2003/04/01 by Yael Olswang, Barak Blum, Hanoch Cassuto +4 · 8 citations
Medicine · Biochemistry, Genetics and Molecular Biology · #Adipose Tissue and Metabolism #Estrogen and related hormone effects #Hormonal Regulation and Hypertension
paper · pdf · doi:10.1074/jbc.m300263200
The cytosolic form of the phosphoenolpyruvate carboxykinase (PEPCK-C) gene is selectively expressed in several tissues, primarily in the liver, kidney, and adipose tissue. The transcription of the gene is reciprocally regulated by glucocorticoids in these tissues. It is induced in the liver and kidney but repressed in the white adipose tissue. To elucidate which adipocyte-specific transcription factors participate in the repression of the gene, DNase I footprinting analyses of nuclear proteins from 3T3-F442A adipocytes and transient transfection experiments in NIH3T3 cells were utilized. Glucocorticoid treatment slightly reduced the nuclear C/EBPα concentration but prominently diminished the binding of adipocyte-derived nuclear proteins to CCAAT/enhancer-binding protein (C/EBP) recognition sites, without affecting the binding to nuclear receptor sites in the PEPCK-C gene promoter. Of members of the C/EBP family of transcription factors, C/EBPα was the strongest trans-activator of the PEPCK-C gene promoter in the NIH3T3 cell line. The glucocorticoid receptor (GR), in the presence of its hormone ligand, inhibited the activation of the PEPCK-C gene promoter by C/EBPα or C/EBPβ but not by the adipocyte-specific peroxisome proliferator-activated receptor γ2. This inhibition effect was similar using the wild type or mutant GR and did not depend on GR binding to the DNA. The glucocorticoid response unit (GRU) in the PEPCK-C gene promoter (−2000 to +73) restrained C/EBPα-mediated trans-activation, because mutation of each single GRU element increased this activation by 3–4-fold. This series of GRU mutations were repressed by wild type GR to the same percent as was the nonmutated PEPCK-C gene promoter. In contrast, the repression by mutant GR depended on the intact AF1 site in the gene promoter, whereby mutation of the AF1 element abolished the repression. The cytosolic form of the phosphoenolpyruvate carboxykinase (PEPCK-C) gene is selectively expressed in several tissues, primarily in the liver, kidney, and adipose tissue. The transcription of the gene is reciprocally regulated by glucocorticoids in these tissues. It is induced in the liver and kidney but repressed in the white adipose tissue. To elucidate which adipocyte-specific transcription factors participate in the repression of the gene, DNase I footprinting analyses of nuclear proteins from 3T3-F442A adipocytes and transient transfection experiments in NIH3T3 cells were utilized. Glucocorticoid treatment slightly reduced the nuclear C/EBPα concentration but prominently diminished the binding of adipocyte-derived nuclear proteins to CCAAT/enhancer-binding protein (C/EBP) recognition sites, without affecting the binding to nuclear receptor sites in the PEPCK-C gene promoter. Of members of the C/EBP family of transcription factors, C/EBPα was the strongest trans-activator of the PEPCK-C gene promoter in the NIH3T3 cell line. The glucocorticoid receptor (GR), in the presence of its hormone ligand, inhibited the activation of the PEPCK-C gene promoter by C/EBPα or C/EBPβ but not by the adipocyte-specific peroxisome proliferator-activated receptor γ2. This inhibition effect was similar using the wild type or mutant GR and did not depend on GR binding to the DNA. The glucocorticoid response unit (GRU) in the PEPCK-C gene promoter (−2000 to +73) restrained C/EBPα-mediated trans-activation, because mutation of each single GRU element increased this activation by 3–4-fold. This series of GRU mutations were repressed by wild type GR to the same percent as was the nonmutated PEPCK-C gene promoter. In contrast, the repression by mutant GR depended on the intact AF1 site in the gene promoter, whereby mutation of the AF1 element abolished the repression. glucocorticoid receptor phosphoenolpyruvate carboxykinase-C CCAAT/enhancer-binding protein glucocorticoid-response element retinoid X receptor peroxisome proliferator-activated receptor cyclic AMP-response element PPAR-response element reverse transcriptase chloramphenicol acetyltransferase glucocorticoid response unit Dulbecco's modified Eagle's medium hepatocyte nuclear factor chicken ovalbumin upstream transcription factor Glucocorticoids play a fundamental role in the maintenance of homeostasis in mammals. Removal