Leptin is an endogenous protective protein against the toxicity exerted bytumor necrosis factor

Tumor necrosis factor (TNF) is a central mediator of a number of important pathologies such as the systemic inflammatory response syndrome. Administra tion of high TNF doses induces acute anorexia, metabolic derangement, infla mmation, and eventually shock and death. The in vivo effects of TNF are lar gely mediated by a complex network of TNF-induced cytokines and hormones ac ting together or antagonistically. Since TNF also induces leptin, a hormone secreted by adipocytes that modulates food intake and metabolism, we quest ioned the role of leptin in TNF-induced pathology. To address this question , we tested mouse strains that were defective either in leptin gene (ob/ob) or in functional leptin receptor gene (db/db), and made use of a receptor antagonist of leptin. Ob/ob and db/db mice, as well as normal mice treated with antagonist, exhibited increased sensitivity to the lethal effect of TN F. Exogenous leptin afforded protection to TNF in ob/ob mice, but failed to enhance the protective effect of endogenous leptin in normal mice. We conc lude that leptin is involved in the protective mechanisms that allow an org anism to cope with the potentially autoaggressive effects of its immune sys tem.