Leptin is an endogenous protective protein against the toxicity exerted by tumor necrosis factor.
Tumor necrosis factor (TNF) is a central mediator of a number of important pathologies such as the systemic inflammatory response syndrome. Administration of high TNF doses induces acute anorexia, metabolic derangement, inflammation, and eventually shock and death. The in vivo effects of TNF are largely mediated by a complex network of TNF-induced cytokines and hormones acting together or antagonistically. Since TNF also induces leptin, a hormone secreted by adipocytes that modulates food intake and metabolism, we questioned 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 TNF. Exogenous leptin afforded protection to TNF in ob/ob mice, but failed to enhance the protective effect of endogenous leptin in normal mice. We conclude that leptin is involved in the protective mechanisms that allow an organism to cope with the potentially autoaggressive effects of its immune system.
Takahashi
N
N
Molecular Pathophysiology and Experimental Therapy Unit, Department of Molecular Biology, Flanders Interuniversity Institute for Technology, University of Ghent, B-9000 Ghent, Belgium. nozomi.takahashi@dumb.rug.ac.be
Waelput
W
W
Guisez
Y
Y
D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D007249:Inflammation / Q000276:immunology; D020738:Leptin; D051379:Mice; D016688:Mice, Inbred NOD; D008820:Mice, Obese; D011506:Proteins / Q000378:metabolism*; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D011994:Recombinant Proteins / Q000633:toxicity; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000633:toxicity*
D002352:Carrier Proteins; D020738:Leptin; D011506:Proteins; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C515447:leptin receptor, mouse