of the adrenals severely compromises the ability of animals to withstand fasting (for reviews see Refs. 1Baxter J.D. Rousseau G.G. Glucocorticoid Hormone Action: An Overview. Springer-Verlag Inc., New York1979: 10-24Google Scholar and 2Berne R.M. Berne R.M. Levy M.N. 4th Ed. Physiology. Mosby, Inc., St. Louis, MO1998: 942-944Google Scholar). Glucocorticoids exert their effects via the glucocorticoid receptor (GR),1 predominantly by modulating gene transcription (3Gustafsson J.A. Carlstedt-Duke J. Poellinger L. Okret S. Wikstrom A.C. Bronnegard M. Gillner M. Dong Y. Fuxe K. Cintra A. Endocr. Rev. 1987; 8: 185-234Crossref PubMed Scopus (350) Google Scholar, 4Tronche F. Kellendonk C. Reichardt H.M. Schutz G. Curr. Opin. Genet. & Dev. 1998; 8: 532-538Crossref PubMed Scopus (158) Google Scholar, 5Hu X. Lazar M.A. Trends Endocrinol. Metab. 2000; 11: 6-10Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar). An attractive mode of regulation, especially in light of the coordinated effects of glucocorticoids in maintaining homeostasis, is the opposing control of the samegene in different tissues by GR. PEPCK-C gene provides an optimal model for studying this mode of regulation. The transcription of this gene is stimulated by glucocorticoids in the liver and kidney (6Meisner H. Loose D.S. Hanson R.W. Biochemistry. 1985; 24: 421-425Crossref PubMed Scopus (62) Google Scholar, 7Sasaki K. Crip T.P. Koch S.R. Andreone T.L. Petersen D.D. Beale E.G. Granner D.K. J. Biol. Chem. 1984; 259: 15242-15251Abstract Full Text PDF PubMed Google Scholar) but is repressed in the adipose tissue (8Nechushtan H. Benvenisty N. Brandeis R. Reshef L. Nucleic Acids Res. 1987; 15: 6405-6417Crossref PubMed Scopus (54) Google Scholar). PEPCK-C catalyzes a key reaction that determines the rates of gluconeogenesis in the liver and kidney and glyceroneogenesis in the adipose tissue and liver (9Hanson R.W. Reshef L. Annu. Rev. Biochem. 1997; 66: 581-611Crossref PubMed Scopus (634) Google Scholar). Glyceroneogenesis, the de novosynthesis of 3-glycerophosphate from pyruvate and amino acids (via an abbreviated version of gluconeogenesis), provides this precursor for the synthesis of triglycerides (10Ballard F.J. Hanson R.W. Leveille G.A. J. Biol. Chem. 1967; 242: 2746-2750Abstract Full Text PDF PubMed Google Scholar, 11Reshef L. Niv J. Shapiro B. J. Lipid Res. 1967; 8: 688-691Abstract Full Text PDF PubMed Google Scholar). Recently, we have performed a targeted mutation in the adipose tissue-specific enhancer of the PEPCK-C gene in embryonic stem cells. The mutation ablated PEPCK-C gene expression in white adipose tissue of mice homozygous for this mutation and caused a decrease in the storage of triglycerides, which in some mice developed into lipodystrophy (12Olswang Y. Cohen H. Papo O. Cassuto H. Croniger C.M. Hakimi P. Tilghman S.M. Hanson R. Reshef L. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 625-630Crossref PubMed Scopus (119) Google Scholar). This mutation therefore established the importance of PEPCK-C and glyceroneogenesis in the homeostasis of triglycerides in the adipose tissue. Because PEPCK-C is encoded by a unique copy gene, and is transcribed from a single promoter, it is likely that tissue-specific factors are involved in the reciprocal regulation that leads to and or repression of the gene transcription in the presence of and PubMed Scopus Google Scholar) the to a that the GR in is of repression or activation of The in the PEPCK-C gene Carlstedt-Duke J. J.A. Granner D.K. Biol. PubMed Scopus Google Scholar) is a that GR a and is not by to a response to In PEPCK-C gene promoter a GR unit (GRU) sites and AF1 and not but their is for the response of the PEPCK-C gene to glucocorticoids in The factors binding to the AF1 element are nuclear these hepatocyte nuclear factor chicken ovalbumin upstream transcription factor retinoid X receptor and members of the peroxisome proliferator-activated receptor The site S. R.M. Granner D.K. R. J. Biol. Chem. Full Text PDF PubMed Google Scholar) Granner D.K. Endocrinol. Google Scholar, D.K. C. Granner D.K. