Galnt2 neurons in the ventromedial hypothalamus counterregulate hypoglycemia via a brain-liver neurocircuit

IF 30.9 1区生物学 Q1 CELL BIOLOGY

Cell metabolism Pub Date : 2025-10-14 DOI:10.1016/j.cmet.2025.09.006

Junjie Wang, Xinyuan Sun, Xiangfei Gong, Wenling Dai, Hao Hong, Li Jiang, Zhonglong Wang, Zhiyuan Tang, Xiaobo Wu, Peng Sun, Yongjie Zhang, Kun Hao, Fang Zhou, Ying Cui, Tianyu Tang, Xiao Zheng, Lanqun Mao, Guangji Wang, Haiping Hao, Hao Xie

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引用次数: 0

Abstract

The brain relies heavily on glucose for energy resources, and thus prompt counterregulatory responses to hypoglycemia in connection with glucose production are fundamental. We identified a biphasic pattern in blood and hypothalamic glucose dynamics during prolonged fasting, revealing an additional threshold-dependent mechanism for counterregulation. This mechanism is mediated by a ventromedial hypothalamus (VMH)→paraventricular hypothalamic nucleus (PVH)→lateral paragigantocellular nucleus (LPGi)→liver neurocircuit that detects neuroglycopenia and transmits neural signals to drive hepatic glucose production via intrahepatic sympathetic activation. Using viral tracing, single-nucleus RNA sequencing, and various unbiased methods, we identified Galnt2 as both a genetic marker and molecular brake of VMH glucose-inhibited neurons, modulating the glycemic threshold for hypoglycemia perception and metabolic homeostasis. Our results highlight a VMH^Galnt2-originated brain-liver neurocircuit that perceives and counterregulates hypoglycemia and may pave the way to innovative therapeutic strategies against metabolic disorders characterized by glucose dysregulation.

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下丘脑腹内侧的Galnt2神经元通过脑-肝神经回路对低血糖进行反调节

大脑在很大程度上依赖葡萄糖作为能量来源，因此，与葡萄糖产生有关的低血糖的快速反调节反应是基本的。我们确定了长时间禁食期间血液和下丘脑葡萄糖动力学的双相模式，揭示了一个额外的阈值依赖机制。该机制由下丘脑腹内侧（VMH）→室旁下丘脑核（PVH）→外侧副巨细胞核（LPGi）→肝脏神经回路介导，该神经回路检测神经性糖减少症并通过肝内交感神经激活传递神经信号以驱动肝脏葡萄糖产生。通过病毒追踪、单核RNA测序和各种无偏方法，我们发现Galnt2既是VMH葡萄糖抑制神经元的遗传标记和分子刹车，调节低血糖感知和代谢稳态的血糖阈值。我们的研究结果强调了vmhgalnt2起源的脑-肝神经回路可以感知和反调节低血糖，并可能为针对以葡萄糖失调为特征的代谢紊乱的创新治疗策略铺平道路。

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来源期刊

Cell metabolism 生物-内分泌学与代谢

CiteScore

48.60

自引率

1.40%

发文量

173

审稿时长

2.5 months

期刊介绍： Cell Metabolism is a top research journal established in 2005 that focuses on publishing original and impactful papers in the field of metabolic research.It covers a wide range of topics including diabetes, obesity, cardiovascular biology, aging and stress responses, circadian biology, and many others. Cell Metabolism aims to contribute to the advancement of metabolic research by providing a platform for the publication and dissemination of high-quality research and thought-provoking articles.