title: A superactive leptin antagonist alters metabolism and locomotion in high-leptin mice.
abstract: Transgenic alpha murine urokinase-type plasminogen activator (αMUPA) mice are resistant to obesity and their locomotor activity is altered. As these mice have high leptin levels, our objective was to test whether leptin is responsible for these characteristics. αMUPA, their genetic background control (FVB/N), and C57BL mice were injected s.c. every other day with 20  mg/kg pegylated superactive mouse leptin antagonist (PEG-SMLA) for 6 weeks. We tested the effect of PEG-SMLA on body weight, locomotion, and bone health. The antagonist led to a rapid increase in body weight and subsequent insulin resistance in all treated mice. Food intake of PEG-SMLA-injected animals increased during the initial period of the experiment but then declined to a similar level to that of the control animals. Interestingly, αMUPA mice were found to have reduced bone volume (BV) than FVB/N mice, although PEG-SMLA increased bone mass in both strains. In addition, PEG-SMLA led to disrupted locomotor activity and increased corticosterone levels in C57BL but decreased levels in αMUPA or FVB/N mice. These results suggest that leptin is responsible for the lean phenotype and reduced BV in αMUPA mice; leptin affects corticosterone levels in mice in a strain-specific manner; and leptin alters locomotor activity, a behavior determined by the central circadian clock.
authors.affiliation: Robert H Smith Faculty of Agriculture, Food and Environment, Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot 76100, Israel.
authors.forename: Nava
authors.initials: N
authors.lastname: Chapnik
authors.forename: Gili
authors.initials: G
authors.lastname: Solomon
authors.forename: Yoni
authors.initials: Y
authors.lastname: Genzer
authors.forename: Ruth
authors.initials: R
authors.lastname: Miskin
authors.forename: Arieh
authors.initials: A
authors.lastname: Gertler
authors.forename: Oren
authors.initials: O
authors.lastname: Froy
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects*; D001842:Bone and Bones / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D007328:Insulin / Q000378:metabolism; D020738:Leptin / Q000031:analogs & derivatives* / Q000097:blood* / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects*; D011092:Polyethylene Glycols / Q000494:pharmacology*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
chemical_list: D007328:Insulin; D020738:Leptin; C484843:pegylated leptin; D011092:Polyethylene Glycols; D014568:Urokinase-Type Plasminogen Activator