title: Hyperleptinemia and reduced TNF-alpha secretion cause resistance of db/db mice to endotoxin.
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.
authors.affiliation: Department of Foods and Nutrition, University of Georgia, Athens, Georgia 30602, USA.
authors.forename: Abram M
authors.initials: AM
authors.lastname: Madiehe
authors.forename: Tiffany D
authors.initials: TD
authors.lastname: Mitchell
authors.forename: Ruth B S
authors.initials: RB
authors.lastname: Harris
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D004351:Drug Resistance; D004731:Endotoxins / Q000494:pharmacology*; D005215:Fasting / Q000097:blood; D005260:Female; D007274:Injections, Intraperitoneal; D020738:Leptin / Q000097:blood* / Q000172:deficiency / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000506:poisoning; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D008817:Mice, Mutant Strains / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D054411:Receptors, Leptin; D012007:Rectum / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D004731:Endotoxins; D020738:Leptin; D008070:Lipopolysaccharides; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D014409:Tumor Necrosis Factor-alpha; D003345:Corticosterone