Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Apr 15;101(8):1557–1564. doi: 10.1172/JCI2293

Adipocyte macrophage colony-stimulating factor is a mediator of adipose tissue growth.

J A Levine 1, M D Jensen 1, N L Eberhardt 1, T O'Brien 1
PMCID: PMC508735  PMID: 9541484

Abstract

Adipose tissue growth results from de novo adipocyte recruitment (hyperplasia) and increased size of preexisting adipocytes. Adipocyte hyperplasia accounts for the severalfold increase in adipose tissue mass that occurs throughout life, yet the mechanism of adipocyte hyperplasia is unknown. We studied the potential of macrophage colony-stimulating factor (MCSF) to mediate adipocyte hyperplasia because of the profound effects MCSF exerts on pluripotent cell recruitment and differentiation in other tissues. We found that MCSF mRNA and protein were expressed by human adipocytes and that adipocyte MCSF expression was upregulated in rapidly growing adipose tissue that encircled acutely inflamed bowel and in adipose tissue from humans gaining weight (4-7 kg) with overfeeding. Localized overexpression of adipocyte MCSF was then induced in rabbit subcutaneous adipose tissue in vivo using adenoviral-mediated gene transfer. Successful overexpression of MCSF was associated with 16-fold increases in adipose tissue growth compared with a control adenovirus expressing beta-galactosidase. This occurred in the absence of increased cell size and in the presence of increased nuclear staining for MIB-1, a marker of proliferation. We conclude that MCSF participates in adipocyte hyperplasia and the physiological regulation of adipose tissue growth.

Full Text

The Full Text of this article is available as a PDF (573.3 KB).

