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-week-old female C57BL/6J mice significantly increased weight gain and food consumption after only 1 month, and the effect lasted for the 3 months of the experiment, proving its central inhibiting activity. Mice showed a significant increase in serum glucose, cholesterol, triglycerides, insulin and homeostasis assessment model-insulin resistance 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 first and third 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 months) affected body weight and eating behavior as in the 1-month-old mice, but had no effect on bone parameters, suggesting that leptin's effecton bones, either directly or through its obesogenic effect, is dependent upon stage of skeletal development. This potent and reversible antagonist enabled study leptin's in-vivo role in whole-body and bone metabolism and holds potential for future therapeutic use in diseases involving leptin signaling.