Martins Dos Santos Karoline, Saunders Sandy E, Antunes Vagner R, Boychuk Carie R
Department of Cellular and Integrative Physiology, Long School of Medicine, University of Texas Health San Antonio, San Antonio, Texas, United States.
Department of Physiology & Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
J Neurophysiol. 2025 Jan 1;133(1):320-332. doi: 10.1152/jn.00284.2024. Epub 2024 Dec 12.
Integration of autonomic and metabolic regulation, including hepatic function, is a critical role played by the brain's hypothalamic region. Specifically, the paraventricular nucleus of the hypothalamus (PVN) regulates autonomic functions related to metabolism, such as hepatic glucose production. Although insulin can act directly on hepatic tissue to inhibit hepatic glucose production, recent evidence implicates that central actions of insulin within PVN also regulate glucose metabolism. However, specific central circuits responsible for insulin signaling with relation to hepatic regulation are poorly understood. As a heterogeneous nucleus essential to controlling parasympathetic motor output with notable expression of insulin receptors, PVN is an appealing target for insulin-dependent modulation of parasympathetic activity. Here, we tested the hypothesis that insulin activates hepatic-related PVN (PVN) neurons through a parasympathetic pathway. Using transsynaptic retrograde tracing, labeling within PVN was first identified 24 h after its expression in the dorsal motor nucleus of the vagus (DMV) and 72 h after hepatic injection. Critically, nearly all labeling in medial PVN was abolished after a left vagotomy, indicating that PVN neurons in this region are part of a central circuit innervating parasympathetic motor neurons. Insulin also significantly increased the firing frequency of PVN neurons in this subregion. Mechanistically, rapamycin pretreatment inhibited insulin-dependent activation of PVN neurons. Therefore, central insulin signaling can activate a subset of PVN neurons that are part of a unique parasympathetic network in control of hepatic function. Taken together, PVN neurons related to parasympathetic output regulation could serve as a key central network in insulin's ability to control hepatic functions. Increased peripheral insulin concentrations are known to decrease hepatic glucose production through both direct actions on hepatocytes and central autonomic networks. Despite this understanding, how (and in which brain regions) insulin exerts its action is still obscure. Here, we demonstrate that insulin activates parasympathetic hepatic-related PVN neurons (PVN) and that this effect relies on mammalian target of rapamycin (mTOR) signaling, suggesting that insulin modulates hepatic function through autonomic pathways involving insulin receptor intracellular signaling cascades.
自主神经调节与代谢调节（包括肝功能）的整合是大脑下丘脑区域发挥的关键作用。具体而言，下丘脑室旁核（PVN）调节与代谢相关的自主神经功能，如肝脏葡萄糖生成。尽管胰岛素可直接作用于肝脏组织以抑制肝脏葡萄糖生成，但最近的证据表明，胰岛素在PVN内的中枢作用也调节葡萄糖代谢。然而，与肝脏调节相关的胰岛素信号传导的特定中枢回路仍知之甚少。作为控制副交感神经运动输出必不可少的异质性核，且有明显的胰岛素受体表达，PVN是胰岛素依赖性调节副交感神经活动的一个有吸引力的靶点。在此，我们测试了胰岛素通过副交感神经途径激活肝脏相关PVN神经元的假说。使用跨突触逆行追踪法，在迷走神经背核（DMV）中表达后24小时以及肝脏注射后72小时首次在PVN内发现标记。至关重要的是，左侧迷走神经切断术后，PVN内侧几乎所有的标记都消失了，这表明该区域的PVN神经元是支配副交感神经运动神经元的中枢回路的一部分。胰岛素还显著增加了该亚区域PVN神经元的放电频率。从机制上讲，雷帕霉素预处理抑制了PVN神经元的胰岛素依赖性激活。因此，中枢胰岛素信号传导可激活PVN神经元的一个子集，这些神经元是控制肝功能的独特副交感神经网络的一部分。综上所述，与副交感神经输出调节相关PVN神经元可能是胰岛素控制肝功能能力的关键中枢网络。已知外周胰岛素浓度升高可通过对肝细胞的直接作用和中枢自主神经网络降低肝脏葡萄糖生成。尽管有此认识，但胰岛素如何（以及在哪些脑区）发挥其作用仍不清楚。在此，我们证明胰岛素激活与肝脏相关的副交感神经PVN神经元，且这种作用依赖于雷帕霉素靶蛋白（mTOR）信号传导，这表明胰岛素通过涉及胰岛素受体内细胞信号级联反应的自主神经途径调节肝功能。
