FOXO1 Represses Peroxisome Proliferator-activated Receptor-γ1 and -γ2 Gene Promoters in Primary Adipocytes
FOXO1 and peroxisome proliferator-activated receptor-γ (PPARγ) are crucial transcription factors that regulate glucose metabolism and insulin responsiveness in insulin target tissues. We have shown that, in primary rat adipocytes, both factors regulate transcription of the insulin-responsive GLUT4 gene and that PPARγ2 detachment from the GLUT4 promoter upon thiazolidinedione binding up-regulates GLUT4 gene expression, thus increasing insulin sensitivity (Armoni, M., Kritz, N., Harel, C., Bar-Yoseph, F., Chen, H., Quon, M. J., and Karnieli, E. (2003) J. Biol. Chem. 278, 30614–30623). However, the mechanisms regulating PPARγ gene transcription are largely unknown. We studied the effects of FOXO1 on human PPARγ gene expression in primary rat adipocytes and found that both genes are endogenously expressed. FOXO1 coexpression dose-dependently repressed transcription from either the PPARγ 1 or PPARγ2 promoter reporter by 65%, whereas insulin (100 nm, 20–24 h) either partially or completely reversed this effect. Phosphorylation-defective FOXO1 mutants T24A, S256A, S319A, and T24A/S256A/S319A still repressed the PPARγ1 promoter and partially lost their effects on the PPARγ2 promoter in either basal or insulin-stimulated cells. Use of DNA binding-defective FOXO1 (H215R) indicated that this domain is crucial for FOXO1 repression of the PPARγ2 (but not PPARγ1) promoter. Progressive 5′-deletion and gel retardation analyses revealed that this repression involves direct and specific binding of FOXO1 to the PPARγ2 promoter; chromatin immunoprecipitation analysis confirmed that this binding occurs in cellulo. We suggest a novel paradigm to increase insulin sensitivity in adipocytes in which FOXO1 repression of PPARγ, the latter being a repressor of the GLUT4 promoter, consequently leads to GLUT4 derepression/up-regulation, thus enhancing cellular insulin sensitivity. The newly identified FOXO1-binding site on the PPARγ2 promoter may serve as a therapeutic target for type 2 diabetes. FOXO1 and peroxisome proliferator-activated receptor-γ (PPARγ) are crucial transcription factors that regulate glucose metabolism and insulin responsiveness in insulin target tissues. We have shown that, in primary rat adipocytes, both factors regulate transcription of the insulin-responsive GLUT4 gene and that PPARγ2 detachment from the GLUT4 promoter upon thiazolidinedione binding up-regulates GLUT4 gene expression, thus increasing insulin sensitivity (Armoni, M., Kritz, N., Harel, C., Bar-Yoseph, F., Chen, H., Quon, M. J., and Karnieli, E. (2003) J. Biol. Chem. 278, 30614–30623). However, the mechanisms regulating PPARγ gene transcription are largely unknown. We studied the effects of FOXO1 on human PPARγ gene expression in primary rat adipocytes and found that both genes are endogenously expressed. FOXO1 coexpression dose-dependently repressed transcription from either the PPARγ 1 or PPARγ2 promoter reporter by 65%, whereas insulin (100 nm, 20–24 h) either partially or completely reversed this effect. Phosphorylation-defective FOXO1 mutants T24A, S256A, S319A, and T24A/S256A/S319A still repressed the PPARγ1 promoter and partially lost their effects on the PPARγ2 promoter in either basal or insulin-stimulated cells. Use of DNA binding-defective FOXO1 (H215R) indicated that this domain is crucial for FOXO1 repression of the PPARγ2 (but not PPARγ1) promoter. Progressive 5′-deletion and gel retardation analyses revealed that this repression involves direct and specific binding of FOXO1 to the PPARγ2 promoter; chromatin immunoprecipitation analysis confirmed that this binding occurs in cellulo. We suggest a novel paradigm to increase insulin sensitivity in adipocytes in which FOXO1 repression of PPARγ, the latter being a repressor of the GLUT4 promoter, consequently leads to GLUT4 derepression/up-regulation, thus enhancing cellular insulin sensitivity. The newly identified FOXO1-binding site on the PPARγ2 promoter may serve as a therapeutic target for type 2 diabetes. The peroxisome proliferator-activated receptor (PPAR) 2The abbreviations used are: PPAR, peroxisome proliferator-activated receptor; PKB, protein kinase B; PRAs, primary rat adipocytes; IRS, insulin response sequence; Luc, luciferase; BSA, bovine serum albumin; HEK, human embryonic kidney; DAPI, 4′, 6-diamidino-2-phenylindole; EMSA, electrophoretic mobility shift assay; ChIP, chromatin immunoprecipitation; DBD, DNA binding domain. family of nuclear receptors and the FOXO (forkhead box class O) family of winged helix/forkhead