Search tips
Search criteria 


Logo of jcinvestThe Journal of Clinical Investigation
J Clin Invest. 1995 May; 95(5): 2409–2415.
PMCID: PMC295872

Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance.


Obesity is frequently associated with insulin resistance and abnormal glucose homeostasis. Recent studies in animal models have indicated that TNF-alpha plays an important role in mediating the insulin resistance of obesity through its overexpression in fat tissue. However, the mechanisms linking obesity to insulin resistance and diabetes in humans remain largely unknown. In this study we examined the expression pattern of TNF-alpha mRNA in adipose tissues from 18 control and 19 obese premenopausal women by Northern blot analysis. TNF-alpha protein concentrations in plasma and in conditioned medium of explanted adipose tissue were measured by ELISA. Furthermore, the effects of weight reduction by dietary treatment of obesity on the adipose expression of TNF-alpha mRNA were also analyzed in nine premenopausal obese women, before and after a controlled weight-reduction program. These studies demonstrated that obese individuals express 2.5-fold more TNF-alpha mRNA in fat tissue relative to the lean controls (P < 0.001). Similar increases were also observed in adipose production of TNF-alpha protein but circulating TNF-alpha levels were extremely low or undetectable. A strong positive correlation was observed between TNF-alpha mRNA expression levels in fat tissue and the level of hyperinsulinemia (P < 0.001), an indirect measure of insulin resistance. Finally, body weight reduction in obese subjects which resulted in improved insulin sensitivity was also associated with a decrease in TNF-alpha mRNA expression (45%, P < 0.001) in fat tissue. These results suggest a role for the abnormal regulation of this cytokine in the pathogenesis of obesity-related insulin resistance.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.3M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Moller DE, Flier JS. Insulin resistance--mechanisms, syndromes, and implications. N Engl J Med. 1991 Sep 26;325(13):938–948. [PubMed]
  • Old LJ. Tumor necrosis factor (TNF). Science. 1985 Nov 8;230(4726):630–632. [PubMed]
  • Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Derynck R, Palladino MA, Kohr WJ, Aggarwal BB, Goeddel DV. Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature. 1984 Dec 20;312(5996):724–729. [PubMed]
  • Beutler B, Cerami A. The biology of cachectin/TNF--a primary mediator of the host response. Annu Rev Immunol. 1989;7:625–655. [PubMed]
  • Grunfeld C, Feingold KR. The metabolic effects of tumor necrosis factor and other cytokines. Biotherapy. 1991;3(2):143–158. [PubMed]
  • Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993 Jan 1;259(5091):87–91. [PubMed]
  • Hotamisligil GS, Spiegelman BM. Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Diabetes. 1994 Nov;43(11):1271–1278. [PubMed]
  • Hofmann C, Lorenz K, Braithwaite SS, Colca JR, Palazuk BJ, Hotamisligil GS, Spiegelman BM. Altered gene expression for tumor necrosis factor-alpha and its receptors during drug and dietary modulation of insulin resistance. Endocrinology. 1994 Jan;134(1):264–270. [PubMed]
  • Folli F, Saad MJ, Backer JM, Kahn CR. Insulin stimulation of phosphatidylinositol 3-kinase activity and association with insulin receptor substrate 1 in liver and muscle of the intact rat. J Biol Chem. 1992 Nov 5;267(31):22171–22177. [PubMed]
  • Heydrick SJ, Jullien D, Gautier N, Tanti JF, Giorgetti S, Van Obberghen E, Le Marchand-Brustel Y. Defect in skeletal muscle phosphatidylinositol-3-kinase in obese insulin-resistant mice. J Clin Invest. 1993 Apr;91(4):1358–1366. [PMC free article] [PubMed]
  • Saad MJ, Araki E, Miralpeix M, Rothenberg PL, White MF, Kahn CR. Regulation of insulin receptor substrate-1 in liver and muscle of animal models of insulin resistance. J Clin Invest. 1992 Nov;90(5):1839–1849. [PMC free article] [PubMed]
  • Thies RS, Molina JM, Ciaraldi TP, Freidenberg GR, Olefsky JM. Insulin-receptor autophosphorylation and endogenous substrate phosphorylation in human adipocytes from control, obese, and NIDDM subjects. Diabetes. 1990 Feb;39(2):250–259. [PubMed]
  • Freidenberg GR, Henry RR, Klein HH, Reichart DR, Olefsky JM. Decreased kinase activity of insulin receptors from adipocytes of non-insulin-dependent diabetic subjects. J Clin Invest. 1987 Jan;79(1):240–250. [PMC free article] [PubMed]
  • Feinstein R, Kanety H, Papa MZ, Lunenfeld B, Karasik A. Tumor necrosis factor-alpha suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates. J Biol Chem. 1993 Dec 15;268(35):26055–26058. [PubMed]
  • Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM. Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4854–4858. [PubMed]
  • Hotamisligil GS, Budavari A, Murray D, Spiegelman BM. Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha. J Clin Invest. 1994 Oct;94(4):1543–1549. [PMC free article] [PubMed]
  • Chirgwin JM, Przybyla AE, MacDonald RJ, Rutter WJ. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. [PubMed]
  • Spiegelman BM, Frank M, Green H. Molecular cloning of mRNA from 3T3 adipocytes. Regulation of mRNA content for glycerophosphate dehydrogenase and other differentiation-dependent proteins during adipocyte development. J Biol Chem. 1983 Aug 25;258(16):10083–10089. [PubMed]
  • Gray PW, Aggarwal BB, Benton CV, Bringman TS, Henzel WJ, Jarrett JA, Leung DW, Moffat B, Ng P, Svedersky LP, et al. Cloning and expression of cDNA for human lymphotoxin, a lymphokine with tumour necrosis activity. Nature. 1984 Dec 20;312(5996):721–724. [PubMed]
  • Boeck MA, Chen C, Cunningham-Rundles S. Altered immune function in a morbidly obese pediatric population. Ann N Y Acad Sci. 1993 Oct 29;699:253–256. [PubMed]
  • Prager R, Wallace P, Olefsky JM. In vivo kinetics of insulin action on peripheral glucose disposal and hepatic glucose output in normal and obese subjects. J Clin Invest. 1986 Aug;78(2):472–481. [PMC free article] [PubMed]
  • Raptis S, Mitrakou A, Hadjidakis D, Diamantopoulos E, Anastasiou C, Fountas A, Müller R. 24-h blood glucose pattern in type I and type II diabetics after oral treatment with pentoxifylline as assessed by artificial endocrine pancreas. Acta Diabetol Lat. 1987 Jul-Sep;24(3):181–192. [PubMed]
  • Strieter RM, Remick DG, Ward PA, Spengler RN, Lynch JP, 3rd, Larrick J, Kunkel SL. Cellular and molecular regulation of tumor necrosis factor-alpha production by pentoxifylline. Biochem Biophys Res Commun. 1988 Sep 30;155(3):1230–1236. [PubMed]
  • Nolan JJ, Ludvik B, Beerdsen P, Joyce M, Olefsky J. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med. 1994 Nov 3;331(18):1188–1193. [PubMed]

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