A Role for C/EBPβ in Regulating Peroxisome Proliferator-activated Receptor γ Activity during Adipogenesis in 3T3-L1 Preadipocytes

The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor γ (PPARγ) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin. In this study, we demonstrate that exposure of 3T3-L1 preadipocytes to DEX and insulin fails to induce adipogenesis as indicated by a lack of C/EBPα, PPARγ2, and adipose protein 2/fatty acid-binding protein expression; however, PPARγ1 is expressed. Treatment of these MIX-deficient cells with a PPARγ ligand, troglitazone, induces C/EBPα expression and rescues the block in adipogenesis. In this regard, we also show that induction of C/EBPα gene expression by troglitazone in C3H10T1/2 cells ectopically expressing PPARγ occurs in the absence of ongoing protein synthesis, suggesting a direct transactivation of the C/EBPα gene by PPARγ. Furthermore, ectopic expression of a dominant negative isoform of C/EBPβ (liver-enriched transcriptional inhibitory protein (LIP)) inhibits the induction of C/EBPα, PPARγ2, and adipose protein 2/fatty acid-binding protein by DEX, MIX, and insulin in 3T3-L1 cells without affecting the induction of PPARγ1 by DEX. Exposure of LIP-expressing preadipocytes to troglitazone along with DEX, MIX, and insulin induces differentiation into adipocytes. Additionally, we show that sustained expression of C/EBPα in these LIP-expressing adipocytes requires constant exposure to troglitazone. Taken together, these observations suggest that inhibition of C/EBPβ activity not only blocks C/EBPα and PPARγ2 expression, but it also renders the preadipocytes dependent on an exogenous PPARγ ligand for their differentiation into adipocytes. We propose, therefore, an additional role for C/EBPβ in regulating PPARγ activity during adipogenesis, and we suggest an alternative means of inducing preadipocyte differentiation that relies on the dexamethasone-associated induction of PPARγ1 expression. The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor γ (PPARγ) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin. In this study, we demonstrate that exposure of 3T3-L1 preadipocytes to DEX and insulin fails to induce adipogenesis as indicated by a lack of C/EBPα, PPARγ2, and adipose protein 2/fatty acid-binding protein expression; however, PPARγ1 is expressed. Treatment of these MIX-deficient cells with a PPARγ ligand, troglitazone, induces C/EBPα expression and rescues the block in adipogenesis. In this regard, we also show that induction of C/EBPα gene expression by troglitazone in C3H10T1/2 cells ectopically expressing PPARγ occurs in the absence of ongoing protein synthesis, suggesting a direct transactivation of the C/EBPα gene by PPARγ. Furthermore, ectopic expression of a dominant negative isoform of C/EBPβ (liver-enriched transcriptional inhibitory protein (LIP)) inhibits the induction of C/EBPα, PPARγ2, and adipose protein 2/fatty acid-binding protein by DEX, MIX, and insulin in 3T3-L1 cells without affecting the induction of PPARγ1 by DEX. Exposure of LIP-expressing preadipocytes to troglitazone along with DEX, MIX, and insulin induces differentiation into adipocytes. Additionally, we show that sustained expression of C/EBPα in these LIP-expressing adipocytes requires constant exposure to troglitazone. Taken together, these observations suggest that inhibition of C/EBPβ activity not only blocks C/EBPα and PPARγ2 expression, but it also renders the preadipocytes dependent on an exogenous PPARγ ligand for their differentiation into adipocytes. We propose, therefore, an additional role for C/EBPβ in regulating PPARγ activity during adipogenesis, and we suggest an alternative means of inducing preadipocyte differentiation that relies on the dexamethasone-associated induction of PPARγ1 expression. CCAAT/enhancer-binding protein Dulbecco's modified Eagle's medium dexamethasone 3-isobutyl-1-methylxanthine fetal bovine serum peroxisome proliferator-activated receptor adipose protein 2/fatty acid-binding protein liver-enriched transcriptional inhibitory protein liver-enriched transcriptional activator protein polymerase chain reaction sterol regulatory element-binding protein The differentiation of preadipocytes into mature fat cells is regulated by a cascade of transcription factors that interact in a complex fashion to control expression of several hundred adipogenic genes (1Morrison R.F. Farmer S.R. J. Cell. Biochem. 1999; 75 Suppl. 