Skip to main content
NCBI home page
The Journal of Cell Biology logoLink to The Journal of Cell Biology
. 1989 Mar 1;108(3):1105–1113. doi: 10.1083/jcb.108.3.1105

Modulation of adipocyte differentiation by tumor necrosis factor and transforming growth factor beta

PMCID: PMC2115404  PMID: 2921280

Abstract

Cultured TA1 adipocytes treated with tumor necrosis factor alpha (TNF) lose intracytoplasmic lipid and, over a period of days, come to resemble their predifferentiated progenitors (preadipocytes). To examine the extent to which this phenotypic reversion represents a return to a less differentiated cell, we examined three major characteristics that distinguish preadipocytes from adipocytes: (a) pattern of gene expression; (b) hormonal requirement for accelerated adipogenesis; and (c) pattern of protein synthesis. We found that within hours of TNF addition to adipocytes, mRNAs for genes whose expression is augmented during adipogenesis decreased to predifferentiated levels; in addition, like preadipocytes, TNF-treated adipocytes required exposure to hormones to accelerate adipogenesis. Further, the pattern of protein synthesis seen on polyacrylamide gels reverted to that seen before differentiation. Transforming growth factor-beta (TGF-beta) also caused a rapid decrease in expression of adipose genes when added to fully differentiated cells, an effect that was achieved by treatment with either TGF-beta 1 or TGF-beta 2. These effects were seen in the absence of a demonstrable proliferative response to either TNF or TGF-beta. Thus characteristics that define the "terminally" differentiated state in adipocytes are subject to modulation by environmental influences.

