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Transcription, adipocyte differentiation, and obesity

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Abstract

Differentiation of adipogenic precursor cells into mature adipocytes is a complex phenomenon, characterized by an ordered expression of adipocyte-specific genes, triggered by a set of interacting transcription factors. The most important transcription factors involved in this process are the γ form of peroxisome proliferator activated receptors (PPARγ) and the various members of the CCAAT enhancer binding proteins (α, β, and δ). In addition to PPARγ and these enhancer binding proteins, several other transcription factors, including ADD-1 (SRE-BP), HMGI-C, are involved in regulating this process. Altered activity and/or expression of these transcription factors, will induce the expression of target genes in the differentiating cells, ultimately resulting in the phenotypical characteristics of the adipocytes. It is speculated that modulation of these transcription factors by either pharmacological or dietary manipulations might influence adipocyte differentiation and prove beneficial in the prevention and treatment of obesity.

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Abbreviations

ADD-1 :

Adipocyte differentiation and determination factor-1

bHLH :

Basic helix-loop-helix transcription factors

C/EBP :

CCAATT enhancer binding protein

HMG :

High-mobility group

PPAR :

Peroxisome proliferator activated receptor

PRE :

Preadipocyte repressor element

WAT :

White adipose tissue

References

  1. Flier JS (1995) The adipocyte: storage depot or node on the energy information superhighway. Cell 80:15–18

    Google Scholar 

  2. Lardy H, Shrago E (1990) Biochemical aspects of obesity. Annu Rev Biochem 59:689–710

    Google Scholar 

  3. Spiegelman BM, Choy L, Hotamisligil GS, Graves RA, Tontonoz P (1993) Regulation of adipocyte gene expression in differentiation and syndromes of obesity/diabetes. J Biol Chem 268:6823–6826

    Google Scholar 

  4. Ailhaud G, Grimaldi P, Negrel R (1994) Hormonal regulation of adipose differentiation. Trends Endocrinol Metabolism 5:132–135

    Google Scholar 

  5. MacDougald O, Lane D (1995) Transcriptional regulation of gene expression during adipocyte differentiation. Annu Rev Biochem 64:345–373

    Google Scholar 

  6. Tontonoz P, Hu E, Spiegelman BM (1994) Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell 79:1147–1156

    Google Scholar 

  7. Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM (1994) mPPARγ2: tissue-specific regulator of an adipocyte enhancer. Genes Dev 8:1224–1234

    Google Scholar 

  8. Christy RJ, Yang VW, Ntambi JM, Geiman DE, Landschulz WH, Friedman AD, Nakabeppu Y, Kelly TJ, Lane MD (1989) Differentiation-induced gene expression in 3T3-L1 preadipocytes: CCAAT/enhancer binding protein interacts with and activates the promoters of two adipocyte-specific genes. Genes Dev 3:1323–1335

    Google Scholar 

  9. Freytag SO, Geddes TJ (1992) Reciprocal regulation of adipogenesis by Myc and C/EBPα. Science 256:379–382

    Google Scholar 

  10. Freytag SO, Paielli DL, Gilbert JD (1994) Ectopic expression of the CCAAT/enhancer-binding protein α promotes the adipogenic program in a variety of mouse fibroblastic cells. Genes Dev 8:1654–1663

    Google Scholar 

  11. Isseman I, Green S (1990) Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347:645–650

    Google Scholar 

  12. Auwerx J (1993) Regulation of gene expression by fatty acids and fibric acid derivatives: an integrative role for peroxisome proliferator activated receptors. Hormone Res 38:269–277

    Google Scholar 

  13. Desvergne B, Wahli W (1994) PPAR: a key nuclear factor in nutrient/gene interactions. In: Bauerle P (ed) Inducible gene expression, vol 1. Birkhauser, Boston, pp 142–176

    Google Scholar 

  14. Schoonjans K, Staels B, Auwerx J (1996) Role of the peroxisome proliferator activated receptor (PPAR) in mediating effects of fibrates and fatty acids on gene expression. J Lipid Res (in press)