32: 59-67Crossref Google Scholar, 2Rosen E.D. Walkey C.J. Puigserver P. Spiegelman B.M. Genes Dev. 2000; 14: 1293-1307PubMed Google Scholar). Many different nuclear factors have been shown to influence the adipogenic process, but two families of factors in particular have received the most attention as follows: the CCAAT enhancer-binding proteins (C/EBPs)1 and the peroxisome proliferator-activated receptors (PPAR) family of nuclear hormone receptors. Three members of the C/EBP family, α, β, and δ, have been shown to play important roles in regulating adipose tissue development in mice and preadipocyte differentiation in vitro (3Darlington G.J. Ross S.E. MacDougald O.A. J. Biol. Chem. 1998; 273: 30057-30060Abstract Full Text Full Text PDF PubMed Scopus (598) Google Scholar). In contrast, only the γ form of the PPAR family is considered to regulate adipogenesis in vitro and in vivo (4Wu Z. Puigserver P. Spiegelman B.M. Curr. Opin. Cell Biol. 1999; 11: 689-694Crossref PubMed Scopus (106) Google Scholar). The temporal pattern of expression of these important adipogenic factors, and control of their activity during adipogenesis, is dependent on a variety of biological effectors and other transcription factors (5Gregoire F.M. Smas C.M. Sul H.S. Physiol. Rev. 1998; 78: 783-809Crossref PubMed Scopus (1808) Google Scholar, 6Rosen E.D. Spiegelman B.M. Annu. Rev. Cell Dev. Biol. 2000; 16: 145-171Crossref PubMed Scopus (1028) Google Scholar, 7Morrison R.F. Farmer S.R. J. Nutr. 2000; 130: 3116-3121Crossref PubMed Google Scholar). The C/EBPs belong to a larger family of basic leucine zipper (bZIP) transcription factors, which have a C-terminal leucine zipper domain for dimerization and a basic domain for binding to DNA. There are at least six members of this family, α, β, δ, γ, ε, and ζ, that can both homodimerize and heterodimerize with each other and bind to the same C/EBP regulatory element in the promoters/enhancers of many different genes. In addition, each family member can give rise to several isoforms by a process of selective use of translational start sites within each mRNA or by proteolysis of a larger precursor protein (8Welm A.L. Timchenko N.A. Darlington G.J. Mol. Cell. Biol. 1999; 19: 1695-1704Crossref PubMed Google Scholar). The C/EBPβ mRNA, for instance, gives rise to at least four isoforms corresponding to the following peptides, 38, 34, 30, and 20 kDa. The 34-kDa protein is often referred to as LAP (liver-enriched transcriptional activator protein) since it has been shown to be a potent transactivator of liver gene expression (9Descombes P. Schibler U. Cell. 1991; 67: 569-579Abstract Full Text PDF PubMed Scopus (855) Google Scholar). The 20-kDa polypeptide, however, can inhibit hepatic gene expression and is, therefore, referred to as LIP (liver-enriched transcriptional inhibitory protein) (9Descombes P. Schibler U. Cell. 1991; 67: 569-579Abstract Full Text PDF PubMed Scopus (855) Google Scholar). This LIP isoform of C/EBPβ corresponds to the C-terminal portion of the LAP protein that lacks the transactivation domain but contains the basic leucine zipper region. Consequently, LIP can act as a potent dominant negative repressor of C/EBPβ activity. In fact, ectopic expression of LIP, resulting in a LAP/LIP ratio of ∼1, blocks adipogenesis in preadipocytes in culture (10Yeh W.C. Cao Z. Classon M. McKnight S.L. Genes Dev. 1995; 9: 168-181Crossref PubMed Scopus (802) Google Scholar). PPARγ exists as two protein isoforms, γ1 and γ2, that are generated by alternative splicing of at least three different mRNAs, which are transcribed from the same gene (11Zhu Y. Qi C. Korenberg J.R. Chen X.-N. Noya D. Rao M.S. Reddy J.K. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 7921-7925Crossref PubMed Scopus (596) Google Scholar, 12Fajas L. Fruchart J.C. Auwerx J. FEBS Lett. 1998; 438: 55-60Crossref PubMed Scopus (307) Google Scholar). PPARγ1 and the same contains an additional at the isoforms of PPARγ form an with the receptor to bind to regulatory within the promoters/enhancers of many genes with of requires with a of that as as as for PPARγ S. S. S. P. C. P. J. J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). The and their as as the family of insulin as troglitazone B.M. P. Chen J. Spiegelman B.M. Cell. 1995; Full Text PDF PubMed Scopus Google Scholar, Cell. 1995; Full Text PDF PubMed Scopus Google Scholar, B.M. Chen J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). from