Scopus (542) Google Scholar). Rev-Erbα (NR1D1) is another nuclear receptor, the expression of which is induced during adipocyte differentiation (18Chawla A. Lazar M.A. J. Biol. Chem. 1993; 268: 16265-16269Abstract Full Text PDF PubMed Google Scholar). Rev-Erbα is highly expressed in adipose tissue but also in skeletal muscle, liver and brain (18Chawla A. Lazar M.A. J. Biol. Chem. 1993; 268: 16265-16269Abstract Full Text PDF PubMed Google Scholar, 19Forman B.M. Chen J. Blumberg B. Kliewer S.A. Henshaw R. Ong E.S. Evans R.M. Mol. Endocrinol. 1994; 8: 1253-1261Crossref PubMed Scopus (184) Google Scholar, 20Lazar M.A. Hodin R.A. Darling D.S. Chin W.W. Mol. Cell. Biol. 1989; 9: 1128-1136Crossref PubMed Scopus (264) Google Scholar, 21Miyajima N. Horiuchi R. Shibuya Y. Fukushige S. Matsubara K. Toyoshima K. Yamamoto T. Cell. 1989; 57: 31-39Abstract Full Text PDF PubMed Scopus (200) Google Scholar). Since no ligand has been identified so far, Rev-Erbα is considered as an orphan member of the nuclear receptor superfamily. Rev-Erbα has been shown to act as a negative regulator of transcription (22Laudet V. Adelmant G. Curr. Biol. 1995; 5: 124-127Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar) binding either as monomer on nuclear receptor half-site motifs flanked 5′ by an A/T rich sequence (A/T PuGGTCA), or as a homodimer to a direct repeat of the PuGGTCA motif spaced by two nucleotides (DR2). We have previously shown that PPARα activates the expression of Rev-Erbα through an atypical PPRE, a DR-2 element, in the Rev-Erbα promoter (23Gervois P. Chopin-Delannoy S. Fadel A. Dubois G. Kosykh V. Fruchart J.C. Najib J. Laudet V. Staels B. Mol. Endocrinol. 1999; 13: 400-409PubMed Google Scholar). Transcriptional activation by PPARγ through a DR-2 element has so far not been reported. However, since Rev-Erbα is induced during the course of adipocyte differentiation, we decided to investigate whether PPARγ could be involved in transcriptional induction of Rev-Erbα expression in adipocytes. Furthermore, we wanted to investigate whether Rev-Erbα plays a modulatory role in the process of adipogenesis. Our results from both in vivo and in vitro studies demonstrate that treatment with the PPARγ agonist rosiglitazone increases Rev-Erbα gene expression and that PPARγ activates Rev-Erbα transcription via the Rev-DR2 response element present in the human Rev-Erbα promoter. Finally, we show that ectopic expression of Rev-Erbα in 3T3-L1 preadipocytes significantly augments the adipogenic activity of the PPARγ selective ligand rosiglitazone. Animals—Male Sprague-Dawley rats (10 weeks old) were treated for 14 days by gavage with rosiglitazone (10 mg/kg/d) suspended in 1% carboxymethylcellulose solution. Control animals received an equal volume (5 ml/kg/d) of carboxymethylcellulose solution. At the end of the experiments, animals were sacrified by exsanguination under ether anesthesia. Adipose tissues were removed immediately and frozen in liquid nitrogen. RNA Analysis—RNA extraction of mice adipose tissues and 3T3-L1 cells and Northern blot analysis were performed as previously described (24Staels B. van Tol A. Andreu T. Auwerx J. Arterioscler. Thromb. 1992; 12: 286-294Crossref PubMed Google Scholar) using rat Rev-Erbα (20Lazar M.A. Hodin R.A. Darling D.S. Chin W.W. Mol. Cell. Biol. 1989; 9: 1128-1136Crossref PubMed Scopus (264) Google Scholar), mouse PPARγ (25Barak Y. Nelson M.C. Ong E.S. Jones Y.Z. Ruiz-Lozano P. Chien K.R. Koder A. Evans R.M. Mol. Cell. 1999; 4: 585-595Abstract Full Text Full Text PDF PubMed Scopus (1659) Google Scholar), rat aP2 (26Ross S.R. Graves R.A. Greenstein A. Platt K.A. Shyu H.L. Mellovitz B. Spiegelman B.M. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 9590-9594Crossref PubMed Scopus (184) Google Scholar), chicken β-actin (27Cleveland D.W. Lopata M.A. MacDonald R.J. Cowan N.J. Rutter W.J. Kirschner M.W. Cell. 1980; 20: 95-105Abstract Full Text PDF PubMed Scopus (1312) Google Scholar), or rat 36B4 (28Masiakowski P. Breathnach R. Bloch J. Gannon F. Krust A. Chambon P. Nucleic Acids Res. 1982; 10: 7895-7903Crossref PubMed Scopus (702) Google Scholar) cDNA probes. For extraction of RNA, Trizol reagent (Invitrogen) was used following the manufacturer's instructions. Northern analysis was performed using Ultrahyb hybridization solution (Ambion, Austin, TX). Hybridization and washes were done according to the manufacturer's directions. Reverse transcription was performed with MMLV with of RNA following the manufacturer's For were by on a using specific in was performed in a volume of of the reagent as by the The were for by of at at and at mRNA were to The are of in a human Rev-Erbα promoter were described previously G. A. D. Laudet V. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar), 3T3-L1 and cells were from were in DMEM, with and in a at were as described previously (23Gervois P. Chopin-Delannoy S. Fadel A. Dubois G. Kosykh V. Fruchart J.C. Najib J. Laudet V. Staels B. Mol. Endocrinol. 1999; 13: 400-409PubMed Google Scholar). 3T3-L1 preadipocytes were using the lipid as described previously E. J. J. Fruchart J.C. R. Staels B. J. Res. 1999; Full Text Full Text PDF PubMed Google Scholar). were on using a were performed in and at In and and were in vitro with and using the mobility shift with were performed as described previously (23Gervois P. Chopin-Delannoy S. Fadel A. Dubois G. Kosykh V. Fruchart J.C. Najib J. Laudet V. Staels B. Mol. Endocrinol. 1999; 13: 400-409PubMed Google Scholar). For experiments, increasing of the were the The were on in at were and at to and cells D. S. A. J. PubMed Google Scholar) were in at in a In to that the sequence of human Rev-Erbα was in of the site and the gene of the G. E. A. P. K. V. D. Proc. Natl. Acad. Sci. U. S. A. 1993; PubMed Scopus Google Scholar) using the to the Rev-Erbα sequence was and used the as a negative The was to expression of the Rev-Erbα protein and the by the cells were with the using (Invitrogen) and for using the 3T3-L1 cells were with the or as previously described V. C. F. T. C. V. B. 2000; PubMed Scopus Google Scholar). were used for the studies and cells were in and The cells were by the of Lane M.D. M.A. Kelly T.J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). days cells were to differentiation and for the cells were in with or rosiglitazone The was 3T3-L1 preadipocytes were under the but either with differentiation or differentiation treatment the cells were with in and with or RNA was as described P. Hu E. J. Spiegelman B.M. Mol. Cell. Biol. 1995; PubMed Google Scholar). of PPARγ Rev-Erbα mRNA in Adipose to whether PPARγ activation Rev-Erbα expression in rats were treated for 14 days with a highly specific and potent PPARγ ligand J.M. T.M. Kliewer S.A. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). The expression of Rev-Erbα was in epididymal and perirenal adipose tissue by Northern blot with treated rosiglitazone treatment Rev-Erbα mRNA both in epididymal and perirenal adipose tissue no in β-actin mRNA was These demonstrate that PPARγ Rev-Erbα mRNA in adipose tissue in PPARγ Rev-Erbα mRNA in 3T3-L1 the molecular and of this we the of Rev-Erbα mRNA expression by rosiglitazone in the 3T3-L1 were in days cells cells were to and with the differentiation IBMX, and either rosiglitazone or was RNA was at and and used for Northern previously (18Chawla A. Lazar M.A. J. Biol. Chem. 1993; 268: 16265-16269Abstract Full Text PDF PubMed Google Scholar), Rev-Erbα mRNA differentiation of preadipocytes adipocytes and However, with the differentiation Rev-Erbα mRNA were induced in the of rosiglitazone. Rev-Erbα mRNA were days in 3T3-L1 adipocytes treated with rosiglitazone with and is known to be a potent of differentiation, in to direct of rosiglitazone on Rev-Erbα gene expression and via differentiation, we whether rosiglitazone was to Rev-Erbα in adipocytes. shown in and rosiglitazone activated the expression of Rev-Erbα as well as the adipocyte protein a PPARγ target gene P. Hu E. Graves R.A. Budavari A.I. Spiegelman B.M. Genes Dev. 1994; 8: 1224-1234Crossref PubMed Scopus (2005) Google Scholar), in adipocytes. of protein synthesis by a of Rev-Erbα and could not be used to investigate whether the induction of Rev-Erbα was by PPARγ not demonstrate that activation of PPARγ increases Rev-Erbα mRNA during in vitro differentiation of 3T3-L1 preadipocytes as well as in adipocytes. PPARγ Rev-Erbα at the Transcriptional has previously been shown to the human Rev-Erbα promoter in via a DR-2 element (23Gervois P. Chopin-Delannoy S. Fadel A. Dubois G. Kosykh V. Fruchart J.C. Najib J. Laudet V. Staels B. Mol. Endocrinol. 1999; 13: 400-409PubMed Google Scholar), through which Rev-Erbα also its transcription G. A. D. Laudet V. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar). whether this site also the activation of the Rev-Erbα promoter by PPARγ in were using by the Rev-Erbα promoter. 