Inflammatory cytokines and human adipose tissue: Regulation and biological effects

The chronic inflammatory state associated with obesity is implicated in the development of metabolic abnormalities that contribute to increased risk for diabetes and cardiovascular disease. It has recently been realized that adipose tissue expresses a number of cytokines, including tumor necrosis factor-α (TNF), interleukin-6 (IL6), interleukin-8 (IL8), and leptin, that influence metabolism in an endocrine and paracrine fashion. The level of adipose tissue cytokines is increased in proportion to obesity. In addition, adipose tissue from different anatomical regions has distinct metabolic properties. TNF, IL6, and IL8 release was higher in omental than subcutaneous adipose tissue. To investigate the factors that drive cytokine over-expression, omental and subcutaneous human adipose tissues were cultured for 7 days in the absence or presence of insulin and glucocorticoids because these hormones are important regulators of adipose metabolism and are increased in obesity. Long-term culture with insulin increased TNF, IL6, and IL8 release from both omental and subcutaneous adipose tissue. Glucocorticoids decreased IL6 and IL8, but increased TNF release. These effects were especially robust in omental adipose tissue and may explain our finding that levels of omental adipose tissue cytokine release were higher in this depot.; We also tested the effect of TNF and IL6 on adipose tissue function. When added in the presence of glucocorticoid, both cytokines increased leptin secretion into the culture medium. In the absence of insulin, culture with TNF or IL6 increased lipolysis. To determine the signaling mechanisms involved, we tested the effects of inhibitors of the mitogen-activated kinases (MAPK) on basal and TNF-stimulated leptin production and lipolysis. The TNF-stimulated increase in leptin production was blocked by inhibition of p38, while the inhibition of p38 and p44/42 MAPKs decreased basal leptin production. In contrast, inhibition of MAPK did not influence lipolysis. These results suggest that increased endogenous cytokines contribute to increased leptin expression and high rates of lipolysis in obese adipose tissue, but by different mechanisms.