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) and to an element as R.M. M.A. Granner D.K. PubMed Scopus Google Scholar). To tissue-specific factors that are involved in the repression of PEPCK-C gene transcription in we have a DNase I footprinting of the PEPCK-C gene promoter, using nuclear in the repression using transient transfection experiments in NIH3T3 cells. The from these the of members of the C/EBP but not of in the GR repression of the PEPCK-C gene promoter experiments in NIH3T3 cells a of PEPCK-C gene promoter by the GRU wild type and mutant GR of binding the the by of the is or the repression by mutant GR an intact AF1 site in the PEPCK-C Dulbecco's modified Eagle's medium and and were from was from the glucocorticoid was from the for the of tissue was from were using a transcriptase was from was from and the was from The for the of was from 3T3-F442A from H. O. Full Text PDF PubMed Scopus Google were to in and of the cells to was by was a concentration of and the cells were for The cells were for in a medium of cells was to NIH3T3 cells expression of the gene was were of to cell 3T3-F442A adipocytes were for was from a single of 3T3-F442A adipocytes or from of liver using the to the of was to using the reverse transcriptase in the presence of as and that the was for was performed using the PEPCK-C from and from for gene were from and from for were the same as S. H. 1998; PubMed Scopus Google Scholar). was performed in the presence of a of to S. H. 1998; PubMed Scopus Google Scholar). The for for and for each of for for and for The was by on and using a and by its to proteins were from liver to K. M. U. Full Text PDF PubMed Scopus Google Scholar) as modified M. Benvenisty N. Cohen H. Reshef L. Biol. PubMed Scopus Google Scholar). protein from adipocytes were as M. Benvenisty N. Cohen H. Reshef L. Biol. PubMed Scopus Google that the to the was DNase I footprinting were performed as M. Benvenisty N. Cohen H. Reshef L. Biol. PubMed Scopus Google Scholar). The of in the were using version of nuclear proteins from adipocytes or were on and to & C/EBPα was from and was using protein was O. D.S. J. K. R. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar) from and using to O. D.S. J. K. R. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). were NIH3T3 cells were on in cells were to was performed to and C. H. Biol. 1987; PubMed Scopus Google as O. Cohen H. M. A. Benvenisty N. Reshef L. Biol. PubMed Scopus Google or the cells and to a of were and the transfection was as O. Cohen H. M. A. Benvenisty N. Reshef L. Biol. PubMed Scopus Google Scholar). each of the expression for C/EBPα and or GR was The optimal of C/EBPβ or expression to the transfection was In of of the expression to the that optimal for chloramphenicol acetyltransferase were as O. Cohen H. M. A. Benvenisty N. Reshef L. Biol. PubMed Scopus Google and using a The was as the by the of the of The of the PEPCK-C gene promoter to the gene N. H. Cohen H. Reshef L. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). The of the PEPCK-C gene promoter H. A. Cohen H. Reshef L. PubMed Scopus Google Scholar). The AF1 the mutation of and J. Hanson R.W. Google and the Croniger C.M. Hakimi P. C. C. Hanson R.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) of the PEPCK-C gene promoter these The and or upstream from the transcription site of PEPCK-C gene promoter, from a and to the gene as N. H. Cohen H. Reshef L. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). The a mutation of the The mutation was by the sites and and to the This to the site of the and that the site of the was The concentration of the the PEPCK-C gene was to the same of as that of the PEPCK-C gene transcription factors in this the C/EBPα Dev. Scopus Google Scholar) from C/EBPβ Dev. PubMed Scopus Google Scholar) from P. J. Biol. Chem. Full Text PDF PubMed Google Scholar) from P. J. Beale E.G. Biol. 15: PubMed Google Scholar) from J.A. R.M. PubMed Scopus Google Scholar) and GR S.M. R.M. Full Text PDF PubMed Scopus Google Scholar) from the of and wild type and mutant GR were a from PubMed Scopus Google Scholar). The of glucocorticoids to 3T3-F442A adipocytes for caused a repression of PEPCK-C gene expression as by the of its This repression was because glucocorticoids to the expression of the adipocyte-specific gene In to GR the binding of nuclear proteins to sites in the PEPCK-C gene promoter, we the gene promoter, using nuclear proteins from 3T3-F442A cells that without or of PEPCK-C gene promoter the binding sites of transcription factors is The the binding sites for nuclear proteins in the liver, liver the gene for PEPCK-C is not transcribed M. Benvenisty N. Cohen H. Reshef L. Biol. PubMed Scopus Google Scholar, N. Reshef L. Proc. Natl. Acad. Sci. U. S. A. 1987; PubMed Scopus Google kidney, and adipocytes that nuclear proteins from the liver and adipocytes to sites to of the transcription site of the PEPCK-C gene promoter. nuclear proteins not to the site recognition