Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction.
Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction.
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DOI：
10.1038/s42255-022-00677-8
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发表时间：
2022-11
影响因子：
20.8
通讯作者：
Friedman, Jeffrey M.
中科院分区：
文献类型：
--
作者：
Schneeberger, Marc;Brice, Nicola L.;Pellegrino, Kyle;Parolari, Luca;Shaked, Jordan T.;Page, Keith J.;Marchildon, Francois;Barrows, Douglas W.;Carroll, Thomas S.;Tolpiko, Thomas;Mulligan, Victoria M.;Newman, Robert;Doyle, Kevin;Burli, Roland;Barker, Daniel F.;Glen, Angela;Ortuno, Maria Jose;Nectow, Alexander R.;Renier, Nicolas;Cohen, Paul;Carlton, Mark;Heintz, Nathaniel;Friedman, Jeffrey M.
食物摄入和体重由特定脑区（包括脑干）内的神经元严格调节，其中表达谷氨酸转运蛋白VEGF3（DRNVEGF3）的中缝背核（DRN）神经元的急性激活驱动对食物摄入的强烈抑制并增强运动。激活DRN中的VEGF3神经元会抑制食物摄入并增加运动，这表明调节这些神经元的活动可能会改变体重。在这里，我们发现DRNVB3神经元投射到外侧下丘脑（LHA），这是一个典型的摄食中心，也可以减少食物摄入。此外，慢性DRNVB3激活降低瘦素缺乏（ob/ob）和瘦素抗性饮食诱导的肥胖（DIO）雄性小鼠的体重。分子分析显示，食欲素1受体（Hcrtr1）是高度富集在DRN VEGF3神经元，在大脑中的其他地方的表达有限。最后，口服生物可利用的，高选择性Hcrtr1拮抗剂（CVN 45502）显着减少DIO的喂养和体重。Hcrtr1在人DRN中也与VEGF3共表达，这表明在人类中可能存在类似的作用。这些结果确定了一种通过靶向DRNV β 3神经元治疗肥胖的潜在疗法，同时也建立了开发中枢神经系统疾病药物的一般策略。Schneeberger等人表明，脑干中缝背核内的多巴胺能神经元富含食欲素1受体Hcrtr1，其可以被靶向治疗小鼠的肥胖症。
Food intake and body weight are tightly regulated by neurons within specific brain regions, including the brainstem, where acute activation of dorsal raphe nucleus (DRN) glutamatergic neurons expressing the glutamate transporter Vglut3 (DRNVglut3) drive a robust suppression of food intake and enhance locomotion. Activating Vglut3 neurons in DRN suppresses food intake and increases locomotion, suggesting that modulating the activity of these neurons might alter body weight. Here, we show that DRNVglut3 neurons project to the lateral hypothalamus (LHA), a canonical feeding center that also reduces food intake. Moreover, chronic DRNVglut3 activation reduces weight in both leptin-deficient (ob/ob) and leptin-resistant diet-induced obese (DIO) male mice. Molecular profiling revealed that the orexin 1 receptor (Hcrtr1) is highly enriched in DRN Vglut3 neurons, with limited expression elsewhere in the brain. Finally, an orally bioavailable, highly selective Hcrtr1 antagonist (CVN45502) significantly reduces feeding and body weight in DIO. Hcrtr1 is also co-expressed with Vglut3 in the human DRN, suggesting that there might be a similar effect in human. These results identify a potential therapy for obesity by targeting DRNVglut3 neurons while also establishing a general strategy for developing drugs for central nervous system disorders. Schneeberger et al. show that glutamatergic neurons within the dorsal raphe nucleus of the brainstem are enriched with the orexin 1 receptor Hcrtr1, which can be pharmacologically targeted to treat obesity in mice.
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影响因子：
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作者：
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影响因子：
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影响因子：
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作者：
Reference Genome Group of the Gene Ontology Consortium
通讯作者：
Reference Genome Group of the Gene Ontology Consortium
影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
25
作者：
Cai, Haijiang;Haubensak, Wulf;Anthony, Todd E.;Anderson, David J.
通讯作者：
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