the PPARγ gene has been in many in which the γ1 isoform is the C. M. PubMed Scopus Google Scholar). In contrast, transcription from the PPARγ2 is adipose rise to of the PPARγ2 in to the PPARγ1 isoform P. Spiegelman B.M. Genes Dev. PubMed Scopus Google Scholar). expression of PPARγ2 or in in potent induction of differentiation P. Spiegelman B.M. Cell. Full Text PDF PubMed Scopus Google Scholar). have been to the many different in regulating adipogenesis. are 3T3-L1 which can be to into mature fat cells following exposure to a of dexamethasone (DEX), (MIX), and and DEX induce expression of C/EBPβ and which in C/EBPα and PPARγ expression (10Yeh W.C. Cao Z. Classon M. McKnight S.L. Genes Dev. 1995; 9: 168-181Crossref PubMed Scopus (802) Google Scholar, Z. McKnight S.L. Genes Dev. 1991; PubMed Scopus Google Scholar, Z. Y. Farmer S.R. Genes Dev. 1995; 9: PubMed Scopus Google Scholar). PPARγ and C/EBPα are of each other as as expression of the mature Z. E.D. S. C. Darlington G.J. Spiegelman B.M. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google J.K. Farmer S.R. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). The differentiation of preadipocytes in culture not of an exogenous PPARγ In contrast, that ectopically a C/EBP or PPARγ exposure to a potent PPARγ ligand to into adipocytes P. B.M. Chen J. Spiegelman B.M. Genes Dev. PubMed Scopus Google Scholar, Z. Y. R.F. Farmer S.R. J. 1998; PubMed Scopus Google Scholar). have the to an ligand of PPARγ. The that regulate of are not by M. Spiegelman B.M. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google have a role for the sterol regulatory element-binding proteins We demonstrate that of C/EBPβ activity by from the culture medium or ectopically expressing a dominant negative form of C/EBPβ renders 3T3-L1 preadipocytes dependent on an exogenous PPARγ ligand for their differentiation into adipocytes. have also an alternative of adipogenesis, which a induction of PPARγ1 in the absence of C/EBPβ activity. Furthermore, activation of PPARγ1 in the LIP-expressing cells with troglitazone C/EBPα gene expression. and from Dulbecco's modified Eagle's medium and fetal bovine serum by and from of polymerase from from We a and the α, β, and and serum by of The cells D. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google and expression P. Spiegelman B.M. Cell. Full Text PDF PubMed Scopus Google of Spiegelman The expressing the LAP or LIP isoforms of C/EBPβ by corresponding of the C/EBPβ Z. McKnight S.L. Genes Dev. 1991; PubMed Scopus Google into and sites of the The LAP generated the following and and the LIP generated and of cells and of cells as by P. Spiegelman B.M. Cell. Full Text PDF PubMed Scopus Google D. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). cells for in medium 3T3-L1 preadipocytes and as J. Biol. Chem. Full Text PDF PubMed Google Scholar, Z. Farmer S.R. Mol. Cell. Biol. 16: PubMed Google Scholar). cells and for in with by the medium to and insulin. cells in 3T3-L1 cells expressing C/EBPβ LIP or control and cells expressing PPARγ by the same for 3T3-L1 medium and of and the cells and in the or absence of troglitazone, as following the Z. Farmer S.R. Mol. Cell. Biol. 16: PubMed Google Scholar). The cells the indicated cells in with and in of and for and for at in a and at of the in from as J.K. Farmer S.R. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google and to in the with in for at with the and an for to the of and P. Biochem. PubMed Scopus Google Scholar). in with and in at on 20 of each as for C/EBPα and PPARγ of polymerase and by protein as with and in nuclear at in a and in nuclear on for and at at The resulting at the protein binding as Y. D. Farmer S.R. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). of nuclear with of of and at for corresponding to a and with to the and at for with on for and on at for at in for exposure to for C/EBP the same as in negative control the roles of and the C/EBPs in regulating adipogenesis, we generated 3T3-L1 expressing or the dominant negative LIP the of the different on expression of PPARγ and C/EBPα, we cells to by exposure to different of dexamethasone (DEX), and in the or absence of troglitazone. to the and protein the expression of PPARγ and C/EBPα by of differentiation following exposure to DEX, MIX, and The of troglitazone to expression of these transcription factors of DEX from the culture medium differentiation of these preadipocytes into mature