Pro-inflammatory cytokines and adipose tissue

Cytokines appear to be major regulators of adipose tissue metabolism. Thera peutic modulation of cytokine systems offers the possibility of major chang es in adipose tissue behaviour. Cytokines within adipose tissue originate f rom adipocyte, preadipocyte and other cell types. mRNA expression studies s how that adipocytes can synthesise both tumour necrosis factor alpha (TNF-a lpha) and several interleukins (IL), notably IL-1 beta and IL-6. Other adip ocyte products with 'immunological' actions include complement system produ cts and macrophage colony-stimulating factor. Cytokine secretion within adi pocytes appears similar to that of other cells. There is general agreement that circulating TNF-alpha and IL-6 concentrations are mildly elevated in o besity. Most studies suggest increased TNF-alpha mRNA expression or secreti on in vitro in adipose tissue from obese subjects. The factors regulating c ytokine 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 tissu e 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-alp ha also down regulates insulin-stimulated glucose uptake via effects on glu cose transporter 4, insulin receptor autophosphorylation and insulin recept or substrate-1. All these effects will tend to reduce lipid accumulation wi thin adipose tissue. Other effects appear more 'trophic', and include the i nduction of apoptosis, regulation of cell size and induction of de-differen tiation (the latter involving reduced peroxisome proliferator-activated rec eptor gamma). Cytokines are important stimulators and repressors of other c ytokines. In addition, cytokines appear to modulate other regulatory system s. Examples of the latter include effects on leptin secretion (probably sti mulation followed by inhibition) and reduction of beta (3)-adrenoceptor exp ression. 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 syste m in whole-body energy balance provides a rationale for the links between c ytokines and adipose tissue. It seems clear that TNF-alpha is a powerful au tocrine and paracrine regulator of adipose tissue. Other cytokines, notably leptin, and possibly IL-6, have lesser actions on adipose tissue. These cy tokines act as hormones, reporting the state of adipose tissue stores throu ghout the body.