Full Text

The Full Text of this article is available as a PDF (5.2 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anzano M. A., Roberts A. B., Meyers C. A., Komoriya A., Lamb L. C., Smith J. M., Sporn M. B. Synergistic interaction of two classes of transforming growth factors from murine sarcoma cells. Cancer Res. 1982 Nov;42(11):4776–4778. [PubMed] [Google Scholar]
  2. Assoian R. K., Fleurdelys B. E., Stevenson H. C., Miller P. J., Madtes D. K., Raines E. W., Ross R., Sporn M. B. Expression and secretion of type beta transforming growth factor by activated human macrophages. Proc Natl Acad Sci U S A. 1987 Sep;84(17):6020–6024. doi: 10.1073/pnas.84.17.6020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Beutler B., Cerami A. Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature. 1986 Apr 17;320(6063):584–588. doi: 10.1038/320584a0. [DOI] [PubMed] [Google Scholar]
  4. Beutler B., Greenwald D., Hulmes J. D., Chang M., Pan Y. C., Mathison J., Ulevitch R., Cerami A. Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature. 1985 Aug 8;316(6028):552–554. doi: 10.1038/316552a0. [DOI] [PubMed] [Google Scholar]
  5. Beutler B., Mahoney J., Le Trang N., Pekala P., Cerami A. Purification of cachectin, a lipoprotein lipase-suppressing hormone secreted by endotoxin-induced RAW 264.7 cells. J Exp Med. 1985 May 1;161(5):984–995. doi: 10.1084/jem.161.5.984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Blau H. M., Pavlath G. K., Hardeman E. C., Chiu C. P., Silberstein L., Webster S. G., Miller S. C., Webster C. Plasticity of the differentiated state. Science. 1985 Nov 15;230(4727):758–766. doi: 10.1126/science.2414846. [DOI] [PubMed] [Google Scholar]
  7. Broudy V. C., Kaushansky K., Segal G. M., Harlan J. M., Adamson J. W. Tumor necrosis factor type alpha stimulates human endothelial cells to produce granulocyte/macrophage colony-stimulating factor. Proc Natl Acad Sci U S A. 1986 Oct;83(19):7467–7471. doi: 10.1073/pnas.83.19.7467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Carswell E. A., Old L. J., Kassel R. L., Green S., Fiore N., Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A. 1975 Sep;72(9):3666–3670. doi: 10.1073/pnas.72.9.3666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Centrella M., McCarthy T. L., Canalis E. Mitogenesis in fetal rat bone cells simultaneously exposed to type beta transforming growth factor and other growth regulators. FASEB J. 1987 Oct;1(4):312–317. doi: 10.1096/fasebj.1.4.3498658. [DOI] [PubMed] [Google Scholar]
  10. Chapman A. B., Knight D. M., Dieckmann B. S., Ringold G. M. Analysis of gene expression during differentiation of adipogenic cells in culture and hormonal control of the developmental program. J Biol Chem. 1984 Dec 25;259(24):15548–15555. [PubMed] [Google Scholar]
  11. Chapman A. B., Knight D. M., Ringold G. M. Glucocorticoid regulation of adipocyte differentiation: hormonal triggering of the developmental program and induction of a differentiation-dependent gene. J Cell Biol. 1985 Oct;101(4):1227–1235. doi: 10.1083/jcb.101.4.1227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cheifetz S., Weatherbee J. A., Tsang M. L., Anderson J. K., Mole J. E., Lucas R., Massagué J. The transforming growth factor-beta system, a complex pattern of cross-reactive ligands and receptors. Cell. 1987 Feb 13;48(3):409–415. doi: 10.1016/0092-8674(87)90192-9. [DOI] [PubMed] [Google Scholar]
  13. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  14. Clegg C. H., Linkhart T. A., Olwin B. B., Hauschka S. D. Growth factor control of skeletal muscle differentiation: commitment to terminal differentiation occurs in G1 phase and is repressed by fibroblast growth factor. J Cell Biol. 1987 Aug;105(2):949–956. doi: 10.1083/jcb.105.2.949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Collins T., Lapierre L. A., Fiers W., Strominger J. L., Pober J. S. Recombinant human tumor necrosis factor increases mRNA levels and surface expression of HLA-A,B antigens in vascular endothelial cells and dermal fibroblasts in vitro. Proc Natl Acad Sci U S A. 1986 Jan;83(2):446–450. doi: 10.1073/pnas.83.2.446. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  17. Friedman R. L., Manly S. P., McMahon M., Kerr I. M., Stark G. R. Transcriptional and posttranscriptional regulation of interferon-induced gene expression in human cells. Cell. 1984 Oct;38(3):745–755. doi: 10.1016/0092-8674(84)90270-8. [DOI] [PubMed] [Google Scholar]
  18. Gamble J. R., Harlan J. M., Klebanoff S. J., Vadas M. A. Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8667–8671. doi: 10.1073/pnas.82.24.8667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Green H., Kehinde O. An established preadipose cell line and its differentiation in culture. II. Factors affecting the adipose conversion. Cell. 1975 May;5(1):19–27. doi: 10.1016/0092-8674(75)90087-2. [DOI] [PubMed] [Google Scholar]
  20. Ignotz R. A., Massagué J. Type beta transforming growth factor controls the adipogenic differentiation of 3T3 fibroblasts. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8530–8534. doi: 10.1073/pnas.82.24.8530. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kawakami M., Cerami A. Studies of endotoxin-induced decrease in lipoprotein lipase activity. J Exp Med. 1981 Sep 1;154(3):631–639. doi: 10.1084/jem.154.3.631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kawakami M., Pekala P. H., Lane M. D., Cerami A. Lipoprotein lipase suppression in 3T3-L1 cells by an endotoxin-induced mediator from exudate cells. Proc Natl Acad Sci U S A. 1982 Feb;79(3):912–916. doi: 10.1073/pnas.79.3.912. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Knight D. M., Chapman A. B., Navre M., Drinkwater L., Bruno J. J., Ringold G. M. Requirements for triggering of adipocyte differentiation by glucocorticoids and indomethacin. Mol Endocrinol. 1987 Jan;1(1):36–43. doi: 10.1210/mend-1-1-36. [DOI] [PubMed] [Google Scholar]
