Hyperleptinemia and reduced TNF- secretion cause resistance of db/db mice to endotoxin

Madiehe, Abram M., Tiffany D. Mitchell, and Ruth B. S. Harris. Hyperleptinemia and reduced TNFsecretion cause resistance of db/db mice to endotoxin. Am J Physiol Regul Integr Comp Physiol 284: R763–R770, 2003; 10.1152/ ajpregu.00610.2002.—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 db3J/ db3J (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 TNFin fed and fasted BL/3J and BL/6J mice. TNFwas increased threeand fourfold in BL/3J and BL/6J, respectively. LPS (100 g) 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 g leptin prevented the drop in rectal temperature, blunted the increase in corticosterone, but had no effect on TNFinduced by 100 g 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.