title: Reanalysis of parabiosis of obesity mutants in the age of leptin.
abstract: In this study we set out to explain the differing effects of parabiosis with genetically diabetic (db) mice versus administration of recombinant leptin. Parabiosis of db mutant, which overexpress leptin, to wildtype (WT) or genetically obese (ob) mice has been reported to cause death by starvation, whereas leptin infusions do not produce lethality at any dose or mode of delivery tested. Leptin is not posttranslationally modified other than a single disulphide bond, raising the possibility that it might require additional factor(s) to exert the maximal appetite-suppressing effect. We reconfirmed the lethal effect of parabiosis of db mutant on WT mice and further showed that this lethality could not be rescued by administration of ghrelin or growth hormone. We then initiated a biochemical fractionation of a high-molecular-weight leptin complex from human plasma and identified clusterin as a major component of this leptin-containing complex. However, in contrast to previous reports, we failed to observe a leptin-potentiating effect of either exogenous or endogenous clusterin, and parabiosis of db clusterin(-/-) double-mutant to WT mice still caused lethality. Intriguingly, in parabiotic pairs of two WT mice, leptin infusion into one of the mice led to an enhanced starvation response during calorie restriction as evidenced by increased plasma ghrelin and growth-hormone levels. Moreover, leptin treatment resulted in death of the parabiotic pairs. These data suggest that the appetite suppression in WT mice after parabiosis to db mutants is the result of induced hyperleptinemia combined with the stress or other aspect(s) of the parabiosis procedure.
authors.affiliation: Laboratory of Molecular Genetics, The Rockefeller University, NY 10065; Howard Hughes Medical Institute, The Rockefeller University, NY 10065.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Zeng
authors.affiliation: Laboratory of Molecular Genetics, The Rockefeller University, NY 10065;
authors.forename: Yi-Hsueh
authors.initials: YH
authors.lastname: Lu
authors.affiliation: Laboratory of Molecular Genetics, The Rockefeller University, NY 10065;
authors.forename: Jonah
authors.initials: J
authors.lastname: Lee
authors.affiliation: Laboratory of Molecular Genetics, The Rockefeller University, NY 10065; Howard Hughes Medical Institute, The Rockefeller University, NY 10065 friedj@mail.rockefeller.edu.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Friedman
mesh_terms: D000818:Animals; D001835:Body Weight; D051152:Clusterin / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000473:pathology; D005247:Feeding Behavior; D020869:Gene Expression Profiling; D006801:Humans; D020738:Leptin / Q000097:blood*; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008970:Molecular Weight; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D009765:Obesity / Q000097:blood* / Q000235:genetics*; D010227:Parabiosis; D054411:Receptors, Leptin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D051152:Clusterin; D020738:Leptin; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor
keywords: clusterin; db mutant; leptin; obesity; parabiosis