Long-term benefits of central leptin gene therapy in insulin-deficient diabetes are not known despite its therapeutic effects in obesity animal models such as ob/ob and diet-induced obese mice. Adult male mice were injected intraperitoneally with streptozotocin (STZ, 200mg/kg) to induce insulitis. A week later, only diabetic STZ-pretreated mice (blood glucose >350 mg/dl) received intracerebroventricularly (icv) an injection of recombinant adeno-associated virus vector (rAAV) encoding either green fluorescent protein (control), or leptin gene (rAAV-lep). Body weight (BW), food intake, blood glucose, insulin and survival rate responses were monitored post-icv injection at regular intervals for 52 weeks. The STZ pre-injected diabetic mice remained hyperphagic, gradually lost BW and died by week 6 after receiving control vector. In marked contrast, injection of rAAV-lep to raise hypothalamic leptin levels, rescued the STZ-pretreated mice from early mortality, gradually curbed hyperphagia to normalize intake by week 20, and maintained BW at significantly lower than the control range. Blood glucose levels in these mice started to recede dramatically by week 2-3 to normalize by week 8, and euglycemia was sustained during the remaining course of the experiment. rAAV-lep injected mice did not exhibit any discernible untoward gross behavioral changes and diabetic complications and showed a partial return of pancreatic beta-cell function. These results show for the first time that one time central leptin gene therapy is effective and durable in reinstating euglycemia and energy homeostasis for extended periods in the absence of insulin.