The role of TNF-alpha in human adipose tissue: Prevention of weight gain at the expense of insulin resistance?

Since evidence has appeared that tumor necrosis factor-alpha (TNF) is invol ved in the loss of body fat in the course of wasting diseases, a large numb er of studies have investigated the physiological role of this cytokine in adipose tissue. TNF treatment of several in vitro models of adipogenesis cl early showed that TNF is a potent inhibitor of adipose differentiation. Thi s antiadipogenic property is accompanied by suppression of developmental an d metabolic markers of fat cell differentiation, such as peroxisome prolife rator-activated receptor (PPAR)-gamma 2, lipoprotein lipase (LPL), glycerol -3-phosphate dehydrogenase (GPDH) and GLUT4. Moreover, INF promotes lipolys is in mature adipocytes and, subsequently, a reversion of the adipocyte phe notype. Recent studies demonstrated that TNF directly interferes with the i nsulin signaling cascade at early steps and, thus, impairs insulin-stimulat ed glucose transport. Further progress in understanding the role of TNF in adipose tissue was made when endogenous TNF mRNA expression was demonstrate d in adipose tissue. Obesity was found to represent a state of overexpressi on of the TNF system. Such findings support the hypothesis that TNF is a me diator of obesity-linked insulin resistance. However, this concept is mainl y based on animal data and is so far only partially supported by studies in humans. Taken together, the results of a variety of experimental and clini cal studies suggest that TNF may act as an important auto/paracrine regulat or of fat cell function which serves to limit adipose tissue expansion, pro bably by inducing insulin resistance which may in turn cause metabolic dist urbances. Elucidation of the molecular mechanisms of TNF production and act ion in adipose tissue may help to find new approaches for the treatment of insulin resistance in humans.