in the PEPCK-C gene promoter H. Y. H. Hanson R.W. Reshef L. 1997; PubMed Scopus Google nuclear proteins from the liver to recognition site the kidney and liver, nuclear proteins from adipocytes and liver C/EBP recognition the and sites is a Of of the C/EBP family Hakimi P. A. Hanson R.W. J. Biol. Chem. Full Text PDF PubMed Google Scholar). and sites as and P. M. S. L. A. Y. H. G. J. 2002; and J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). C/EBPα but a protein in the liver nuclear proteins M. Benvenisty N. Cohen H. Reshef L. Biol. PubMed Scopus Google Scholar). footprinting that nuclear proteins from adipocytes to to C/EBP recognition sites in the PEPCK-C gene and and the single site The inhibition of binding to these sites the of of the C/EBP recognition sites to which from the to the M. Benvenisty N. Cohen H. Reshef L. Biol. PubMed Scopus Google Scholar, J. J.D. J. A. Hanson R.W. Biol. PubMed Scopus Google Scholar). In binding to the site factor recognition in the PEPCK-C gene promoter was inhibited this is not a C/EBP recognition In Hakimi P. A. Hanson R.W. J. Biol. Chem. Full Text PDF PubMed Google Scholar) the binding of C/EBPβ to to the binding to the a reduced binding to site have to a effect on the binding to the The binding of nuclear proteins to the recognition sites of nuclear in the PEPCK-C gene promoter not by the glucocorticoid binding to AF1 site similar using nuclear proteins from adipocytes not or glucocorticoids AF1 site is a nuclear receptor recognition site that a of nuclear and members of the to nuclear proteins the AF1 site which not by the glucocorticoid is recognition site of the nuclear In to the nuclear binding of nuclear proteins to the site their binding to the AF1 site the site the of the in the presence of nuclear It was in the of nuclear proteins and in the presence of liver nuclear proteins in the liver are in nuclear To of the glucocorticoid we the of and the of the and AF1 The footprinting of the site was from the by the of a the site from the transcription site of the PEPCK-C and a by the footprinting of the AF1 site was by the of and and a the AF1 The the and the were The from the footprinting without nuclear proteins were and to of the footprinting in the presence of nuclear have that treatment the nuclear protein footprinting of the site but not the footprinting of the AF1 site of the gene for C/EBPα is repressed by glucocorticoids but for a P. J. Biol. Chem. Full Text PDF PubMed Google Scholar). this repression to a of C/EBPα protein concentration in P. J. Biol. Chem. Full Text PDF PubMed Google in an of binding to its recognition we the concentration of C/EBPα in to the diminished footprinting of the PEPCK-C gene promoter. The concentration of C/EBPα in the of nuclear proteins for footprinting was by The treatment diminished the nuclear concentration of C/EBPα by to the of the nuclear protein this reduced concentration of C/EBPα for the inhibited footprinting of nuclear proteins from adipocytes was we of nuclear proteins from adipocytes and the to the gene promoter the and This to the site the for C/EBP binding and the site the for C/EBP binding The that of nuclear proteins sites of the site was as for the in the of proteins was to a of of protein and a of of protein The effect on footprinting that was a of in the presence of of nuclear proteins from and in the presence of of nuclear proteins from adipocytes In contrast, footprinting the AF1 site similar and using of nuclear proteins from or adipocytes therefore that in to the of C/EBPα in the the treatment the binding to their recognition sites in the PEPCK-C gene promoter. The of transcription factors in the repression of PEPCK-C gene transcription by glucocorticoids was using transient transfection in NIH3T3 cells. these cells not PEPCK-C or the adipocyte-specific transcription factors or C/EBPα P. Full Text PDF PubMed Scopus Google expression for and were to transcription from the PEPCK-C gene promoter in these cells P. J. Beale E.G. Biol. 15: PubMed Google Scholar). have the of the PEPCK-C gene promoter by and by C/EBPα expression using by or of the PEPCK-C gene promoter H. A. Cohen H. Reshef L. PubMed Scopus Google Scholar). stimulated the transcription from PEPCK-C gene promoter, C/EBPα and stimulated transcription from the gene promoter The is likely because of the of a of C/EBP recognition sites in the of the PEPCK-C gene promoter (9Hanson R.W. Reshef L. Annu. Rev. Biochem. 1997; 66: 581-611Crossref PubMed Scopus (634) Google Scholar). see the of the PEPCK-C gene promoter In to members of the C/EBP family the PEPCK-C gene promoter but to a C/EBPα was the C/EBPβ was as and was the was a in the of C/EBPα and the effect of GR and its hormone on the of of the gene promoter by or of GR expression and the of for the transfection inhibited the activation of transcription from the PEPCK-C gene promoter by C/EBPα or by In contrast, was effect of GR and on the by of or gene The of the of the PEPCK-C gene promoter, or gene and and is to the recognition sites AF1 and a mutation of the in gene promoter abolished its response to it the site that the of PEPCK-C gene promoter is the E.G. K. Granner D.K. J. Biol. Chem. 1985; Full Text PDF PubMed Google Scholar) and the C. P. J. K. M.A. Granner D.K. C. R. Endocrinol. PubMed Scopus Google Scholar). mutation of the ablated PEPCK-C gene expression in the adipose tissue in as the PEPCK-C in mice P. Beale E.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) and the targeted mutation in the PEPCK-C gene (12Olswang Y. Cohen H. Papo O. Cassuto H. Croniger C.M. Hakimi P. Tilghman S.M. Hanson R. Reshef L. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 625-630Crossref PubMed Scopus (119) Google Scholar). In contrast, mutation of the site in the of gene promoter increased the of the gene promoter The of the wild type AF1 site of the PEPCK-C gene promoter in NIH3T3 cells have in by C. Beale E.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). that the AF1 site the nuclear receptor expression inhibited the of the PEPCK-C gene promoter via the site C. Beale E.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of AF1 site are not by GRU because mutation of the site effect on the of by C/EBPα-mediated of the gene is the by in this mutations of single element of the GRU Carlstedt-Duke J. J.A. Granner D.K. Biol. PubMed Scopus Google and of gene, the C/EBPα-mediated of the gene promoter by not the AF1 site but the GRU the C/EBPα of the Because each of the the GRU the C/EBPα of the gene, we of GR to the PEPCK-C gene promoter is for its repression. To this the of the wild type GR was its mutant GR that is of binding to the PubMed Scopus Google Scholar, Dev. PubMed Scopus Google Scholar) to the C/EBPα-mediated of The that wild type or mutant GR repressed the of transcription from the PEPCK-C gene promoter by C/EBPα we have the C/EBPα-mediated of the series of repressed by GR and the mutant GR was The wild type GR repressed the C/EBPα-mediated of the GRU series of to a similar as that of the wild type The mutant GR repressed the of the wild type and mutant of to a similar the but to the of mutant the AF1 site is for the repression by mutant GR but not by the wild type GR In the AF1 site as an element on transcription from the PEPCK-C gene promoter because it the of gene promoter by or by C/EBPα and intact AF1 is for the mutant repression of C/EBPα of the PEPCK-C gene promoter. AF1 is the repression by mutant GR is abolished light on the of transcription from the C/EBP but not from the in the repression of PEPCK-C gene transcription in Glucocorticoid treatment of 3T3-F442A adipocytes to a reduced nuclear concentration of in to a diminished binding of nuclear proteins to the C/EBP recognition sites not to the recognition in the PEPCK-C gene promoter. from N. H. Cohen H. Reshef L. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar) a for the C/EBP recognition sites of the PEPCK-C gene promoter that were for its in transfection in NIH3T3 cells that GR glucocorticoids inhibited the but not of PEPCK-C gene promoter. have the of members of the C/EBP family in the adipocyte-specific glucocorticoid repression of PEPCK-C gene This in by the concentration of C/EBPα in and the binding of nuclear proteins to the C/EBP recognition sites in the and as a or in the of PEPCK-C gene promoter by C/EBP using nuclear proteins from the adipocytes and transient transfection in the NIH3T3 cells and of which the of C/EBP but not in the glucocorticoid repression of PEPCK-C gene because GR to the C/EBP by it is likely that factors members of C/EBP family participate in PEPCK-C gene transcription in the using NIH3T3 cells have a regulation of PEPCK-C gene in the on the gene promoter response to activation by the GRU element in the PEPCK-C gene promoter. single element the GRU this and the by C/EBPα is This is different from by which is but in this it is not via each element of the GRU but by the AF1 In that the AF1 site as a unique element mutation by the response of to or of AF1 are by the response of this site to activation of transcription from the PEPCK-C gene promoter The element is that an adipose tissue-specific as in mice P. Beale E.