TNF (Tumor Necrosis Factor)

Tumor necrosis factor (cachexin, cachectin, TNF) is a multifunction cytokine. When produced in normal amounts, it is a beneficial part of the immune inflammatory system. However, when it is produced in abnormally large quantities, numerous pathologic conditions result. This is especially true in obesity.

TNF is but one cytokine of the tumor necosis factor family, all of which have 157 amino acids and a tetramer structure. In normal circumstances, TNF plays a vital role in programmed cell death, cellular proliferation, differentiation, inflammation, tumrogenesis, fever, acute phase reactions, appetite regulation, neutrophil migration, tumor cell death, coagulation, and endothelial cell function. It is usually thought of as a product of macrophages, but it is also produced by lymphoid cells, adipocytes, fibroblasts, neuronal tissue, and mast cells.

In obesity, high levels of TNF are produced by adipocytes throughout the body, but especially in the waist-hip region. Adipocyte TNF messenger RNA expression rises with elevated body mass index (BMI) and falls with weight loss. This affects numerous organ systems and is in part responsible for the morbidity that affects the obese.

In the coagulation system serum levels of TNF seem to induce production of plasminogen activator inhibitor (which impairs the breakdown of blood clots) and increase plasma levels of von Willebrand factor (which increases the likelyhood of blood clots, and is a marker of inflammation). This is believed to contribute to the higher occurrence of thrombotic events such as deep venous thrombosis, pulmonary embolism, myocardial infarction, and stroke.

The higher incidence of insulin resistance and diabetes in obesity is believed to result from adipocytes and macrophages, which are found in white adipose tissue that secrete TNF and other cytokines (adiponectin, resistin, interleukin-6 [IL-6]) which exert lipotoxic effects on pancreatic beta cells. TNF impairs insulin signaling by downregulating the activity of the insulin receptor. It also increases serum glucose due to a reduced number of muscle cell glucose receptors. These impairments that are partly caused by obesity may promote the cycle of insulin resistance and encourage the development of diabetes.

TNF along with IL-6 plays a role in dyslipidemia (high levels of blood lipids) in obesity. These cytokines inhibit lipoprotein lipase which increases very-low-density lipids and increases the secretion of triglycerides. These cytokines also increase lipolysis which causes elevation in free fatty acids. The cytokines also activate serum amyloid A in the liver which causes a [Page 748]drop in high-density lipoproteins. TNF alone stimulates hormone-sensitive lipase, and downregulates fatty acid binding protein and fatty acid synthetase.

It seems that there are numerous other effects of TNF in obesity being discovered almost daily. Weight loss, however achieved, results in falling levels of TNF. This causes improvement in the organ system affected.