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TNF α or tumour necrosis factor alpha, is a pro-inflammatory cytokine which is identical to cachectin, Nature. 1985 Aug 8-14;316(6028):552-4   a factor secreted by macrophages invitro. It was named TNF as it was initially described as an endotoxin induced factor causing necrosis of tumours. Proc Natl Acad Sci U S A. 1975 Sep;72(9):3666-70.     TNF α has the ability to induce cachexia in vivo J Exp Med. 1988 Mar 1;167(3):1211-27.   which makes it important in energy balance.  In the adipose tissue, adipocytes are the major producers of TNF α.   J Clin Invest. 1995 May;95(5):2111-9.   TNF α exerts multiple actions  including production of  inflammation, apoptosis, as well as stimulating production of cytokines as IL-1 and IL-6. TNF α is released from its membrane bound precursor protein by TACE ( TNF α Converting Enzyme). Nature. 1997 Feb 20;385(6618):729-33.    Type I and Type 2 receptors have been described for TNF α, with both types being present in adipose tissue. Cytokine Growth Factor Rev. 2003 Oct;14(5):447-55  TNF α expression is greater in visceral adipocytes than in subcutaneous adipose tissue. Endocr Rev. 2000 Dec;21(6):697-738   TNF α produces its effects in a paracrine and autocrine manner rather than endocrine. J Clin Endocrinol Metab. 1997 Dec;82(12):4196-200
Obese rodents and obese humans have increased expression of TNF α in the adipose tissue. TNF α expression in adipose tissue thus positively correlates with adiposity and insulin resistanceEndocr Rev. 2003 Jun;24(3):278-301.  while the correlation between plasma TNF α and insulin resistance is variable in different studies. Chronic exposure to exogenous TNF α in vivo and in vitro induces insulin resistance, Endocrinology. 1992 Jan;130(1):43-52  Gene deletion of TNF α or its receptors in obese rodents (fa/fa Zucker rats) improves insulin sensitivity and circulating NEFAs. Nature. 1997 Oct 9;389(6651):610-4   ;   J Clin Invest. 1994 Oct;94(4):1543-9.    But while treatment with neutralising soluble TNF α receptors improved insulin sensitivity in obese rodents, a similar effect was not seen in type 2 diabetic patients infused with TNF α neutralising antibodies.  Diabetes. 1996 Jul;45(7):881-5.  This clearly necessitates further studies to delineate the role of endogenous TNF α in the production of insulin resistance. On the other hand, this lack of effect of systemically infused TNF α neutralising antibodies is probably due to the fact that neutralising antibodies in circulation may not be able to counter the autocrine or paracrine actions effected by the TNF α in adipose tissue. Thus methods to target TNF α in tissues is probably warranted to produce meaningful effects in humans.
In the adipose tissue, TNF α suppresses genes involved in uptake and storage of NEFAs and glucose as well as adipogenesis. It also modifies expression of adipocyte secreted factors as adiponectin  Am J Physiol Endocrinol Metab. 2003 Sep;285(3):E527-33    and IL-6. Diabetes. 2002 Nov;51(11):3176-88.  In the liver, TNF α suppresses expression of the genes involved in glucose uptake and metabolism and fatty acid oxidation while increasing expression of genes involved in de novo synthesis of cholesterol and fatty acids. Insulin signalling is also impaired by TNF α directly and indirectly. The direct mechanism is by activation of serine kinases that increase serine phosphorylation of insulin receptor substrates 1 and 2, thus making them poor substrates for insulin receptor kinases and increasing their degradation Int J Obes Relat Metab Disord. 2003 Dec;27 Suppl 3:S53-5.  Insulin signalling is indirectly impaired by TNF α through increased serum NEFA levels. Thiazolidinediones improve the inhibitory effects of TNF α on insulin action.  J Clin Invest. 1997 Oct 1;100(7):1863-9.  Weight loss results in a decrease in TNF α levels. J Clin Invest. 1995 May;95(5):2111-9.  Thalidomide, a potent inhibitor of TNF-alpha reduces protein catabolism in AIDS patients with the wasting syndrome producing median weight gain of 4 kg at 3 months.