fat cells as indicated by the expression of C/EBPα and in each and PPARγ1 is in cells to DEX or but not to the same as that the two are with and PPARγ2, however, to be in cells to DEX with to of PPARγ1 in these cells of DEX or by exposure to troglitazone in an induction of C/EBPα and and and a corresponding of the preadipocytes into adipocytes not by and (10Yeh W.C. Cao Z. Classon M. McKnight S.L. Genes Dev. 1995; 9: 168-181Crossref PubMed Scopus (802) Google Scholar, Z. Y. Farmer S.R. Genes Dev. 1995; 9: PubMed Scopus Google Scholar, Z. Farmer S.R. Mol. Cell. Biol. 16: PubMed Google have shown that of the by which DEX and induce adipogenesis is to expression of C/EBPβ and during the of adipogenesis in 3T3-L1 which in expression of PPARγ and that these effectors in be regulating two in which DEX can induce PPARγ1 expression, but is along with DEX for C/EBPα expression. Consequently, since has been shown to regulate C/EBPβ Z. McKnight S.L. Genes Dev. 1991; PubMed Scopus Google we the induction of C/EBPα by troglitazone in cells of to a corresponding induction of In the in 3T3-L1 cells to insulin and DEX in the or absence of or troglitazone, and protein at the indicated to C/EBPβ is in cells with the of and C/EBPβ is in the absence of and of troglitazone has on C/EBPβ expression in the or absence of with and with This also that expression of PPARγ1 occurs in cells to cells in the and PPARγ1 is in both of cells or however, PPARγ2 and C/EBPα are to only in cells to DEX and and The of troglitazone in an induction of C/EBPα and PPARγ2 in cells but also expression of C/EBPα in cells to The induction of C/EBPα by troglitazone that PPARγ be of the C/EBPα this we ectopically PPARγ2 in C3H10T1/2 cells to a differentiation into adipocytes dependent on an exogenous PPARγ The in that exposure of these cells to troglitazone in the induction of C/EBPα mRNA expression that also occurs in the absence of ongoing protein are with the that PPARγ is with the C/EBPα gene to C/EBPα mRNA the selective of on C/EBPα with PPARγ1 expression to role in regulating we generated a 3T3-L1 ectopically expressing a dominant negative isoform of C/EBPβ expression of LIP in 3T3-L1 preadipocytes with of this in the cells shown is the ectopic expression of the LAP isoform of C/EBPβ in a corresponding by McKnight and (10Yeh W.C. Cao Z. Classon M. McKnight S.L. Genes Dev. 1995; 9: 168-181Crossref PubMed Scopus (802) Google ectopic expression of LIP blocks the of DEX, MIX, and to induce the differentiation of 3T3-L1 preadipocytes to into fat The shown in this but also show that troglitazone can this inhibitory of LIP as by the of following exposure of the cells to troglitazone. into the of LIP and troglitazone on the differentiation of cells to as in DEX from the culture of protein at and to that expression of LIP adipogenesis as indicated by a lack of C/EBPα and expression DEX is of PPARγ1 expression the in the of insulin and but it has on PPARγ2 expression and of troglitazone along with DEX induces adipogenesis as indicated by the expression of C/EBPα, PPARγ2, and is that DEX has a on gene expression in the or absence of LIP and with In contrast, exposure of LIP cells to and insulin only PPARγ1 with PPARγ2 expression, and troglitazone is these it not induce adipogenesis and C/EBPα This pattern of gene expression from that in the absence of induces both PPARγ1 and in the and exposure of these cells to troglitazone adipogenesis and with Taken together, these are with a in which DEX is of the preadipocytes to be to troglitazone in the absence of this induction of PPARγ1 expression. MIX, however, is only of a process C/EBPβ is in the absence of also suggest that C/EBPβ activity blocks of an activator of which renders the 3T3-L1 preadipocytes dependent on an exogenous PPARγ ligand for their differentiation into adipocytes. into the ligand of these LIP-expressing we the temporal pattern of gene expression following exposure to troglitazone as as the of troglitazone to induce adipogenesis. In the shown in cells to DEX, MIX, and insulin in the or absence of troglitazone, and proteins to The of DEX, MIX, and insulin is of the of adipogenesis in these LIP-expressing cells as indicated by induction of C/EBPβ as as PPARγ1 and with Exposure of these cells to troglitazone to have on this pattern of gene expression during the this however, troglitazone is for the induction of C/EBPα and expression. Taken together, the shown demonstrate