Selected References

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

  1. Ailhaud G., Grimaldi P., Négrel R. Cellular and molecular aspects of adipose tissue development. Annu Rev Nutr. 1992;12:207–233. doi: 10.1146/annurev.nu.12.070192.001231. [DOI] [PubMed] [Google Scholar]
  2. Bastard J. P., Cuevas J., Cohen S., Jardel C., Hainque B. Percutaneous adipose tissue biopsy by mini-liposuction for metabolic studies. JPEN J Parenter Enteral Nutr. 1994 Sep-Oct;18(5):466–468. doi: 10.1177/0148607194018005466. [DOI] [PubMed] [Google Scholar]
  3. Björntorp P., Karlsson M., Pertoft H., Pettersson P., Sjöström L., Smith U. Isolation and characterization of cells from rat adipose tissue developing into adipocytes. J Lipid Res. 1978 Mar;19(3):316–324. [PubMed] [Google Scholar]
  4. Borycki A. G., Smadja F., Stanley R., Leibovitch S. A. Colony-stimulating factor 1 (CSF-1) is involved in an autocrine growth control of rat myogenic cells. Exp Cell Res. 1995 May;218(1):213–222. doi: 10.1006/excr.1995.1149. [DOI] [PubMed] [Google Scholar]
  5. Chagnon Y. C., Pérusse L., Lamothe M., Chagnon M., Nadeau A., Dionne F. T., Gagnon J., Chung W. K., Leibel R. L., Bouchard C. Suggestive linkages between markers on human 1p32-p22 and body fat and insulin levels in the Quebec Family Study. Obes Res. 1997 Mar;5(2):115–121. doi: 10.1002/j.1550-8528.1997.tb00651.x. [DOI] [PubMed] [Google Scholar]
  6. Cohen P. E., Chisholm O., Arceci R. J., Stanley E. R., Pollard J. W. Absence of colony-stimulating factor-1 in osteopetrotic (csfmop/csfmop) mice results in male fertility defects. Biol Reprod. 1996 Aug;55(2):310–317. doi: 10.1095/biolreprod55.2.310. [DOI] [PubMed] [Google Scholar]
  7. Cohen P. E., Zhu L., Pollard J. W. Absence of colony stimulating factor-1 in osteopetrotic (csfmop/csfmop) mice disrupts estrous cycles and ovulation. Biol Reprod. 1997 Jan;56(1):110–118. doi: 10.1095/biolreprod56.1.110. [DOI] [PubMed] [Google Scholar]
  8. Cunningham J. M., Kimmel D. W., Scheithauer B. W., O'Fallon J. R., Novotny P. J., Jenkins R. B. Analysis of proliferation markers and p53 expression in gliomas of astrocytic origin: relationships and prognostic value. J Neurosurg. 1997 Jan;86(1):121–130. doi: 10.3171/jns.1997.86.1.0121. [DOI] [PubMed] [Google Scholar]
  9. FOLCH J., LEES M., SLOANE STANLEY G. H. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957 May;226(1):497–509. [PubMed] [Google Scholar]
  10. Filonzi E. L., Zoellner H., Stanton H., Hamilton J. A. Cytokine regulation of granulocyte-macrophage colony stimulating factor and macrophage colony-stimulating factor production in human arterial smooth muscle cells. Atherosclerosis. 1993 Mar;99(2):241–252. doi: 10.1016/0021-9150(93)90026-q. [DOI] [PubMed] [Google Scholar]
  11. Flier J. S. The adipocyte: storage depot or node on the energy information superhighway? Cell. 1995 Jan 13;80(1):15–18. doi: 10.1016/0092-8674(95)90445-x. [DOI] [PubMed] [Google Scholar]
  12. French B. A., Mazur W., Geske R. S., Bolli R. Direct in vivo gene transfer into porcine myocardium using replication-deficient adenoviral vectors. Circulation. 1994 Nov;90(5):2414–2424. doi: 10.1161/01.cir.90.5.2414. [DOI] [PubMed] [Google Scholar]
  13. Hotamisligil G. S., Johnson R. S., Distel R. J., Ellis R., Papaioannou V. E., Spiegelman B. M. Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science. 1996 Nov 22;274(5291):1377–1379. doi: 10.1126/science.274.5291.1377. [DOI] [PubMed] [Google Scholar]
  14. Hotamisligil G. S., Peraldi P., Budavari A., Ellis R., White M. F., Spiegelman B. M. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science. 1996 Feb 2;271(5249):665–668. doi: 10.1126/science.271.5249.665. [DOI] [PubMed] [Google Scholar]
  15. Hume D. A., Yue X., Ross I. L., Favot P., Lichanska A., Ostrowski M. C. Regulation of CSF-1 receptor expression. Mol Reprod Dev. 1997 Jan;46(1):46–53. doi: 10.1002/(SICI)1098-2795(199701)46:1<46::AID-MRD8>3.0.CO;2-R. [DOI] [PubMed] [Google Scholar]
  16. Kamanna V. S., Pai R., Bassa B., Kirschenbaum M. A. Activation of mesangial cells with TNF-alpha stimulates M-CSF gene expression and monocyte proliferation: evidence for involvement of protein kinase C and protein tyrosine kinase. Biochim Biophys Acta. 1996 Aug 28;1313(2):161–172. doi: 10.1016/0167-4889(96)00064-x. [DOI] [PubMed] [Google Scholar]
