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We hypothesized that leptin is expressed in a specific time sequence during fracture healing, and its deficiency leads to impaired healing.Control (C57BL/6) mice and leptin −/− obese (ob/ob) mice were used.Fracture callus was harvested at 1, 3, 5, 7, 10, 14, and 21 days (n = 8/time point) after closed middiaphyseal femur fractures were created in 56 C57BL/6 mice, and reverse transcriptase polymerase chain reaction analysis was then performed. Levels of leptin were tracked at each time point listed.Forty-two C57BL/6 controls and 42 ob/ob mice underwent open stabilized middiaphyseal femur fractures, and tissues were harvested at 14, 21, and 42 days and radiographic, histologic, and quantitative computerized tomography analyses were performed.Murine recombinant leptin was applied directly at the newly created fracture site in 2 separate groups (10 or 100 μg of leptin) of 42 ob/ob mice. Two-factor analysis of variance and the Student t-test were used for statistical analysis.The time course of Leptin mRNA expression within a fracture callus was detected. Delay in callus maturation was demonstrated radiographically and histologically in the ob/ob mice. ob/ob fractures had an increase in total callus volume by quantitative computerized tomography (P < 0.05). Application of local leptin at both doses reversed the delay in healing.Leptin is expressed in a unique time course during fracture healing and leptin deficiency leads to impaired fracture healing that reverses by local application of leptin.