box factors are two key families of transcription factors that dominate the regulation of glucose metabolism and insulin responsiveness in insulin target tissues. Members of both families are crucial for a multitude of biological processes, including the cell cycle, cell death, differentiation, and metabolism, and have prominent roles in insulin signaling pathways. A convergence of nuclear receptors and forkhead pathways in general and of FOXO1 and PPARγ in particular has been implicated in the pathophysiological states of insulin resistance and diabetes, supporting the importance of these transcription factors (1.Arden K.C. Mol. Cell. 2004; 14: 416-418Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 2.Tran H. Brunet A. Griffith E.C. Greenberg M.E. Sci. STKE. 2003; 2003: RE5Crossref PubMed Google Scholar). However, despite their importance to glucose homeostasis and adipocyte differentiation, the molecular mechanism(s) regulating transcription of the PPARγ gene and the roles of both PPARγ and FOXO1 transcription factors in these processes are not fully known. The PPAR family of ligand-activated transcription factors includes three PPAR isoforms (α, β/δ, and γ) that differ in their tissue distribution and ligand specificity. PPARβ/δ is expressed ubiquitously in many tissues; PPARα is found predominantly in hepatocytes, cardiomyocytes, and enterocytes; and PPARγ is expressed mainly in insulin-responsive tissues, where it has a pivotal role in adipocyte differentiation and the expression of adipose-specific genes (3.Gilde A.J. Van Bilsen M. Acta. Physiol. Scand. 2003; 178: 425-434Crossref PubMed Scopus (134) Google Scholar). There are two PPARγ isotypes (γ1 and γ2) that arise from the use of different promoters and alternative splicing (4.Fajas 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 (1086) Google Scholar). PPARγ2 is adipose-specific, whereas both are expressed in muscle. We have shown that, in primary adipocytes, both PPARγ1 and PPARγ2 repress GLUT4 transcription via direct and specific binding of the heterodimer PPARγ/retinoid X receptor-α to a GLUT4 promoter region (5.Armoni M. Kritz N. Harel C. Bar-Yoseph F. Chen H. Quon M.J. Karnieli E. J. Biol. Chem. 2003; 278: 30614-30623Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). We discovered that rosiglitazone (an important thiazolidinedione ligand of PPARγ that improves insulin sensitivity) exerts its beneficial effect on insulin action by detaching PPARγ from its binding site on the GLUT4 promoter, thus alleviating this transrepression. However, the mechanisms regulating the PPARγ gene promoter itself are largely unknown. The winged helix/forkhead family of transcription factors is characterized by a 100-amino acid monomeric DNA-binding domain called the FOX domain. The DNA-binding domain folds into a variant of the helix-turn-helix motif and is made up of three helices and two characteristic large loops or “wings”; hence, the DNA-binding motif has been named the winged helix DNA-binding domain. Other portions of the forkhead proteins such as the DNA transactivation or DNA transrepression domains are highly divergent (6.Kaestner K.H. Knochel W. Martinez D.E. Genes Dev. 2000; 14: 142-146PubMed Google Scholar). The forkhead domain is responsible for DNA binding specificity and binds DNA as a monomer. Following a standardized nomenclature for these proteins (6.Kaestner K.H. Knochel W. Martinez D.E. Genes Dev. 2000; 14: 142-146PubMed Google Scholar), all are used for human and the is for The FOXO family of transcription factors the transcription of target genes in many cell processes, including cell cell DNA and insulin sensitivity in 2.Tran H. Brunet A. Griffith E.C. Greenberg M.E. Sci. STKE. 2003; 2003: RE5Crossref PubMed Google Scholar). FOXO1 is the FOXO in insulin-responsive such as and cells. have shown that FOXO1 is by human protein kinase a kinase that of in the insulin signaling and that this regulation includes a and of FOXO1 three and H. Brunet A. Griffith E.C. Greenberg M.E. Sci. STKE. 2003; 2003: RE5Crossref PubMed Google Scholar). J. K.C. D. PubMed Scopus Google that is expressed mainly in tissue and is a of insulin sensitivity in and insulin signaling to a for the of type 2 diabetes. the importance of FOXO1 in both insulin signaling and have shown that FOXO1 (forkhead either or transcription from the GLUT4 gene on the cell whereas a gene that is to human GLUT4 promoter via direct binding to specific promoter M. Quon M.J. S. Harel C. D. Karnieli E. J. PubMed Scopus Google Scholar). both PPARγ and FOXO1 are the transcription factors in tissue and are in and insulin their have