  17. Kern P. A., Saghizadeh M., Ong J. M., Bosch R. J., Deem R., Simsolo R. B. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest. 1995 May;95(5):2111–2119. doi: 10.1172/JCI117899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kullo I. J., Mozes G., Schwartz R. S., Gloviczki P., Crotty T. B., Barber D. A., Katusic Z. S., O'Brien T. Adventitial gene transfer of recombinant endothelial nitric oxide synthase to rabbit carotid arteries alters vascular reactivity. Circulation. 1997 Oct 7;96(7):2254–2261. doi: 10.1161/01.cir.96.7.2254. [DOI] [PubMed] [Google Scholar]
  19. Marks S. C., Jr, Lane P. W. Osteopetrosis, a new recessive skeletal mutation on chromosome 12 of the mouse. J Hered. 1976 Jan-Feb;67(1):11–18. doi: 10.1093/oxfordjournals.jhered.a108657. [DOI] [PubMed] [Google Scholar]
  20. Miller G. G., Blair G. K., Murphy J. J. Diagnostic laparoscopy in childhood Crohn's disease. J Pediatr Surg. 1996 Jun;31(6):846–848. doi: 10.1016/s0022-3468(96)90150-5. [DOI] [PubMed] [Google Scholar]
  21. Mulligan R. C. The basic science of gene therapy. Science. 1993 May 14;260(5110):926–932. doi: 10.1126/science.8493530. [DOI] [PubMed] [Google Scholar]
  22. Pollard J. W., Hennighausen L. Colony stimulating factor 1 is required for mammary gland development during pregnancy. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9312–9316. doi: 10.1073/pnas.91.20.9312. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Saito S., Saito M., Enomoto M., Ito A., Motoyoshi K., Nakagawa T., Ichijo M. Human macrophage colony-stimulating factor induces the differentiation of trophoblast. Growth Factors. 1993;9(1):11–19. doi: 10.3109/08977199308991578. [DOI] [PubMed] [Google Scholar]
  24. Sjöström L., Björntorp P., Vrána J. Microscopic fat cell size measurements on frozen-cut adipose tissue in comparison with automatic determinations of osmium-fixed fat cells. J Lipid Res. 1971 Sep;12(5):521–530. [PubMed] [Google Scholar]
  25. Smith J. D., Trogan E., Ginsberg M., Grigaux C., Tian J., Miyata M. Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E. Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8264–8268. doi: 10.1073/pnas.92.18.8264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Suresh M. R., Cuello A. C., Milstein C. Advantages of bispecific hybridomas in one-step immunocytochemistry and immunoassays. Proc Natl Acad Sci U S A. 1986 Oct;83(20):7989–7993. doi: 10.1073/pnas.83.20.7989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Umezawa A., Tachibana K., Harigaya K., Kusakari S., Kato S., Watanabe Y., Takano T. Colony-stimulating factor 1 expression is down-regulated during the adipocyte differentiation of H-1/A marrow stromal cells and induced by cachectin/tumor necrosis factor. Mol Cell Biol. 1991 Feb;11(2):920–927. doi: 10.1128/mcb.11.2.920. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Volkert F. C., Young C. S. The genetic analysis of recombination using adenovirus overlapping terminal DNA fragments. Virology. 1983 Feb;125(1):175–193. doi: 10.1016/0042-6822(83)90072-7. [DOI] [PubMed] [Google Scholar]
  29. Wiktor-Jedrzejczak W., Gordon S. Cytokine regulation of the macrophage (M phi) system studied using the colony stimulating factor-1-deficient op/op mouse. Physiol Rev. 1996 Oct;76(4):927–947. doi: 10.1152/physrev.1996.76.4.927. [DOI] [PubMed] [Google Scholar]
  30. Wiktor-Jedrzejczak W., Ratajczak M. Z., Ptasznik A., Sell K. W., Ahmed-Ansari A., Ostertag W. CSF-1 deficiency in the op/op mouse has differential effects on macrophage populations and differentiation stages. Exp Hematol. 1992 Sep;20(8):1004–1010. [PubMed] [Google Scholar]
  31. Wiktor-Jedrzejczak W., Urbanowska E., Aukerman S. L., Pollard J. W., Stanley E. R., Ralph P., Ansari A. A., Sell K. W., Szperl M. Correction by CSF-1 of defects in the osteopetrotic op/op mouse suggests local, developmental, and humoral requirements for this growth factor. Exp Hematol. 1991 Nov;19(10):1049–1054. [PubMed] [Google Scholar]
  32. Yost T. J., Rodgers C. M., Eckel R. H. Suction lipectomy: outcome relates to region-specific lipoprotein lipase activity and interval weight change. Plast Reconstr Surg. 1993 Nov;92(6):1101–1111. [PubMed] [Google Scholar]
  33. Yu M. F., Ewaskiewicz J. I., Adda S., Bailey K., Harris V., Sosnoski D., Tomasic M., Wilson J., Kotlikoff M. I. Gene transfer by adenovirus in smooth muscle cells. Respir Physiol. 1996 Aug;105(1-2):155–162. doi: 10.1016/0034-5687(96)00016-3. [DOI] [PubMed] [Google Scholar]
  34. Zamboni M., Armellini F., Turcato E., Todesco T., Bissoli L., Bergamo-Andreis I. A., Bosello O. Effect of weight loss on regional body fat distribution in premenopausal women. Am J Clin Nutr. 1993 Jul;58(1):29–34. doi: 10.1093/ajcn/58.1.29. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES