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.