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J. Exp. Med.,
Volume 189, Number 1, January 4, 1999 207-212
By
From the * Molecular Pathophysiology and Experimental Therapy Unit, Department of Molecular
Biology; and the 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.
Department of Medical Protein Research, Flanders Interuniversity Institute for
Biotechnology and University of Ghent, B-9000 Ghent, Belgium; and § Roche Research Ghent,
B-9000 Ghent, Belgium
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