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Systemically and Topically Administered Leptin Both Accelerate Wound Healing in Diabetic ob/ob Mice

Department of Pathology (B.D.R., S.A.S., C.R.D., D.M.D.), Department of Neuroscience (M.B.B., M.J.C., M.A.P.), Amgen Inc., Thousand Oaks, California 91320-1789

Address all correspondence and requests for reprints to: Dimitry M. Danilenko, Amgen, Inc., One Amgen Center Drive, MS 15-2-B, Department of Pathology, Thousand Oaks, California 91320-1789. E-mail: ddanilen{at}amgen.com

Leptin is a 16 kD protein that is produced by adipocytes and induces weight loss in both normal and genetically obese ob/ob mice. ob/ob mice are obese, have multiple metabolic abnormalities, and exhibit impaired wound healing. Exogenous administration of leptin to these animals induces weight loss and corrects their metabolic defects. Leptin’s effect on wound repair, however, has not been studied. Systemic administration of leptin at doses ranging from 0.1 to 10 mg/kg/day induced a highly significant acceleration in wound repair in ob/ob mice (p<0.0001), but not in db/db mice, indicating that leptin’s effects on wound repair were mediated through the leptin receptor. We then investigated the possibility that leptin was acting directly at the wound site by administering leptin topically, and found that topical leptin also induced a dose dependent acceleration in wound repair (p<0.0001). In addition, we found that all forms of leptin receptor, including the signal transducing long form, were present in skin by RNase protection assay, and that leptin receptor localized to subcutaneous vessels of wounded skin by in situ hybridization. Finally, we investigated the possibility that leptin stimulated angiogenesis in wounds by analyzing wound hemoglobin and wound vessel density. Neither systemic nor topical leptin induced any significant changes in either parameter, suggesting that leptin accelerates would repair by a mechanism other than stimulation of angiogenesis. In summary, both systemic and topical leptin accelerate would reapir in diabetic ob/ob mice, possibly via the direct interaction of leptin with its receptors in wounded skin, but do not appear to significantly stimulate wound angiogenesis. Further studies to better elucidate the mechanisms of leptin’s effects on wound repair are warranted.

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