Role of cholinergic innervation of the liver

肝脏胆碱能神经支配的作用

• 批准号: 10559045
• 负责人: YOUNG-HWAN JO
• 金额: $ 50.53万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-23 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559045
• 关键词: Ablation; Acetylcholine; Action Potentials; Acute; Address; Anatomy; Animals; Autonomic nervous system; Blood Glucose; Brain; Cholera Toxin; Choline O-Acetyltransferase; Cholinergic Fibers; Coupled; Diabetes Mellitus; Diet; Diphtheria Toxin; Energy Metabolism; Fatty Liver; Fatty acid glycerol esters; Feeding behaviors; Fiber; Genes; Glucagon; Glucose; Hepatic; Hepatocyte; High Fat Diet; Homeostasis; Insulin; Insulin Resistance; Link; Lipolysis; Literature; Liver; Metabolic; Motor Neurons; Mus; Muscarinic Acetylcholine Receptor; Nerve; Neurons; Nutrient; Obese Mice; Pancreatic Hormones; Parasympathetic Nervous System; Patients; Photometry; Physiological; Pilot Projects; Plasma; Population; Potassium Channel; Proteins; Publishing; Publishing Peer Reviews; Regulation; Reporter; Role; System; Testing; Thinness; Tracer; Work; blood glucose regulation; cholinergic; cholinergic neuron; diet-induced obesity; dorsal motor nucleus; feeding; functional status; glucose metabolism; glucose output; glucose production; hepatic gluconeogenesis; improved; in vivo; inducible Cre; insulin sensitivity; interest; intrahepatic; knock-down; lipid metabolism; liver ablation; liver function; loss of function; mad itch virus; nerve supply; neural circuit; neurophysiology; new therapeutic target; optogenetics; postsynaptic; presynaptic; receptor; type I and type II diabetes

Studies in this proposal will define the role of this cholinergic innervation of the liver in controlling glucose and lipid metabolism. The dorsal motor nucleus of the vagus (DMV) contains parasympathetic cholinergic neurons. Although there is a contradictory finding of the lack of cholinergic innervation to the mouse liver, prior studies with the retrograde neuronal tracers such as cholera toxin B, pseudorabies virus, and AAV encoding a Cre-inducible reporter protein strongly support that the mouse liver receives DMV cholinergic innervation. Furthermore, we have recently published peer reviewed work demonstrating that hepatocytes receive direct DMV cholinergic input and express muscarinic acetylcholine receptors, suggesting that the hepatic cholinergic system is critical for proper liver function. In our recent studies, optogenetic excitation of cholinergic fibers innervating the liver reduces blood glucose, consistent with the ability of parasympathetic efferent outflow to the liver to suppress hepatic glucose output. Conversely, optogenetic silencing of liver-projecting cholinergic nerves elevates blood glucose levels and also stimulates the expression of key hepatic gluconeogenic genes. As there is no change in plasma glucagon that drives hepatic glucose production, this effect appears to be pancreatic hormone-independent. In contrast to the traditional view that the activation of sympathetic nerves promotes, while the parasympathetic innervation suppresses, hepatic glucose output, our recently published work strongly supports the significant contribution of DMV cholinergic neurons to hepatic glucose output in lean mice. Importantly, our pilot studies reveal that ablation of liver-projecting cholinergic neurons increases hepatic lipolysis and insulin sensitivity in mice fed a high-fat diet. As hepatic gluconeogenesis and intrahepatic lipolysis are closely linked to each other, studies in Aim 1 will identify the necessity of these neurons in the control of ingestive behaviors and hepatic energy metabolism in lean and diet-induced obese mice. Despite the importance of parasympathetic cholinergic neurons to the regulation of hepatic glucose output via both insulin-dependent and -independent ways, it is not known that glucose sensing is an important physiological trigger for this DMV- liver neural circuit. To address this major gap, studies in Aim 2 will determine if glucose-sensing by DMV liver- projecting cholinergic neurons controls cholinergic tone to the liver. While high-fat feeding elevates hepatic sympathetic nerve activity, diet-induced obesity (DIO) reduces action potential firing of parasympathetic motor neurons. Thus, we have begun to probe if the hepatic cholinergic system is subject to modulation by the nutrient status. Our pilot studies reveal that high-fat feeding upregulates Gi-coupled muscarinic acetylcholine receptor type 2 (M2R) and 4 (M4R) expression in the liver. Accordingly, studies in Aim 3 will test the hypothesis that diet-induced alterations in the hepatic cholinergic system disrupt whole- body energy homeostasis and hepatic energy metabolism, causing insulin resistance and hepatic steatosis in DIO.

该提案中的研究将定义肝脏这种胆碱能神经的作用 控制葡萄糖和脂质代谢。迷走神经（DMV）的背运动核包含 副交感神经能神经元。尽管存在缺乏的发现 对小鼠肝的胆碱能神经，先前对逆行神经元示踪剂的研究 例如霍乱毒素B，伪造病毒和编码CRE诱导者蛋白的AAV 强烈支持小鼠肝脏接受DMV胆碱能神经。此外，我们 最近发表了同行评审的工作，证明肝细胞直接接收 DMV胆碱能输入和表达毒蕈碱乙酰胆碱受体，表明 肝胆碱能系统对于适当的肝功能至关重要。 在我们最近的研究中，胆碱能纤维的光遗传学激发为肝脏支配 减少血糖，与副交感传递流出的能力一致 肝脏抑制肝葡萄糖输出。相反，肝脏预测的光遗传学沉默 胆碱能神经升高血糖水平，也刺激钥匙的表达 肝糖原性基因。由于血浆胰高血糖素没有变化，可以驱动肝 葡萄糖产生，这种作用似乎是胰腺激素无关的。与 传统观点激活交感神经的激活促进了 副交感神经神经抑制，肝葡萄糖输出，我们最近发表的工作 强烈支持DMV胆碱能神经元对肝葡萄糖的显着贡献 输出瘦小鼠。重要的是，我们的试点研究表明肝脏预防 胆碱能神经元增加了喂养高脂的小鼠的肝脂解和胰岛素敏感性 饮食。由于肝糖异生和肝内脂解彼此紧密相关， AIM 1中的研究将确定这些神经元控制的必要性 瘦肉和饮食引起的肥胖小鼠的行为和肝能代谢。 尽管副交感神经能神经元对调节很重要 通过胰岛素依赖性和非依赖性的方式，肝葡萄糖输出，尚不清楚 葡萄糖传感是该DMV-肝神经回路的重要生理触发因素。到 解决这一主要差距，AIM 2中的研究将确定DMV肝脏的葡萄糖感应是否 投射胆碱能神经元将胆碱能张力控制到肝脏。 高脂喂养提高了肝交感神经活动，而饮食引起的肥胖症 （DIO）减少了副交感神经神经元的动作潜在发射。因此，我们已经开始 探测肝胆碱能系统是否受到养分状态的调节。我们的 试点研究表明，高脂喂养会上调gi耦合的毒蕈碱乙酰胆碱 肝脏中的2型2（M2R）和4（M4R）表达。因此，AIM 3中的研究将 检验以下假设，即饮食诱导的肝胆碱能系统的改变破坏了整体 人体能量稳态和肝能量代谢，引起胰岛素抵抗和 DIO中的肝脂肪变性。