3T3-L1 cells were with the PPARγ expression or and treated with rosiglitazone or Rev-Erbα promoter activity was induced by PPARγ an that was in the of rosiglitazone Rev-Erbα promoter activity was by rosiglitazone in the of to the of endogenous PPARγ in These that Rev-Erbα gene transcription is induced by rosiglitazone via investigate the of the DR-2 element in the induction by Rev-Erbα promoter in which the Rev-DR2 site was were Mutations the motif as described G. A. D. Laudet V. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar) of the Rev-DR2 site in the of Rev-Erbα promoter by rosiglitazone and PPARγ These results that the Rev-DR2 site the transcriptional induction of Rev-Erbα by whether the Rev-DR2 site could also as a element in of a were performed using the or of the Rev-DR2 site in of the promoter and In cells, of on the Rev-DR2 to a induction of transcription activity with was in the of rosiglitazone. PPARγ not the Rev-DR2 site in its half-site Furthermore, of the of the site also by These results demonstrate that the Rev-Erbα human promoter is by PPARγ and that this induction is via the Rev-DR2 PPARγ as a with to the Rev-DR2 investigate whether PPARγ to the Rev-DR2 electrophoretic mobility shift were performed using in vitro PPARγ and Since the Rev-DR2 site was previously described as a Rev-Erbα response element, binding of Rev-Erbα was as a G. A. D. Laudet V. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar), Rev-Erbα both as and as monomer to the Rev-DR2 Furthermore, no binding was on the Rev-DR2 a in the Rev-Erbα as a monomer to the Rev-DR2 a in the in with G. A. D. Laudet V. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar). or PPARγ not bind to either or Rev-DR2 that PPARγ bind as a binding to the Rev-DR2 site was PPARγ was in the of The binding was specific since was by of The of the binding complex was by the of a specific D. E. K. R. Najib J. M. Fruchart J.C. S. A. Flier J. Staels B. Auwerx J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), which of the The binding was by of both the or half-sites of the Rev-DR2 element. the binding affinity of the for the Rev-DR2 were performed binding of to the site in the aP2 promoter P. Hu E. Graves R.A. Budavari A.I. Spiegelman B.M. Genes Dev. 1994; 8: 1224-1234Crossref PubMed Scopus (2005) Google Scholar) and the Rev-DR2 shown in with the Rev-DR2 site binding to both the Rev-DR2 and aP2 These demonstrate that PPARγ as a with to the Rev-DR2 site of the Rev-Erbα with significantly affinity with the aP2 site Rev-Erbα the of PPARγ a role of Rev-Erbα in human Rev-Erbα was a and 3T3-L1 preadipocytes were with the or the of cells but not 3T3-L1 cells were with an differentiation which PPARγ activation with rosiglitazone for differentiation, and either rosiglitazone or was from to The of Rev-Erbα in or cells was by blot and Northern blot analysis of 3T3-L1 cells treated for days with the differentiation blot analysis the of ectopic expressed human Rev-Erbα protein in but not in the cells Since the used was a its affinity was to endogenous Rev-Erbα However, both ectopic and endogenous Rev-Erbα expression was by Northern blot analysis in cells, cells expressed endogenous Rev-Erbα The of ectopic Rev-Erbα on adipocyte differentiation was using to in 3T3-L1 cells induced to in and IBMX, but no differentiation is on the of the PPARγ agonist rosiglitazone. In the of ectopic expression of Rev-Erbα induced a in and However, rosiglitazone was a in was in the cells Rev-Erbα with These were by a induction of mRNA of the adipocyte-specific and PPARγ target expression was induced by rosiglitazone and Rev-Erbα a in PPARγ mRNA was in with cells, which be a of the differentiation of the In addition, rosiglitazone treatment induced PPARγ expression to PPARγ E. S. A. J. P. Chen S. E.D. K. Spiegelman B.M. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). mRNA of another differentiation were also induced by Rev-Erbα as mRNA level was induced by rosiglitazone in cells, to the of PPARγ and Z. E.D. R. S. Adelmant G. C. Spiegelman B.M. Mol. Cell. 1999; 3: Full Text Full Text PDF PubMed Scopus Google Scholar). However, in Rev-Erbα cells, rosiglitazone treatment not the expression of an of adipocyte differentiation, and were rosiglitazone to the differentiation of the cells under the mRNA of transcription were not by expression the of Rev-Erbα on the expression of PPARγ and was 3T3-L1 cells were under IBMX, and induction of and endogenous Rev-Erbα were in the with the to of adipogenic were cells and cells that the cells not Rev-Erbα cells expressed Rev-Erbα mRNA to present in 3T3-L1 cells in that the Rev-Erbα Rev-Erbα the Rev-Erbα and