been in insulin target cells. PPARγ is in processes, the mechanisms regulating transcription of the PPARγ gene itself are still unknown. this to the molecular mechanisms by which FOXO1 the expression of the PPARγ gene the of PPARγ1 and PPARγ2 transcription in primary rat adipocytes cellular from the a and and specific for PPARγ, and PPARγ2 on from the and a in the of the of from on and by as M. Quon M.J. S. Harel C. D. Karnieli E. J. PubMed Scopus Google Scholar). and FOXO1 in by of and have been J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). a the of the mutants T24A, S256A, S319A, and and the DNA binding-defective A reporter three of insulin response in by J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The human PPARγ1 and PPARγ2 promoters in and from and have been (4.Fajas 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 (1086) Google Scholar). A of promoter from the reporter the confirmed by direct and adipocytes from rat and to (5.Armoni M. Kritz N. Harel C. Bar-Yoseph F. Chen H. Quon M.J. Karnieli E. J. Biol. Chem. 2003; 278: 30614-30623Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). adipocytes by and of either PPARγ1 or PPARγ2 promoter reporter of expression for FOXO1 or and of of bovine serum and either or to the and the for 20–24 of the promoter reporter to used as a for FOXO1 transcription the of DNA by the expression to for by the promoter a reporter and a as J. A Scholar). expressed as a of the basal PPARγ promoter the in promoter reporter by to in of FOXO1 by expression of FOXO1 proteins and the of the FOXO1 and by in either cell or of nuclear and and as by M. Harel C. Bar-Yoseph F. S. Karnieli E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of cell of and PRAs, as for the reporter in and and The and the including the cell protein the acid protein of of protein by either for of FOXO1 or for of by a to and embryonic on in a of and as by (5.Armoni M. Kritz N. Harel C. Bar-Yoseph F. Chen H. Quon M.J. Karnieli E. J. Biol. Chem. 2003; 278: 30614-30623Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). expression for or FOXO1 for The and to and either or insulin as the in and for primary by a FOXO1 proteins and 4′, and and of FOXO1 proteins and as (5.Armoni M. Kritz N. Harel C. Bar-Yoseph F. Chen H. Quon M.J. Karnieli E. J. Biol. Chem. 2003; 278: 30614-30623Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). The used to in FOXO1 proteins from the and the protein used in expression confirmed by by analysis of proteins in the of protein to use in and PPARγ to of reporter these and in the of binding in a of which of the in FOXO1 and of in 1 1 and in the of and of which to the of the used either or and for to the of the for by on gel and in and in acid for and by the of J. M. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google as a for human PPARγ2 promoter that in the of the human FOXO1 in the expression either or promoter reporter as The and and for The and of DNA and proteins either or to D.E. B. PubMed Scopus Google Scholar). in cell M. Harel C. Bar-Yoseph F. S. Karnieli E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google to DNA of of of the cell used for of and the of the protein and for and either or or for DNA by by and either DNA or used for to the human PPARγ2 promoter region and the region the in on gel and by gene expression the and protein by and shown in expression of for PPARγ, and expression of GLUT4 as a for insulin-responsive expression of FOXO1 protein in cell from these basal FOXO1 to the nuclear and in the We the expression of FOXO1 in by and found that FOXO1 to of the protein of PPARγ1 and PPARγ2 by FOXO1 and the expression of and FOXO1 proteins in PRAs, studied the effects of FOXO1 on human PPARγ1 and PPARγ2 gene expression the promoter for either human PPARγ1 or PPARγ2 the expression for FOXO1 We found that expression of FOXO1 repressed the of both the PPARγ1 and PPARγ2 promoters in a to as as basal of insulin in a of the FOXO1 effects on the PPARγ1 promoter, of basal the FOXO1 FOXO1 repression of the PPARγ2 promoter, to a FOXO1 the insulin response from the which used as a by as as not this the of either or effects in the expression that FOXO1 transcription from the PPARγ1 and PPARγ2 whereas insulin this effect in of FOXO1 to PPARγ of the domains of FOXO1 to PPARγ promoter repression studied basal as as as in The of of the three of FOXO1 studied mutants of FOXO1 S256A, and and a in which all three to PPARγ promoter the FOXO1 mutants and either basal or insulin for We found that of the not the basal of FOXO1 to repress the PPARγ1 promoter, the of insulin However, all these