  15. Zhu Y, Alvares K, Huang Q, Rao MS, Reddy JK (1993) Cloning of a new member of the peroxisome proliferator activated receptor gene family from mouse liver. J Biol Chem 268:26817–26820

    Google Scholar 

  16. Tontonoz P, Graves RA, Budavari AI, Erdjument-Bromage H, Lui M, Hu E, Tempst P, Spiegelman BM (1994) Adipocytespecific transcription factor ARF6 is a heterodimeric complex of two nuclear hormone receptors PPARγ and RXRα. Nucl Acids Res 22:5628–5634

    Google Scholar 

  17. Zhu Y, Qi C, Korenberg JR, Chen X-N, Noya D, Rao MS, Reddy JK (1995) Structural organization of mouse peroxisome proliferator activated receptor γ (mPPARγ) gene: alternative promoter use and different splicing yield two mPPARγ isoforms. Proc Nat Acad Sci USA 92:7921–7925

    Google Scholar 

  18. Tontonoz P, Hu E, Devine J, Beale EG, Spiegelman BM (1995) PPARγ2 regulates adipose expression of the phosphoenolpyruvate carboxykinase gene. Mol Cell Biol 15:351–357

    Google Scholar 

  19. Schoonjans K, Peinado-Onsurbe J, Heyman R, Briggs M, Cayet D, Deeb S, Staels B, Auwerx J (1996) PPARα and PPARγ activators direct a tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. (submitted)

  20. Lehmann, JM, LB, M, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA (1995) An antidiabetic thiazolidinedione is a high affinity ligand for Peroxisome Proliferator-Activated Receptor γ (PPARγ). J Biol Chem 270:12953–12956

    Article  CAS  PubMed  Google Scholar 

  21. Gottlicher M, Widmark E, Li Q, Gustafsson JA (1992) Fatty acids activate chimera of the clofibric acid-activated receptor and the glucocorticoid receptor. Proc Natl Acad Sci USA 89:4653–4657

    Google Scholar 

  22. Keller H, Dreyer C, Medin J, Mahfoudi A, Ozato K, Wahli W (1993) Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers. Proc Natl Acad Sci USA 90:2160–2164

    Google Scholar 

  23. Chawla A, Lazar MA (1994) Peroxisome proliferator and retinoid signaling pathways co-regulate preadipocyte phenotype and survival. Proc Natl Acad Sci USA 91:1786–1790

    Google Scholar 

  24. Amri E-Z, Bertrand B, Ailhaud G, Grimaldi P (1991) Regulation of adipose cell differentiation. I Fatty acids are inducers of the aP2 gene expression. J Lipid Res 32:1449–1456

    Google Scholar 

  25. Gaillard D, Negrel R, Lagarde M, Ailhaud G (1989) Requirement and role of arachidonic acid in the differentiation of preadipose cells. Biochem J 257:389–397

    Google Scholar 

  26. Lin FT, Lane MD (1992) Antisense CCAAT/enhancer binding protein RNA suppresses coordinate gene expression and triglyceride accumulation during differentiation of 3T3-L1 adipocytes. Genes Dev 6:533–544

    Google Scholar 

  27. Lin FT, Lane MD (1994) CCAAT/enhancer binding protein a is sufficient to initiate the 3T3-L1 adipocyte differentiation program. Proc Natl Acad Sci USA 91:8757–8761

    Google Scholar 

  28. Wang N, Finegold MJ, Bradley A, Ou C, Abdelsayed SV, Wilde MD, Taylor LR, Wilson DR, Darlington GJ (1995) Impaired energy homeostasis in C/EBPα knockout mice. Science 269:1108–1112

    Google Scholar 

  29. Cao Z, Umek RM, McKnight SL (1991) Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes Dev 5:1538–1552

    Google Scholar 

  30. Yeh WC, Cao Z, Classon M, McKnight S (1995) Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins. Genes Dev 9:168–181