  24. Kuri-Harcuch W., Wise L. S., Green H. Interruption of the adipose conversion of 3T3 cells by biotin deficiency: differentiation without triglyceride accumulation. Cell. 1978 May;14(1):53–59. doi: 10.1016/0092-8674(78)90300-8. [DOI] [PubMed] [Google Scholar]
  25. Massagué J. The TGF-beta family of growth and differentiation factors. Cell. 1987 May 22;49(4):437–438. doi: 10.1016/0092-8674(87)90443-0. [DOI] [PubMed] [Google Scholar]
  26. Miller S. C., Ito H., Blau H. M., Torti F. M. Tumor necrosis factor inhibits human myogenesis in vitro. Mol Cell Biol. 1988 Jun;8(6):2295–2301. doi: 10.1128/mcb.8.6.2295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Min H. Y., Spiegelman B. M. Adipsin, the adipocyte serine protease: gene structure and control of expression by tumor necrosis factor. Nucleic Acids Res. 1986 Nov 25;14(22):8879–8892. doi: 10.1093/nar/14.22.8879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Nawroth P. P., Stern D. M. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med. 1986 Mar 1;163(3):740–745. doi: 10.1084/jem.163.3.740. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ohta M., Greenberger J. S., Anklesaria P., Bassols A., Massagué J. Two forms of transforming growth factor-beta distinguished by multipotential haematopoietic progenitor cells. Nature. 1987 Oct 8;329(6139):539–541. doi: 10.1038/329539a0. [DOI] [PubMed] [Google Scholar]
  30. Oliff A., Defeo-Jones D., Boyer M., Martinez D., Kiefer D., Vuocolo G., Wolfe A., Socher S. H. Tumors secreting human TNF/cachectin induce cachexia in mice. Cell. 1987 Aug 14;50(4):555–563. doi: 10.1016/0092-8674(87)90028-6. [DOI] [PubMed] [Google Scholar]
  31. Pekala P. H., Kawakami M., Angus C. W., Lane M. D., Cerami A. Selective inhibition of synthesis of enzymes for de novo fatty acid biosynthesis by an endotoxin-induced mediator from exudate cells. Proc Natl Acad Sci U S A. 1983 May;80(9):2743–2747. doi: 10.1073/pnas.80.9.2743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Reznikoff C. A., Brankow D. W., Heidelberger C. Establishment and characterization of a cloned line of C3H mouse embryo cells sensitive to postconfluence inhibition of division. Cancer Res. 1973 Dec;33(12):3231–3238. [PubMed] [Google Scholar]
  33. Rigby P. W., Dieckmann M., Rhodes C., Berg P. Labeling deoxyribonucleic acid to high specific activity in vitro by nick translation with DNA polymerase I. J Mol Biol. 1977 Jun 15;113(1):237–251. doi: 10.1016/0022-2836(77)90052-3. [DOI] [PubMed] [Google Scholar]
  34. Roberts A. B., Anzano M. A., Wakefield L. M., Roche N. S., Stern D. F., Sporn M. B. Type beta transforming growth factor: a bifunctional regulator of cellular growth. Proc Natl Acad Sci U S A. 1985 Jan;82(1):119–123. doi: 10.1073/pnas.82.1.119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Rosa F., Roberts A. B., Danielpour D., Dart L. L., Sporn M. B., Dawid I. B. Mesoderm induction in amphibians: the role of TGF-beta 2-like factors. Science. 1988 Feb 12;239(4841 Pt 1):783–785. doi: 10.1126/science.3422517. [DOI] [PubMed] [Google Scholar]
  36. Rosen D. M., Stempien S. A., Thompson A. Y., Seyedin S. M. Transforming growth factor-beta modulates the expression of osteoblast and chondroblast phenotypes in vitro. J Cell Physiol. 1988 Mar;134(3):337–346. doi: 10.1002/jcp.1041340304. [DOI] [PubMed] [Google Scholar]
  37. Seyedin S. M., Thompson A. Y., Bentz H., Rosen D. M., McPherson J. M., Conti A., Siegel N. R., Galluppi G. R., Piez K. A. Cartilage-inducing factor-A. Apparent identity to transforming growth factor-beta. J Biol Chem. 1986 May 5;261(13):5693–5695. [PubMed] [Google Scholar]
  38. Silberstein G. B., Daniel C. W. Reversible inhibition of mammary gland growth by transforming growth factor-beta. Science. 1987 Jul 17;237(4812):291–293. doi: 10.1126/science.3474783. [DOI] [PubMed] [Google Scholar]
  39. Smith M. M., Reeve A. E., Huang R. C. Analysis of RNA initiated in isolated mouse myeloma nuclei using purine nucleoside 5'[gamma-S]triphosphates as affinity probes. Cell. 1978 Oct;15(2):615–626. doi: 10.1016/0092-8674(78)90030-2. [DOI] [PubMed] [Google Scholar]
  40. Sparks R. L., Scott R. E. Transforming growth factor type beta is a specific inhibitor of 3T3 T mesenchymal stem cell differentiation. Exp Cell Res. 1986 Aug;165(2):345–352. doi: 10.1016/0014-4827(86)90588-4. [DOI] [PubMed] [Google Scholar]
  41. Sporn M. B., Roberts A. B., Wakefield L. M., de Crombrugghe B. Some recent advances in the chemistry and biology of transforming growth factor-beta. J Cell Biol. 1987 Sep;105(3):1039–1045. doi: 10.1083/jcb.105.3.1039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Torti F. M., Dieckmann B., Beutler B., Cerami A., Ringold G. M. A macrophage factor inhibits adipocyte gene expression: an in vitro model of cachexia. Science. 1985 Aug 30;229(4716):867–869. doi: 10.1126/science.3839597. [DOI] [PubMed] [Google Scholar]
  43. Torti S. V., Kwak E. L., Miller S. C., Miller L. L., Ringold G. M., Myambo K. B., Young A. P., Torti F. M. The molecular cloning and characterization of murine ferritin heavy chain, a tumor necrosis factor-inducible gene. J Biol Chem. 1988 Sep 5;263(25):12638–12644. [PubMed] [Google Scholar]
  44. Tracey K. J., Beutler B., Lowry S. F., Merryweather J., Wolpe S., Milsark I. W., Hariri R. J., Fahey T. J., 3rd, Zentella A., Albert J. D. Shock and tissue injury induced by recombinant human cachectin. Science. 1986 Oct 24;234(4775):470–474. doi: 10.1126/science.3764421. [DOI] [PubMed] [Google Scholar]
  45. Vannice J. L., Taylor J. M., Ringold G. M. Glucocorticoid-mediated induction of alpha 1-acid glycoprotein: evidence for hormone-regulated RNA processing. Proc Natl Acad Sci U S A. 1984 Jul;81(14):4241–4245. doi: 10.1073/pnas.81.14.4241. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Cell Biology are provided here courtesy of The Rockefeller University Press

RESOURCES