Pro-inflammatory cytokines and adipose tissue.

Cytokines appear to be major regulators of adipose tissue metabolism. Therapeutic modulation of cytokine systems offers the possibility of major changes in adipose tissue behaviour. Cytokines within adipose tissue originate from adipocyte, preadipocyte and other cell types. mRNA expression studies show that adipocytes can synthesise both tumour necrosis factor alpha (TNF-alpha) and several interleukins (IL), notably IL-1beta and IL-6. Other adipocyte products with 'immunological' actions include complement system products and macrophage colony-stimulating factor. Cytokine secretion within adipocytes appears similar to that of other cells. There is general agreement that circulating TNF-alpha and IL-6 concentrations are mildly elevated in obesity. Most studies suggest increased TNF-alpha mRNA expression or secretion in vitro in adipose tissue from obese subjects. The factors regulating cytokine release within adipose tissue appear to include usual 'inflammatory' stimuli such as lipopolysaccaride, but also the size of the fat cells per se and catecholamines. There is conflicting data about whether insulin and cortisol regulate TNF-alpha. The effects of cytokines within adipose tissue include some actions that might be characterised as metabolic. TNF-alpha and IL-6 inhibit lipoprotein lipase, and TNF-alpha additionally stimulates hormone-sensitive lipase and induces uncoupling protein expression. TNF-alpha also down regulates insulin-stimulated glucose uptake via effects on glucose transporter 4, insulin receptor autophosphorylation and insulin receptor substrate-1. All these effects will tend to reduce lipid accumulation within adipose tissue. Other effects appear more 'trophic', and include the induction of apoptosis, regulation of cell size and induction of de-differentiation (the latter involving reduced peroxisome proliferator-activated receptor gamma). Cytokines are important stimulators and repressors of other cytokines. In addition, cytokines appear to modulate other regulatory systems. Examples of the latter include effects on leptin secretion (probably stimulation followed by inhibition) and reduction of beta3-adrenoceptor expression. There seems to be no clear agreement as to which cytokines derived from adipose tissue act as remote regulators, i.e. hormones. Leptin, which is structurally a cytokine, is also a hormone. IL-6 appears to be released systemically by adipose tissue, but TNF-alpha is probably not. Both leptin and IL-6 appear to act on the hypothalamus, IL-6 acts on the liver, while leptin may have actions on the pancreas. The importance of the immune system in whole-body energy balance provides a rationale for the links between cytokines and adipose tissue. It seems clear that TNF-alpha is a powerful autocrine and paracrine regulator of adipose tissue. Other cytokines, notably leptin, and possibly IL-6, have lesser actions on adipose tissue. These cytokines act as hormones, reporting the state of adipose tissue stores throughout the body.