    Google Scholar 

  31. Wu Z, Xie Y, Bucher NLR, Farmer SR (1995) Conditional ectopic expression of C/EBPβ in NIH-3T3 cells induces PPARγ and stimulates adipogenesis. Genes Dev 9:2350–2363

    Google Scholar 

  32. Descombes P, Schibler U (1991) A liver-enriched transcriptional activator protein LAP, and a transcriptional inhibitory protein LIP, are translated from the same mRNA Cell 57:569–579

    Google Scholar 

  33. Ron D, Habener JF (1992) CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant negative inhibitor of gene transcription. Genes Dev 6:439–453

    Google Scholar 

  34. Fornace AJ, Neibert DW, Hollander MC, Luethy JD, Papathanasiou M, Fragoli J, Holbrook NJ (1989) Mammalian genes coordinately regulated by growth arrest signals and DNA-damaging agents. Mol Cell Biol 9:4196–4203

    Google Scholar 

  35. Swick AG, Lane MD (1992) Identification of a transcriptional repressor down-regulated during adipocyte differentiation. Proc Nat Acad Sci USA 89:7895–7899

    Google Scholar 

  36. Enerback S, Ohlsson BG, Samuelson L, Bjursell G (1992) Characterization of the human lipoprotein lipase (LPL) promotor: evidence of two cis-regulatory regions LP-a and LP-b, of importance for the differentiation-linked induction of the LPL gene during adipogenesis. Mol Cell Biol 12:4622–4633

    Google Scholar 

  37. Tontonoz P, Kim JB, Graves RA, Spiegelman BM (1993) ADD1: a novel helix-loop-helix transcription factor associated with adipocyte determination and differentiation. Mol Cell Biol 13:4753–4759

    Google Scholar 

  38. Lovell-Badge R (1995) Living with bad architecture. Nature 376:725–726

    Google Scholar 

  39. Wang X, Sato R, Brown MS, Hua X, Goldstein JL (1994) SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis. Cell 77:53–62

    Google Scholar 

  40. Schoenmakers EFPM, Wanschura S, Mols R, Bullerdiek J, Van den Berghe H, Van de Ven WJW (1995) Recurrent rearrangements in the high mobility group protein gene HMGI-C, in benign mesenchymal tumours. Nature Genet 10:436–443

    Google Scholar 

  41. Ashar HR, Schoenberg Fejzo M, Tkachenko A, Zhou X, Fletcher JA, Weremowicz S, Morton CC, Chada K (1995) Disruption of the architectural factor HMGI-C: DNA binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains. Cell 82:57–65

    Google Scholar 

  42. Zhou X, Benson KF, Ashar HR, Chada K (1995) Mutation responsible for the mouse pygmy phenotype in the developmentally regulated factor HMGI-C. Nature 376:771–774

    Google Scholar 

  43. Auwerx J, Leroy P, Schoonjans K (1992) Lipoprotein lipase: recent contributions from molecular biology. Crit Rev Clin Lab Sciences 29:243–268

    Google Scholar 

  44. Platt KA, Min HY, Ross SR, Spiegelman BM (1989) Obesitylinked regulation of the adipsin gene promoter in transgenic mice. Proc Natl Acad Sci USA 86:7490–7494

    Google Scholar 

  45. Platt KA, Claffey KP, Wilkison WO, Spiegelman BM, Ross SR (1994) Independent regulation of adipose tissue-specificity and obesity response of the adipsin promoter in transgenic mice. J Biol Chem 269:28558–28562

    Google Scholar 

  46. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432

    Article  CAS  PubMed  Google Scholar 

  47. Masuzaki H, Ogawa Y, Isse N, Satoh N, Okazaki T, Shigemoto M, Mori K, Tamura N, Hosoda K, Yoshimasa Y, Jingami H, Kawada T, Nakao K (1995) Human obese gene expression; adipocyte-specific expression and regional differences in the adipose tissue. Diabetes 44:855–858

