美国波士顿儿童医院Umut Ozcan团队取得一项新突破。他们发现了在肥胖过程中，HDAC6的中枢抑制使瘦素信号再敏化，从而导致体重大幅减轻。相关论文发表在2024年4月2日出版的《细胞—代谢》杂志上。

体重增加期间瘦素抵抗显著地促进了，肥胖对以瘦素为基础的药物治疗的再犯。肥胖过程中瘦素受体(LepR)信号抑制的机制尚不清楚。

研究人员报告了组蛋白去乙酰化酶6 (HDAC6)与瘦素受体(LepR)相互作用降低后者的活性，并且HDAC6活性的药理抑制破坏了这种相互作用并增强了瘦素信号传导。用血脑屏障(BBB)可渗透的HDAC6抑制剂治疗饮食诱导的肥胖小鼠，在不影响肌肉质量的情况下，大大减少了食物摄入，并导致了有效的体重减轻。

Agouti相关蛋白(AgRP)表达的神经元中HDAC6的基因缺失，或使用血脑屏障不可渗透的HDAC6抑制剂则缺乏这种抗肥胖作用。总之，这些发现描述了一种机械可验证和药物易于处理的治疗方法，可以直接增加LepR活性，并确定了中枢而不是外周作用的HDAC6抑制剂是有效的瘦素增敏剂和抗肥胖剂。

附：英文原文

Title: Central inhibition of HDAC6 re-sensitizes leptin signaling during obesity to induce profound weight loss

Author: Dongxian Guan, Yuqin Men, Alexander Bartlett, Mario Andrés Salazar Hernández, Jie Xu, Xinchi Yi, Hu-song Li, Dong Kong, Ralph Mazitschek, Umut Ozcan

Issue&Volume: 2024/04/02

Abstract: Leptin resistance during excess weight gain significantly contributes to the recidivismof obesity to leptin-based pharmacological therapies. The mechanisms underlying theinhibition of leptin receptor (LepR) signaling during obesity are still elusive. Here,we report that histone deacetylase 6 (HDAC6) interacts with LepR, reducing the latter’sactivity, and that pharmacological inhibition of HDAC6 activity disrupts this interactionand augments leptin signaling. Treatment of diet-induced obese mice with blood-brainbarrier (BBB)-permeable HDAC6 inhibitors profoundly reduces food intake and leadsto potent weight loss without affecting the muscle mass. Genetic depletion of Hdac6 in Agouti-related protein (AgRP)-expressing neurons or administration with BBB-impermeableHDAC6 inhibitors results in a lack of such anti-obesity effect. Together, these findingsrepresent the first report describing a mechanistically validated and pharmaceuticallytractable therapeutic approach to directly increase LepR activity as well as identifyingcentrally but not peripherally acting HDAC6 inhibitors as potent leptin sensitizersand anti-obesity agents.

DOI: 10.1016/j.cmet.2024.02.007

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00053-6