Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, USA.
J Physiol. 2023 Feb;601(4):801-829. doi: 10.1113/JP283566. Epub 2023 Jan 25.
Prolonged high-fat diet (HFD) exposure is associated with hyperphagia, excess caloric intake and weight gain. After initial exposure to a HFD, a brief (24-48 h) period of hyperphagia is followed by the regulation of caloric intake and restoration of energy balance within an acute (3-5 day) period. Previous studies have demonstrated this occurs via a vagally mediated signalling cascade that increases glutamatergic transmission via activation of NMDA receptors located on gastric-projecting neurons of the dorsal motor nucleus of the vagus (DMV). The present study used electrophysiological recordings from thin brainstem slice preparations, in vivo recordings of gastric motility and tone, measurement of gastric emptying rates, and food intake studies to investigate the hypothesis that activation of brainstem astrocytes in response to acute HFD exposure is responsible for the increased glutamatergic drive to DMV neurons and the restoration of caloric balance. Pharmacological and chemogenetic inhibition of brainstem astrocytes reduced glutamatergic signalling and DMV excitability, dysregulated gastric tone and motility, attenuated the homeostatic delay in gastric emptying, and prevented the decrease in food intake that is observed during the period of energy regulation following initial exposure to HFD. Understanding the mechanisms involved in caloric regulation may provide critical insights into energy balance as well as into the hyperphagia that develops as these mechanisms are overcome. KEY POINTS: Initial exposure to a high fat diet is associated with a brief period of hyperphagia before caloric intake and energy balance is restored. This period of homeostatic regulation is associated with a vagally mediated signalling cascade that increases glutamatergic transmission to dorsal motor nucleus of the vagus (DMV) neurons via activation of synaptic NMDA receptors. The present study demonstrates that pharmacological and chemogenetic inhibition of brainstem astrocytes reduced glutamatergic signalling and DMV neuronal excitability, dysregulated gastric motility and tone and emptying, and prevented the regulation of food intake following high-fat diet exposure. Astrocyte regulation of glutamatergic transmission to DMV neurons appears to involve release of the gliotransmitters glutamate and ATP. Understanding the mechanisms involved in caloric regulation may provide critical insights into energy balance as well as into the hyperphagia that develops as these mechanisms are overcome.
长期高脂肪饮食（HFD）暴露与暴食、热量摄入过多和体重增加有关。在最初接触 HFD 后，会经历短暂的（24-48 小时）暴食期，然后在急性（3-5 天）期间调节热量摄入并恢复能量平衡。先前的研究表明，这是通过一种迷走神经介导的信号级联发生的，该信号级联通过激活位于迷走神经背核（DMV）胃投射神经元上的 NMDA 受体增加谷氨酸能传递。本研究使用薄脑切片制备的电生理记录、胃动力和张力的体内记录、胃排空率的测量以及食物摄入研究来验证以下假设：即急性 HFD 暴露激活脑干星形胶质细胞导致 DMV 神经元谷氨酸能驱动增加，并恢复能量平衡。脑星形胶质细胞的药理学和化学遗传学抑制降低了谷氨酸能信号和 DMV 兴奋性，扰乱了胃张力和动力，减弱了胃排空的稳态延迟，并防止了在最初接触 HFD 后能量调节期间观察到的食物摄入减少。了解参与热量调节的机制可能为能量平衡以及这些机制被克服时出现的暴食提供重要的见解。关键点：最初接触高脂肪饮食后会经历短暂的暴食期，然后再恢复热量摄入和能量平衡。这个稳态调节期与迷走神经介导的信号级联有关，该级联通过激活突触 NMDA 受体增加谷氨酸能传递到迷走神经背核（DMV）神经元。本研究表明，脑星形胶质细胞的药理学和化学遗传学抑制降低了谷氨酸能信号和 DMV 神经元兴奋性，扰乱了胃动力和张力以及排空，并防止了高脂肪饮食暴露后食物摄入的调节。脑星形胶质细胞对 DMV 神经元谷氨酸能传递的调节似乎涉及到谷氨酸和 ATP 等神经胶质递质的释放。了解参与热量调节的机制可能为能量平衡以及这些机制被克服时出现的暴食提供重要的见解。