    Google Scholar 

  48. Geffroy S, DeVos P, Staels B, Duban B, Auwerx J, de Martinville B (1995) Localization of the human ob gene to chromosome 7q32 by fluorescence in situ hybridization. Genomics 28:603–604

    Google Scholar 

  49. Murakami T, Shima K (1995) Cloning of rat obese cDNA and its expression in obese rats. Biochem Biophys Res Commun 209:944–952

    Google Scholar 

  50. Funahashi T, Shimomura I, Hiraoka H, Arai T, Takahashi M, Nakamura T, Nozaki S, Yamashita S, Takemura K, Tokunaga K, Matsuzawa Y (1995) Enhanced expression of rat obese (ob) gene in adipose tissues of ventromedial hypothalamus (VMH)-lesioned rats. Biochem Biophys Res Commun 211:469–475

    Google Scholar 

  51. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM (1995) Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269:543–546

    CAS  PubMed  Google Scholar 

  52. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F (1995) Effect of the obese gene product on body weight regulation in ob/ob mice. Science 269:540–543

    CAS  PubMed  Google Scholar 

  53. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P (1995) Recombinant mouse OB protein; evidence for a peripheral signal linking adiposity and central neural networks. Science 269:546–549

    Google Scholar 

  54. Weigle DS, Bukowski TR, Foster DC, Holderman S, Kramer JM, Lasser G, Lofton-Day CE, Prunkard DE, Raymond C, Kuijper JL (1995) Recombinant ob protein reduces feeding and body weight in the ob/ob mouse. J Clin Invest 96:2065–2070

    Google Scholar 

  55. Rentsch J, Levens N, Chiesi M (1995) Recombinant ob gene product reduces food intake in fasted mice. Biochem Biophys Res Commun 214:131–136

    Google Scholar 

  56. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smuiko JS, Mays GG, Woolf EA, Monroe CA, Tepper RI (1995) Identification and expression cloning of a leptin receptor OB-R Cell 83:1263–1271

    Google Scholar 

  57. Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM (1996) Abnormal splicing of the leptin receptor in diabetic mice. Nature 379:632–635

    Google Scholar 

  58. Saladin R, De Vos P, Guerre-Millo M, Leturque A, Girard J, Staels B, Auwerx J (1995) Transient increase in obese gene expression after food intake and insulin administration. Nature 377:527–529

    Article  CAS  PubMed  Google Scholar 

  59. MacDougald OA, Hwang CS, Fan H, Lane MD (1995) Regulated expression of the obese gene product (leptin) in white adipose tissue and 3T3-L1 adipocytes. Proc Nat Acad Sci USA 92:9034–9037

    Google Scholar 

  60. Trayhurn P, Thomas MEA, Duncan JS, Rayner VD (1995) Effect of fasting and refeeding on ob gene expression in white adipose tissue of lean and (ob /ob) mice. FEBS Lett 368:488–490

    Google Scholar 

  61. Moinat M, Deng C, Muzzin P, Assimacopoulos-Jeannet F, Seydoux J, Dulloo AG, Giacobino J -P (1995) Modulation of obese gene expression in rat brown and white adipose tissues. FEBS Lett 373:131–134

    Google Scholar 

  62. Frederich RC, Lollmann B, Hamann A, Napolitano-Rosen A, Kahn BB, Lowell BB, Flier JS (1995) Expression of ob mRNA and its encoded protein in rodents. Impact of nutrition and obesity. J Clin Invest 96:1658–1663

    Google Scholar 

  63. De Vos P, Saladin R, Auwerx J, Staels B (1995) Induction of ob gene expression by corticosteroids is accompanied by body weight loss and reduced food intake. J Biol Chem 270:15958–15961

    Article  PubMed  Google Scholar 

  64. Murakami T, Iida M, Shima K (1995) Dexamethasone regulates obese expression in isolated rat adipocytes. Biochem Biophys Res Commun 214:1260–1267

