title: Effect of peripherally administered leptin antagonist on whole body metabolism and bone microarchitecture and biomechanical properties in the mouse.
abstract: Leptin's in vivo effect on the rodent skeleton depends on the model used and the mode of administration. Superactive mouse leptin antagonist (SMLA) was produced and then pegylated (PEG) to prolong and enhance its in vivo activity. We blocked leptin signaling by injecting this antagonist peripherally into normal mice at various time points and studied their metabolic and skeletal phenotypes. Subcutaneous PEG-SMLA injections into 4-wk-old female C57BL/6J mice increased weight gain and food consumption significantly after only 1 mo, and the effect lasted for the 3 mo of the experiment, proving its central inhibiting activity. Mice showed a significant increase in serum glucose, cholesterol, triglycerides, insulin, and HOMA-IR throughout the experiment. Quantification of gene expression in "metabolic" tissues also indicated the development of insulin resistance. Bone analyses revealed a significant increase in trabecular and cortical parameters measured in both the lumbar vertebrae and tibiae in PEG-SMLA-treated mice in the 1st and 3rd months as well as a significant increase in tibia biomechanical parameters. Interestingly, 30 days of treatment with the antagonist in older mice (aged 3 and 6 mo) affected body weight and eating behavior, just as they had in the 1-mo-old mice, but had no effect on bone parameters, suggesting that leptin's effect on bones, either directly or through its obesogenic effect, is dependent upon stage of skeletal development. This potent and reversible antagonist enabled us to study leptin's in vivo role in whole body and bone metabolism and holds potential for future therapeutic use in diseases involving leptin signaling.
authors.affiliation: Institute of Biochemistry and Nutrition and.
authors.forename: Gili
authors.initials: G
authors.lastname: Solomon
authors.forename: Ayelet
authors.initials: A
authors.lastname: Atkins
authors.forename: Ron
authors.initials: R
authors.lastname: Shahar
authors.forename: Arieh
authors.initials: A
authors.lastname: Gertler
authors.forename: Efrat
authors.initials: E
authors.lastname: Monsonego-Ornan
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure*; D002784:Cholesterol / Q000097:blood; D003924:Diabetes Mellitus, Type 2; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics; D020738:Leptin / Q000037:antagonists & inhibitors* / Q000502:physiology*; D024821:Metabolic Syndrome; D008660:Metabolism / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D014280:Triglycerides; D002784:Cholesterol
keywords: insulin resistance; leptin signaling; microcomputed tomography; obesity