1. Hyperleptinemia and reduced TNF-alpha secretion cause resistance of db/db mice to endotoxin.
- Author
-
Madiehe AM, Mitchell TD, and Harris RB
- Subjects
- Animals, Body Temperature drug effects, Corticosterone blood, Drug Resistance, Fasting blood, Female, Injections, Intraperitoneal, Leptin deficiency, Leptin pharmacology, Lipopolysaccharides administration & dosage, Lipopolysaccharides poisoning, Mice, Mice, Inbred C57BL genetics, Mice, Mutant Strains genetics, Protein Isoforms genetics, Receptors, Cell Surface genetics, Receptors, Leptin, Rectum physiology, Endotoxins pharmacology, Leptin blood, Tumor Necrosis Factor-alpha metabolism
- Abstract
Leptin deficiency in ob/ob mice increases susceptibility to endotoxic shock, whereas leptin pretreatment protects them against LPS-induced lethality. Lack of the long-form leptin receptor (Ob-Rb) in db/db mice causes resistance. We tested the effects of LPS in C57BL/6J db(3J)/db(3J) (BL/3J) mice, which express only the circulating leptin receptors, compared with C57BL/6J db/db (BL/6J) mice, which express all short-form and circulating isoforms of the leptin receptor. Intraperitoneal injections of LPS significantly decreased rectal temperature and increased leptin, corticosterone, and free TNF-alpha in fed and fasted BL/3J and BL/6J mice. TNF-alpha was increased three- and fourfold in BL/3J and BL/6J, respectively. LPS (100 microg) caused 50% mortality of fasted BL/6J mice but caused no mortality in fasted BL/3J mice. Pretreatment of fasted BL/3J mice with 30 microg leptin prevented the drop in rectal temperature, blunted the increase in corticosterone, but had no effect on TNF-alpha induced by 100 microg LPS. Taken together, these data provide evidence that fasted BL/3J mice are more resistant than BL/6J mice to LPS toxicity, presumably due to the absence of leptin receptors in BL/3J mice. This resistance may be due to high levels of free leptin cross-reacting with other cytokine receptors.
- Published
- 2003
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