expression the was in the of Finally, no was in and mRNA under a role of Rev-Erbα as an of The expression of the nuclear receptor Rev-Erbα has previously been to be during adipocyte differentiation (18Chawla A. Lazar M.A. J. Biol. Chem. 1993; 268: 16265-16269Abstract Full Text PDF PubMed Google Scholar). However, the of this induction and the role of Rev-Erbα in In the present we demonstrate that PPARγ activation by rosiglitazone induces Rev-Erbα mRNA expression both in vivo in adipose tissue of rats and in vitro in 3T3-L1 adipocytes. that the of human Rev-Erbα expression by rosiglitazone at the transcriptional level via activation of of the Rev-DR2 site in the Rev-Erbα promoter Rev-Erbα transcription identifying this site as a novel type of Finally, we show that ectopic Rev-Erbα adipocyte differentiation induced by PPARγ analysis and of Rev-Erbα that the of the ligand is by that this receptor not have endogenous ligands J.M. M. Mol. Endocrinol. 2000; 14: PubMed Scopus Google Scholar). the of Rev-Erbα expression a level of of receptor Rev-Erbα expression has been to be by a of Rev-Erbα its expression via a Rev-DR2 site in its promoter G. A. D. Laudet V. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar). In rat as well as in of human I.P. V. F. R. Laudet V. Fruchart J.C. Kosykh V. Staels B. 2000; PubMed Google Scholar) and rat A. F. U. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar), Rev-Erbα expression in a In addition, rat and human Rev-Erbα expression is also under of nuclear as the receptor I.P. V. F. R. Laudet V. Fruchart J.C. Kosykh V. Staels B. 2000; PubMed Google Scholar). we previously that human Rev-Erbα expression in liver via PPARα binding to the Rev-DR2 site (23Gervois P. Chopin-Delannoy S. Fadel A. Dubois G. Kosykh V. Fruchart J.C. Najib J. Laudet V. Staels B. Mol. Endocrinol. 1999; 13: 400-409PubMed Google Scholar). we that activation of PPARγ induces Rev-Erbα gene expression in adipose tissue. induction at the transcriptional level through binding of PPARγ to the Rev-DR2 in a as described for Rev-Erbα as a PPARγ target gene in adipose tissue. since PPARγ elements so far identified are elements of a direct repeat of the sequence by one identify the DR-2 element as a novel type of PPARγ response element. PPARα and PPARγ a number of target which and expression in which have on but target genes in adipose tissue of rats D.L. F. G. Z. J. M. A. A. J. A. D.E. 2002; PubMed Scopus Google Scholar, K. J. R.A. M. S. Staels B. Auwerx J. J. 1996; PubMed Scopus Google Scholar, G. K. Staels B. Auwerx J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Rev-Erbα is another of a gene expression is induced by PPARα in liver and by PPARγ in adipose tissue. The molecular the of have been The transcription a of expression of different transcription The activation of and PPARs are in the adipogenic process. and are induced during differentiation in 3T3-L1 preadipocytes and to play an role in the of the adipogenic and the expression of PPARγ Z. Xie Y. Bucher N.L. Farmer S.R. Genes Dev. 1995; 9: 2350-2363Crossref PubMed Scopus (481) Google Scholar, 10Wu Z. Bucher N.L. Farmer S.R. Mol. Cell. Biol. 1996; 16: 4128-4136Crossref PubMed Google Scholar) via two binding in the promoter of D. E. 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Our results show that Rev-Erbα is a target gene of PPARγ Rev-Erbα is also a target gene for Since Rev-Erbα is a transcription we whether in the adipogenic Rev-Erbα significantly under the differentiation is on PPARγ Rev-Erbα is not a PPARγ target but also the adipogenic activity of this The that ectopic expression of Rev-Erbα increases the expression of the PPARγ target and that Rev-Erbα the adipogenic of The that Rev-Erbα also induces PPARγ expression could be an of the of adipocyte differentiation, since this is also under of rosiglitazone treatment Rev-Erbα could PPARγ expression by with the expression or activity of a transcription that PPARγ Rev-Erbα not and mRNA appears to play a role as an of of PPARγ Since Rev-Erbα is a of gene also promote adipocyte differentiation via the of or via negative with M. J. F. S. T. T. Y. Shibuya Y. K. S. Biol. 5: PubMed Scopus Google Scholar). the protein B. M. S. 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PubMed Google Scholar) were by and the G. E. A. P. K. V. D. Proc. Natl. Acad. Sci. U. S. A. 1993; PubMed Scopus Google Scholar) by of The Rev-Erbα cDNA and promoter G. A. D. Laudet V. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar) were a of We to for on the