This proposal will optimize NAD functions in the metabolism of fracture tissues for the enhancement of bone fracture repair in an obesity/Type-2 diabetic condition, a condition that is common in the general population and even more frequent among veterans. It is well established that Type-2 diabetics suffer from impaired bone healing caused by an insufficient metabolic response to the requirements of tissue repair. In this study, an obesity/Type-2 diabetes condition will be induced in mice and the redox potential of local tissues improved through the augmentation of NAMPT functions in the fracture tissues. Selected agonists of NAMPT will be screened for their effects in periosteal cells, therapeutic candidates locally applied to the fracture tissues in obesity/Type-2 diabetic mice and fracture healing evaluated. The completion of the proposed studies should facilitate the development of novel therapeutic interventions that improve tissue responses to the metabolic requirements of wound repair.