Li Hongli, Su Cunjin, Xu Yuanzhong, Ludwig Mette Q, Davis Jon, Tong Qingchun
Brown Foundation of Molecular Medicine for the Prevention of Human Diseases of McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Brown Foundation of Molecular Medicine for the Prevention of Human Diseases of McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Neurobiology and Anatomy of McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Cell Rep. 2025 Jul 22;44(7):115863. doi: 10.1016/j.celrep.2025.115863. Epub 2025 Jun 19.
Overconsumption of a palatable Western diet, a condition linked to central leptin resistance, contributes extensively to the current obesity epidemic. In this context, intensive efforts have focused on detailing the molecular mechanisms underlying leptin resistance. Here, we demonstrate that chronic inhibition of hypothalamic arcuate GABAergic neurons (Arc) effectively reduced diet-induced obesity (DIO). Interestingly, palatable food exposure increased the activity level of Arc neurons, which do not express the leptin receptor (non-LepR neurons; nonresponsive to leptin). Chronic activation of Arc non-LepR neurons led to massive obesity, which was associated with normal leptin-induced pSTAT3 signaling but phenotypic leptin resistance; i.e., high leptin levels failing to reduce obesity. In contrast, chronic inhibition of Arc non-LepR neurons effectively prevented and reversed DIO, suggesting a potential anti-obesity treatment strategy. These results reveal that obesogenic stimulation of Arc non-LepR neurons, even with intact leptin-pSTAT3 signaling, results in obesity, identifying a novel neural basis underlying leptin resistance.
美味的西方饮食过度摄入与中枢性瘦素抵抗有关，在很大程度上导致了当前的肥胖流行。在此背景下，人们集中精力深入研究瘦素抵抗背后的分子机制。在此，我们证明对下丘脑弓状核γ-氨基丁酸能神经元（Arc）进行慢性抑制可有效减轻饮食诱导的肥胖（DIO）。有趣的是，接触美味食物会增加Arc神经元的活动水平，这些神经元不表达瘦素受体（非LepR神经元；对瘦素无反应）。对Arc非LepR神经元进行慢性激活会导致严重肥胖，这与瘦素诱导的pSTAT3信号正常但存在表型瘦素抵抗有关；即高瘦素水平无法减轻肥胖。相反，对Arc非LepR神经元进行慢性抑制可有效预防和逆转DIO，提示了一种潜在的抗肥胖治疗策略。这些结果表明，即使瘦素-pSTAT3信号完整，对Arc非LepR神经元的致肥胖刺激也会导致肥胖，从而确定了瘦素抵抗背后的一种新的神经基础。
