Leptin resistance during excess weight gain significantly contributes to the recidivism of obesity to leptin-based pharmacological therapies. The mechanisms underlying the inhibition of leptin receptor (LepR) signaling during obesity are still elusive. Here, we report that histone deacetylase 6 (HDAC6) interacts with LepR, reducing the latter’s activity, and that pharmacological inhibition of HDAC6 activity disrupts this interaction and augments leptin signaling. Treatment of diet-induced obese mice with blood-brain barrier (BBB)-permeable HDAC6 inhibitors profoundly reduces food intake and leads to potent weight loss without affecting the muscle mass. Genetic depletion of Hdac6 in Agouti-related protein (AgRP)-expressing neurons or administration with BBB-impermeable HDAC6 inhibitors results in a lack of such anti-obesity effect. Together, these findings represent the first report describing a mechanistically validated and pharmaceutically tractable therapeutic approach to directly increase LepR activity as well as identifying centrally but not peripherally acting HDAC6 inhibitors as potent leptin sensitizers and anti-obesity agents.

体重过度增加期间的瘦素抵抗显着导致肥胖对基于瘦素的药物治疗的复发。肥胖期间瘦素受体（LepR）信号传导抑制的机制仍不清楚。在这里，我们报告组蛋白脱乙酰酶 6 (HDAC6) 与 LepR 相互作用，降低后者的活性，而 HDAC6 活性的药理学抑制会破坏这种相互作用并增强瘦素信号传导。使用血脑屏障 (BBB) 渗透性 HDAC6 抑制剂治疗饮食诱导的肥胖小鼠，可以显着减少食物摄入量，并在不影响肌肉质量的情况下实现有效的体重减轻。表达 Agouti 相关蛋白 (AgRP) 的神经元中Hdac6的基因缺失或使用 BBB 不可渗透的 HDAC6 抑制剂会导致缺乏这种抗肥胖作用。总之，这些发现代表了第一份报告，描述了一种经机械验证且药物上易于处理的治疗方法，可直接增加 LepR 活性，并确定中枢但非外周作用的 HDAC6 抑制剂作为有效的瘦素敏化剂和抗肥胖剂。