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). a targeted mutation of in embryonic stem cells in of PEPCK-C gene expression in the white adipose tissue of mice homozygous for the mutation (12Olswang Y. Cohen H. Papo O. Cassuto H. Croniger C.M. Hakimi P. Tilghman S.M. Hanson R. Reshef L. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 625-630Crossref PubMed Scopus (119) Google Scholar). the AF1 site involved in the GR repression of the C/EBPα-mediated of The to have established that the GR repression not binding to the DNA. GR in the PubMed Scopus Google it of binding the was as as wild type in the C/EBPα we have that the wild type GR repressed the wild type and GRU the mutant GR repressed the sites to a the site of mutation of the AF1 site abolished the of the mutant GR to the Because the AF1 site did not the repression by wild type we that the AF1 site a role to the mutant repression of the gene promoter. these the of regulation to in to its the wild type AF1 site is for the repression. Because the repression by GR of the not binding of the the GR of PEPCK-C gene transcription via This is by the that the percent repression by GR of the C/EBPα-mediated activation of transcription the activation was type gene or by series of gene of members of the C/EBP family and GR in of the C/EBP family have to to the binding of a of nuclear GR Refs. Lazar M.A. Biol. 1997; PubMed Google Scholar and M. Endocrinol. 1998; PubMed Scopus Google Scholar and for see Refs. 5Hu X. Lazar M.A. Trends Endocrinol. Metab. 2000; 11: 6-10Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar and X. Y. Lazar M.A. Biol. PubMed Scopus Google Scholar). in or inhibition of the and did not binding of GR to the Lazar M.A. Biol. 1997; PubMed Google Scholar, M. Endocrinol. 1998; PubMed Scopus Google Scholar). binding of C/EBPβ to the binding of GR in the GR repression of the gene transcription in from the The gene promoter a site C. G. O. B. 2002; PubMed Scopus Google Scholar). the of the glucocorticoid repression of PEPCK-C gene transcription in adipose its have rates of glyceroneogenesis in the liver of and fasting M.N. 1998; Full Text PDF PubMed Scopus Google Scholar, S. Reshef L. Hanson R.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) or of a in protein but of M.N. 1998; Full Text PDF PubMed Scopus Google Scholar). light on the of the reciprocal control of PEPCK-C gene transcription by PEPCK-C catalyzes the of gluconeogenesis and This by of the PEPCK-C gene in in from P. M. R. C. M.A. Biol. 2000; PubMed Scopus Google Scholar). In a targeted mutation of the adipose tissue-specific site of the PEPCK-C gene promoter, which selectively gene expression in white adipose caused a of glyceroneogenesis in this tissue. homozygous for this mutation from adipose tissue to the of to the of PEPCK-C and glyceroneogenesis in the adipose tissue (12Olswang Y. Cohen H. Papo O. Cassuto H. Croniger C.M. Hakimi P. Tilghman S.M. Hanson R. Reshef L. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 625-630Crossref PubMed Scopus (119) Google Scholar). a adipocyte-specific of for in the adipose mice of without a of triglycerides from adipose tissue O. O. PubMed Scopus Google Scholar). S. S. A. A. P. B. F. 2002; PubMed Scopus Google Scholar) a gene the PEPCK-C gene to the promoter in mice in in these the role of PEPCK-C and glyceroneogenesis in maintaining homeostasis in the adipose tissue. it is that of PEPCK-C gene expression glyceroneogenesis in liver and adipose tissue. Lipid is from the adipose tissue as acids and from the liver as glyceroneogenesis in in the it from adipose tissue L. F.J. Hanson R.W. J. Biol. Chem. Google Scholar) and it from the liver P. Biochem. J. PubMed Scopus Google Scholar). It in that glyceroneogenesis and from L. F.J. Hanson R.W. J. Biol. Chem. Full Text PDF PubMed Google Scholar, L. Shapiro B. Metab. Res. Scholar). In a reciprocal the of to stimulated the synthesis of triglycerides and and as as the of to the medium P. Biochem. J. PubMed Scopus Google Scholar). is homeostasis coordinated the that the reciprocal regulation of PEPCK-C gene transcription by glucocorticoids provides a for because it PEPCK-C gene transcription in the adipose tissue and it in the to this in are are to for the wild type and mutant to for the expression to for the expression and to for the GR and expression especially the from L. of the the the transfection experiments in NIH3T3 by and the