Su Jiaao, Hashsham Abdullah, Kodur Nandan, Burton Carla, Mancuso Amanda, Singer Anjan, Wloszek Jennifer, Tomlinson Abigail J, Yacawych Warren T, Flak Jonathan N, Lewis Kenneth T, Oles Lily R, Mori Hiroyuki, Bozadjieva-Kramer Nadejda, Turcu Adina F, MacDougald Ormond A, Myers Martin G, Affinati Alison H
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Ophthalmology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Mol Metab. 2025 Sep;99:102216. doi: 10.1016/j.molmet.2025.102216. Epub 2025 Jul 18.
The brain mobilizes glucose in emergency situations such as hypoglycemia as well as during day-to-day physiology such as fasting. While most hypothalamic neuronal populations that contribute to glucose mobilization also contribute to other aspects of metabolism, neurons in the ventromedial nucleus of the hypothalamus that express the cholecystokinin b receptor (VMH neurons) support glucose production during hypoglycemia without controlling energy homeostasis. However, their role in day-to-day glucose physiology and the mechanisms they engage to support glucose mobilization is unclear.
We used continuous glucose monitoring in mice with chronically silenced VMH neurons to establish whether these neurons are required during day-to-day glucose homeostasis. Tetanus-toxin based chronic silencing and acute optogenetic activation were followed by analysis of hepatic glucose metabolism and white adipose tissue lipolysis.
We found that VMH neurons support glucose homeostasis during short fasts and contribute to gluconeogenic substrate mobilization and lipolysis. VMH neurons mobilize glucose without depleting hepatic glycogen or increasing gluconeogenic gene expression, but instead mobilize glycerol in a β3-adrenergic receptor (β3-AR)-dependent manner. Restoring glycerol availability following VMH neuron silencing restores glucose. Finally, acute activation of VMH neurons mobilizes additional gluconeogenic substrates beyond glycerol.
VMH neurons represent a distinct subset of glucose-mobilizing VMH neurons that support physiologic glucose homeostasis, likely through control of β3-AR-mediated gluconeogenic substrate mobilization and lipolysis. The presence of different glucose-mobilizing neuronal populations that engage distinct mechanisms in a context-dependent manner may provide the brain with flexibility to coordinate the appropriate glycemic response to different circumstances.
大脑在低血糖等紧急情况下以及禁食等日常生理过程中会调动葡萄糖。虽然大多数参与葡萄糖调动的下丘脑神经元群体也参与新陈代谢的其他方面，但下丘脑腹内侧核中表达胆囊收缩素b受体的神经元（VMH神经元）在低血糖期间支持葡萄糖生成，而不控制能量平衡。然而，它们在日常葡萄糖生理中的作用以及支持葡萄糖调动所涉及的机制尚不清楚。
我们对VMH神经元长期沉默的小鼠进行连续葡萄糖监测，以确定在日常葡萄糖稳态期间这些神经元是否是必需的。基于破伤风毒素的长期沉默和急性光遗传学激活之后，分析肝脏葡萄糖代谢和白色脂肪组织脂解。
我们发现VMH神经元在短期禁食期间支持葡萄糖稳态，并有助于糖异生底物的调动和脂解。VMH神经元调动葡萄糖时不会耗尽肝糖原或增加糖异生基因表达，而是以β3-肾上腺素能受体（β3-AR）依赖的方式调动甘油。VMH神经元沉默后恢复甘油可用性可恢复葡萄糖水平。最后，VMH神经元的急性激活会调动除甘油之外的其他糖异生底物。
VMH神经元代表了一个独特的葡萄糖调动VMH神经元子集，它们可能通过控制β3-AR介导的糖异生底物调动和脂解来支持生理葡萄糖稳态。不同的葡萄糖调动神经元群体以依赖于上下文的方式参与不同机制，这可能为大脑提供灵活性，以协调对不同情况的适当血糖反应。
