Leptin administration results in leptin resistance presenting a significant barrier to therapeutic use of leptin. Consequently, we examined two hypotheses. The first examined the relationship between leptin dose and development of physiological and biochemical signs of leptin resistance. We hypothesized lower doses of leptin would produce proportional reductions in body weight without the adverse leptin-induced leptin resistance. The second compared pulsed central leptin infusion to continuous leptin infusion. We hypothesized that pulsed infusion at specific times of the day would evoke favorable body weight reductions while tempering the development of leptin-induced leptin resistance. The first experiment examined leptin responsiveness, including food intake, body weight and hypothalamic STAT3 phosphorylation to increasing doses of viral gene delivery of leptin. Varying the dose proved inconsequential with respect to long-term therapy and demonstrated proportional development of leptin resistance. The second experiment examined leptin responsiveness to pulsed central leptin infusion, comparing pulsed versus constant infusion of 3 μg/day leptin or a 2 h morning versus a 2 h evening pulsed leptin infusion. Pulsed delivery of the supramaximal dose of 3 μg/day was not different than constant delivery. Morning pulsed infusion of the submaximal dose of 0.25 μg reduces food intake only over subsequent immediate meal period and was associated with body weight reductions, but results in cellular leptin resistance. Evening pulsed infusion did not decrease food intake but reduces body weight and maintains full leptin signaling. The positive benefit for pulsed delivery remains speculative, yet potentially may provide an alternative mode of leptin therapy.