that LIP cells in troglitazone for along with an with DEX, MIX, and in their into adipocytes on of in of the cells and the expression of PPARγ2, C/EBPα, and the troglitazone of LIP both and cells to differentiation medium DEX, MIX, and of troglitazone. protein and to of the indicated that expression of both C/EBPα and PPARγ2 with of troglitazone. of also to troglitazone to the of cells not LIP expression by the PPARγ of adipogenic gene expression in cells and cells to as in in the of of troglitazone proteins and to for expression of the indicated and are The LIP the C-terminal basic leucine zipper of the C/EBPβ and therefore, it can with other C/EBPβ isoforms and bind to DNA. therefore, to LIP troglitazone have on the binding activity of the different C/EBPs during adipogenesis. Consequently, and cells to in the or absence of troglitazone, and nuclear proteins at and The in binding of nuclear protein to an corresponding to the C/EBP regulatory element within the of the C/EBPα gene Y. D. Farmer S.R. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). The and of binding at is in the LIP and with There is a in the LIP cells that corresponds to has on the binding activity in that the in at with a larger the which is to the of This same in is in the LIP following exposure to troglitazone for the of these a of corresponding to C/EBPα, and that a of the at in cells of C/EBPα is a in C/EBPα binding activity in LIP cells following exposure to troglitazone for with In fact, the C/EBPα binding activity is in the LIP cells troglitazone with that in the Furthermore, ectopic expression of LIP has not the of C/EBPα to bind to the C/EBP regulatory This also the of binding to the C/EBP since the in the LIP cells can be with an and is at since is with an that LIP cells an exogenous PPARγ ligand as troglitazone for their into adipocytes that are not of the or it is that PPARγ1 at a for activation by the the for the ligand of the LIP we PPARγ and C/EBPα to by LIP cells to DEX, MIX, and troglitazone for We these LIP adipocytes the exogenous PPARγ ligand to gene expression. This by troglitazone from the at and expression of C/EBPα, and in these and a control of that in troglitazone for the The in of C/EBPα, and following of exposure of LIP cells to troglitazone. of the exogenous ligand at however, in an as indicated by a in expression of C/EBPα and to by of the of both PPARγ1 and constant this in the absence of troglitazone. expression of LIP not troglitazone is on the it to The differentiation of 3T3-L1 cells into mature adipocytes requires their exposure to a of DEX, MIX, and effectors have been shown to a cascade of transcriptional events that in expression of the mature the induction of C/EBPβ and which expression of PPARγ and C/EBPα (10Yeh W.C. Cao Z. Classon M. McKnight S.L. Genes Dev. 1995; 9: 168-181Crossref PubMed Scopus (802) Google Scholar, Z. McKnight S.L. Genes Dev. 1991; PubMed Scopus Google Scholar, Z. Y. Farmer S.R. Genes Dev. 1995; 9: PubMed Scopus Google Scholar, Z. Farmer S.R. Mol. Cell. Biol. 16: PubMed Google Scholar). The in this suggest an additional role for and the effectors that control expression, in regulating the of PPARγ show that adipogenesis can be in 3T3-L1 preadipocytes in the absence of C/EBPβ by the cells to an exogenous PPARγ This alternative to on the of insulin and DEX to induce PPARγ1 expression, which is of inducing C/EBPα and PPARγ2 expression following exposure to troglitazone. of C/EBPα gene expression in the absence of an exogenous PPARγ ligand on C/EBPβ expression. therefore, that expression of C/EBPα during adipogenesis can be regulated by at least two a induction of which a C/EBP regulatory element within the of the C/EBPα gene M.S. Mol. Cell. Biol. 1999; 19: PubMed Scopus Google Scholar). The other can in the absence of C/EBPβ to a induction of which is also of the C/EBPα gene in the of troglitazone. have shown that an important role for and DEX is to induce expression of C/EBPβ and which in C/EBPα and PPARγ2 expression C/EBP regulatory in the of the corresponding genes (10Yeh W.C. Cao Z. Classon M. McKnight S.L. Genes Dev. 1995; 9: 168-181Crossref PubMed Scopus (802) Google Scholar, Y. D. Farmer S.R. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, M.S. Mol. Cell. Biol. 1999; 19: PubMed Scopus Google Scholar, S.L. Biochem. PubMed Scopus Google Scholar, M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). are with these observations since inhibition of C/EBPβ activity by or expressing LIP blocks both C/EBPα and PPARγ2 expression. is the that DEX can induce PPARγ1 expression in the absence of C/EBPβ which be to a induction of however, have shown that ectopic expression of in not induce C/EBPα, or expression (10Yeh W.C. Cao Z. Classon M. McKnight S.L. Genes Dev. 1995; 9: 168-181Crossref PubMed Scopus (802) Google Scholar, Z. Farmer S.R. Mol. Cell. Biol. 16: PubMed Google Scholar). the expression of PPARγ1 in the are of expressing the adipogenic to an exogenous PPARγ ligand along with the of This that C/EBPβ play a role in regulating that to of PPARγ for this are the in a of the LIP cells for troglitazone to adipogenic gene expression have into adipocytes by a exposure to the PPARγ The most of PPARγ activity is the of within the the ligand for PPARγ has not been that of are potent of PPARγ both in in vitro as vivo S. S. S. P. C. P. J. J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, B.M. Chen J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google that control the of or their play an important role in regulating adipogenesis. In this regard, have shown that a transcription that is to to be in the of PPARγ M. Spiegelman B.M. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). In fact, is during adipogenesis, and ectopic expression in cells can fat by the PPARγ2 gene as as of PPARγ M. Spiegelman B.M. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar, Spiegelman B.M. Genes Dev. PubMed Scopus Google Scholar, L. L. J. Fruchart J.C. M. Spiegelman B.M. Auwerx J. Mol. Cell. Biol. 1999; 19: PubMed Scopus Google Scholar). is therefore, that a role for C/EBPβ in regulating PPARγ activity induction activation of have that activation of PPARγ in a variety of different in expression of many adipogenic genes C/EBPα P. Spiegelman B.M. Cell. Full Text PDF PubMed Scopus Google Z. E.D. S. C. Darlington G.J. Spiegelman B.M. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, J.K. Farmer S.R. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, P. B.M. Chen J. Spiegelman B.M. Genes Dev. PubMed Scopus Google Scholar, Z. Y. R.F. Farmer S.R. J. 1998; PubMed Scopus Google Scholar, P. 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The in suggest that PPARγ also be of a direct transactivation of the C/EBPα gene on the that activation of PPARγ by troglitazone in cells induces C/EBPα mRNA expression in the absence of ongoing protein most PPARγ PPARγ transcription by binding to PPAR regulatory at sites within the of the genes P. Spiegelman B.M. Genes Dev. PubMed Scopus Google Scholar, C. A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). that sites within the C/EBPα of in the of the C/EBPα gene have that bind to particular but to PPARγ. J. and S. We are this or other the induction of C/EBPα gene expression. in a variety of have to a for the transcriptional control of adipogenesis, which the activation of C/EBPs and PPARγ. The of C/EBPβ and in this process is to induce expression of both PPARγ2 and mice C/EBPβ suggest an alternative role for these C/EBPs in regulating adipose tissue and in the S. J. 16: PubMed Scopus Google Scholar). mice in expression of C/EBPα and PPARγ. from these have the to adipogenesis in not PPARγ or C/EBPα in to DEX, MIX, and Taken together, these observations suggest a role for C/EBPβ in regulating PPARγ and C/EBPα gene expression in cells or to a of In preadipocytes in adipose however, PPARγ and C/EBPα be by an alternative to the of effectors not in the culture to be a role for C/EBPβ and in the and of adipose tissue in vivo that is of C/EBPα and PPARγ expression, which of PPARγ In we an alternative for the transcriptional control of adipogenesis that the from these with by (10Yeh W.C. Cao Z. Classon M. McKnight S.L. Genes Dev. 1995; 9: 168-181Crossref PubMed Scopus (802) Google Scholar, Z. Y. Farmer S.R. Genes Dev. 1995; 9: PubMed Scopus Google Scholar, Z. E.D. S. C. Darlington G.J. Spiegelman B.M. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). In this C/EBPβ and regulate of PPARγ as as PPARγ2 and C/EBPα expression. Additionally, we suggest that effectors can induce expression of PPARγ1 in the absence of C/EBPβ and as part of a This can a cascade of transcription expression, with C/EBPα, which in induces expression of the adipogenic the preadipocyte is to PPARγ of the transcriptional events that regulate of PPARγ a of the adipogenesis. We and McKnight for their in We also for of the and