    Google Scholar 

  65. Considine RV, Considine EL, Williams CJ, Nyce MR, Magosin SA, Bauer TL, Rosato EL, Colberg J, Caro JF (1995) Evidence against either a premature stop codon or the absence of obese gene mRNA in human obesity. J Clin Invest 95:2986–2988

    Google Scholar 

  66. Lönnqvist F, Arner P, Nordfors L, Schalling M (1995) Overexpression of the obese (ob) gene in adipose tissue of human obese subjects. Nature Med 1:950–953

    Google Scholar 

  67. Hamilton BS, Paglia D, Kwan AYM, Deitel M (1995) Increased obese mRNA expression in omental fat cells from massively obese humans. Nature Med 1:954–956

    Google Scholar 

  68. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S, Kern PA, Friedman JM (1995) Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nature Med 1:1155–1161

    Google Scholar 

  69. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, Caro JF (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334:292–295

    Article  CAS  PubMed  Google Scholar 

  70. Ogawa Y, Masuzaki H, Isse N, Okazaki T, Mori K, Shigemoto M, Satoh N, Tamura N, Hosoda K, Yoshimasa Y, Jingami H, Kawada T, Nakao K (1995) Molecular cloning of rat obese cDNA and augmented gene expression in genetically obese zucker fatty (fa /fa) rats. J Clin Invest 96:1647–1652

    Google Scholar 

  71. Maffei M, Fei H, Lee G-H, Dani C, Leroy P, Zhang Y, Proenica R, Negrel R, Ailhaud G, Friedman JM (1995) Increased expression in adipocytes of ob RNA in mice with lesions of hypothalamus and with mutations at the db locus. Proc Natl Acad Sci USA 92:6957–6960

    Google Scholar 

  72. Masuzaki H, Hosoda K, Ogawa Y, Shigemoto M, Satoh N, Mori K, Tamura N, Nishi S, Yoshimasa Y, Yamori Y, Nakao K (1996) Augmented expression of obese (ob) gene during the process of obesity in genetically obese-hyperglycemic Wistar (fa/fa) rats. FEBS Lett 378:267–271

    Google Scholar 

  73. Miller SG, De Vos P, Guerre-Millo M, Wong K, Hermann T, Staels B, Briggs MR, Auwerx J (1996) The adipocyte specific transcription factor C/EBPa modulates human ob gene expression. Proc Natl Acad Sci USA (in press)

  74. He Y, Chen H, Quon MJ, Reitman M (1995) The mouse obese gene. Genomic organization, promoter activity, and activation by CCAAT/enhancer-binding protein alpha. J Biol Chem 270:28887–28891

    Google Scholar 

  75. Lee GH, Proencer R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM (1996) Abnormal splicing of the leptin receptor in diabetic mice. Nature 379:632–635

    Google Scholar 

  76. Chua SC Jr, Chung WK, Wu-Peng XS, Zhang Y, Liu S-M, Tovitaglia L, Leibel RL (1996) Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science 271:994–996

    CAS  PubMed  Google Scholar 

  77. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriatry A, Moore KJ, Smutko JS, Mays GG, Woolf EA, Monroe CA, Tepper RI (1995) Identification and expression cloning of a leptin receptor, OB R Cell 83:1263–1271

    Google Scholar 

  78. Noben-Trauth K, Naggert JK, North MA, Nishina PM (1996) A candidate gene for the mouse mutation tubby. Nature 380:534–538

    Google Scholar 

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Authors and Affiliations

  1. INSERM U 325, Département d'Athérosclérose, Institut Pasteur, 1 Rue Calmette, F-59019, Lille, France

    J. Auwerx, G. Martin & B. Staels

  2. INSERM U177, Institut des Cordeliers, F-75006, Paris, France

    M. Guerre-Millo

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  1. J. Auwerx
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  2. G. Martin
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  3. M. Guerre-Millo
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  4. B. Staels
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Auwerx, J., Martin, G., Guerre-Millo, M. et al. Transcription, adipocyte differentiation, and obesity. J Mol Med 74, 347–352 (1996). https://doi.org/10.1007/BF00210629

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