Strehler Kevin Y E, Matheny Michael, Kirichenko Nataliya, Sakarya Yasemin, Bruce Erin, Toklu Hale Zerrin, Carter Christy S, Morgan Drake, Tümer Nihal, Scarpace Philip J
Departments of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, FL 32610, United States.
Aging and Geriatric Research, University of Florida College of Medicine, Gainesville, FL 32610, United States.
Eur J Pharmacol. 2016 May 15;779:177-85. doi: 10.1016/j.ejphar.2016.03.026. Epub 2016 Mar 22.
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 3μg/day leptin or a 2h morning versus a 2h evening pulsed leptin infusion. Pulsed delivery of the supramaximal dose of 3μg/day was not different than constant delivery. Morning pulsed infusion of the submaximal dose of 0.25μg 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.
给予瘦素会导致瘦素抵抗，这对瘦素的治疗应用构成了重大障碍。因此，我们研究了两种假设。第一种假设研究了瘦素剂量与瘦素抵抗的生理和生化指标发展之间的关系。我们假设较低剂量的瘦素会使体重成比例下降，而不会产生由瘦素诱导的不良瘦素抵抗。第二种假设将脉冲式中枢瘦素输注与持续瘦素输注进行了比较。我们假设在一天中的特定时间进行脉冲式输注会引起有利的体重下降，同时抑制瘦素诱导的瘦素抵抗的发展。第一个实验研究了瘦素反应性，包括食物摄入量、体重和下丘脑信号转导和转录激活因子3（STAT3）磷酸化对增加剂量的瘦素病毒基因递送的反应。事实证明，就长期治疗而言，改变剂量无关紧要，并且显示出瘦素抵抗的成比例发展。第二个实验研究了对脉冲式中枢瘦素输注的瘦素反应性，比较了每天3μg瘦素的脉冲式输注与持续输注，或者早上2小时与晚上2小时的脉冲式瘦素输注。每天3μg的超最大剂量的脉冲式递送与持续递送没有差异。早上0.25μg的次最大剂量的脉冲式输注仅在随后的即时进餐期减少食物摄入量，并与体重下降有关，但会导致细胞瘦素抵抗。晚上的脉冲式输注不会减少食物摄入量，但会减轻体重并维持完整的瘦素信号传导。脉冲式递送的积极益处仍具有推测性，但可能会提供一种瘦素治疗的替代模式。