mutants either or of FOXO1 to repress the PPARγ2 promoter We used the DNA binding-defective to the of the FOXO1 DNA-binding domain The not the basal of FOXO1 to repress promoter in the of insulin However, this completely lost its to repress the PPARγ2 promoter and responsiveness to insulin analysis on cell from that all used as as expressed as FOXO1 proteins to the whereas not FOXO1 effects its cellular studied the distribution of FOXO1 and the mutants in the basal and for the to the proteins and serve as a to FOXO1 in adipocytes, as have been shown to insulin signaling as as FOXO1 not (5.Armoni M. Kritz N. Harel C. Bar-Yoseph F. Chen H. Quon M.J. Karnieli E. J. Biol. Chem. 2003; 278: 30614-30623Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar), found that, in the basal FOXO1 to the and from it upon insulin both the DNA binding-defective to the whereas the T24A/S256A/S319A which not to not from the in response to on the PPARγ2 by that the of FOXO1 is crucial for the repression of not of on in the PPARγ2 promoter that may serve as FOXO1-binding We a 5′-deletion analysis of the PPARγ2 promoter reporter The promoter are shown in We found that of in the promoter region to a of the of FOXO1 to the promoter in the of not the of insulin to FOXO1 promoter region to FOXO1 to repress the PPARγ2 promoter in either the or of FOXO1 to the PPARγ2 the regulation of PPARγ by FOXO1 involves a direct FOXO1 protein in and for its to the PPARγ2 promoter region FOXO1 protein expressed the as by analysis from a are shown in The of FOXO1 protein to the DNA to the of a binding as and of the for binding in a The specificity of this indicated by a electrophoretic mobility of the in the of specific The in the of either or which is the of human not in the of which is the FOXO1 the of the it may a role for the FOXO1 domains in the the PPARγ gene promoter. 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PubMed Scopus Google Scholar). this have shown for the that the human winged helix transcription FOXO1 transcription from the human PPARγ1 and PPARγ2 gene promoters in insulin target and that this regulation is both and We have that FOXO1 is by of that nuclear nuclear and We have shown that regulation of PPARγ2 gene transcription occurs via direct and specific binding of FOXO1 protein to a (but this as by and 5′-deletion analyses in of the PPARγ2 promoter and that this binding in the of the human from a large of that the effects of FOXO1 in primary adipocytes of PPARγ gene expression either in or in by and J. K.C. D. PubMed Scopus Google have shown that is a of PPARγ in that mutants a to the effects of in and J. K.C. D. Dev. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google that of adipocytes leads to of adipocyte differentiation, which is by of PPARγ gene N. M. 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Full Text Full Text PDF PubMed Scopus Google Scholar), in this on the regulation of PPARγ1 and PPARγ2 gene expression insulin target cells. The of PPARγ gene expression is to We studied the expression of FOXO1 and PPARγ and found that, whereas the for both genes are in not are expressed in fully adipocytes both the and protein this J. K.C. D. Dev. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google found that is the in and tissue and that, being in its up to basal A role for FOXO1 is as both a transcription and repressor of nuclear receptors H. Brunet A. Griffith E.C. Greenberg M.E. Sci. STKE. 2003; 2003: RE5Crossref PubMed Google Scholar). the protein of it is that, a and region that as a DNA domain the it region its which is to serve as a transcription repression and in its to nuclear receptors H. Brunet A. Griffith E.C. Greenberg M.E. Sci. STKE. 2003; 2003: RE5Crossref PubMed Google Scholar). that, on the specific and cellular FOXO1 as either a or of PPARγ gene have that it is the adipose-specific that is by FOXO1 in adipocytes, being in the and in the fully the of L. C. Auwerx J. Dev. Cell. Full Text Full Text PDF PubMed Scopus Google that the expression of PPARγ in in differentiation into adipocytes, that are PPARγ gene expression to a role for PPARγ2 expression where FOXO1 PPARγ2 expression in it PPARγ2 has its as the of FOXO1 as a of insulin the effects of insulin on PPARγ and factors are to of FOXO1 and PPARγ in in the and of these transcription The of FOXO1 is by insulin the of DNA and nuclear different mechanisms the of transcription of FOXO1 target genes by has been that of the three in FOXO1 and FOXO proteins insulin or serum transcription of target genes by the of FOXO proteins from the H. Brunet A. Griffith E.C. Greenberg M.E. Sci. STKE. 2003; 2003: RE5Crossref PubMed Google Scholar). However, the role of insulin in regulating FOXO1 is that the effects of insulin on the distribution of FOXO1 from its effects on the of N. 2003; PubMed Scopus Google have shown that insulin transcription nuclear of is that insulin by direct mechanisms that not on the distribution of the transcription L. H. S. A. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google that of transcription by insulin in not on nuclear in this have shown that of FOXO1 insulin for its regulation of PPARγ in a that is both cell and the of different mechanisms for for insulin and for FOXO1 this regulation is and the of the domains of FOXO1 to PPARγ found that a DNA binding (H215R) its to repress lost its effects on the PPARγ2 promoter. that is crucial for FOXO1 regulation of the PPARγ2 (but not PPARγ1) promoter and suggest the of direct binding of FOXO1 to the PPARγ2 promoter. However, as the of FOXO1 is not for transcription repression of the PPARγ1 FOXO1 has effect on this via E. D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google found that FOXO1 both and nuclear receptors in either a or to regulate the transactivation by different nuclear FOXO1 as a transcription that as both a and of the PPARγ promoter via either direct or prominent for FOXO1 effects on PPARγ1 is the PPARγ has been shown that the and expression of whereas family and the of a large of nuclear including PPARγ in J.C. J. A Biol. Sci. Sci. PubMed Scopus Google Scholar). We the of FOXO1 by have been to three key that are the FOXO mutants of FOXO1 that not found that the of FOXO1 to its basal or to regulate transcription from of the PPARγ gene promoters the effects of insulin on the distribution of FOXO1 and on the of into this of in that the three are by and protein kinase is gene that is in response to and increase of cell to serum or found that, is by both and H. Brunet A. Griffith E.C. Greenberg M.E. Sci. STKE. 2003; 2003: RE5Crossref PubMed Google Scholar). the of to FOXO1 and have We have shown that, whereas a in FOXO1 its basal to repress the PPARγ1 promoter in primary adipocytes, it is a of the of FOXO1 to repress the PPARγ2 promoter in the basal indicated that the of the not differ from that of the protein not N. 2003; PubMed Scopus Google found that, in predominantly to the insulin whereas A. PubMed Scopus Google of nuclear of in effect on its to the in cells. The latter found that promoter is to the by and that the insulin of promoter by by A of insulin in N. M. PubMed Scopus Google Scholar). S. S. J. Biol. Chem. 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FOXO1 response motif in a region that of the PPARγ2 promoter and that to and as from and of the region for motif revealed that it response for PPARγ and two factors that found to regulate PPARγ The response is to that found by L. C. Auwerx J. Dev. Cell. Full Text Full Text PDF PubMed Scopus Google on the PPARγ1 promoter and is of PPARγ1 transcription of the PPARγ response found is to the A PPARγ response in the PPARγ response may to FOXO1 regulation of the PPARγ promoter via a that involves a S. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google have shown that and PPARγ in a the of a convergence of PPARγ and FOXO1 signaling in the action of A general convergence of nuclear receptors and forkhead pathways may important for biological processes, and this convergence may on the suggest a for FOXO1 repression of the PPARγ1 and PPARγ2 promoters that is both and to this both promoters are repressed by FOXO1 via a of as the repression of the PPARγ2 promoter of a direct have shown that PPARγ2 promoter repression occurs via specific and direct binding of FOXO1 to DNA on the promoter both in and in newly identified FOXO1 response may thus serve as a molecular therapeutic target for the of insulin resistance and type 2 diabetes. for regulation of factors its regulation by prominent are of the which have been shown to the of PPARγ in J.C. J. A Biol. Sci. Sci. PubMed Scopus Google Scholar). We a novel paradigm to increase insulin sensitivity in adipocytes in to this FOXO1 PPARγ gene expression or shown by (5.Armoni M. Kritz N. Harel C. Bar-Yoseph F. Chen H. Quon M.J. Karnieli E. J. Biol. Chem. 2003; 278: 30614-30623Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar), both the PPARγ1 and PPARγ2 proteins repress GLUT4 promoter repression of PPARγ by FOXO1 leads to GLUT4 in glucose and cellular insulin sensitivity. the prominent roles by PPARγ and FOXO1 in insulin signaling may a for the of insulin action and its to insulin resistance in type 2 We and of of for for and and for of this