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.

这项建议的研究将确定肝脏的胆碱能神经支配在以下方面的作用： 控制葡萄糖和脂质代谢。迷走神经背侧运动核（DMV）含有 副交感胆碱能神经元虽然有一个矛盾的发现，缺乏 小鼠肝脏的胆碱能神经支配，逆行神经元示踪剂的先前研究 例如霍乱毒素B、伪狂犬病病毒和编码Cre诱导型报道蛋白AAV 强烈支持小鼠肝脏接受DMV胆碱能神经支配。而且我们 最近发表的同行评议的工作表明，肝细胞直接接受 DMV胆碱能输入和表达毒蕈碱型乙酰胆碱受体，这表明DMV的胆碱能输入和表达的乙酰胆碱受体， 肝胆碱能系统对于正常的肝功能至关重要。 在我们最近的研究中， 降低血糖，与副交感神经传出流出到 肝脏抑制肝葡萄糖输出。相反，肝脏投射的光遗传学沉默 胆碱能神经升高血糖水平，也刺激关键的表达， 肝硬化基因由于血浆胰高血糖素没有变化， 葡萄糖的产生，这种作用似乎是胰腺癌无关的。相比 传统的观点认为，交感神经的激活促进，而 副交感神经支配抑制，肝葡萄糖输出，我们最近发表的工作， 强烈支持DMV胆碱能神经元对肝脏葡萄糖的显着贡献 瘦小鼠的输出。重要的是，我们的初步研究表明， 胆碱能神经元增加高脂饮食小鼠肝脏脂肪分解和胰岛素敏感性 饮食.由于肝硬化的发生与肝内脂肪分解密切相关， 目标1中的研究将确定这些神经元在控制摄食中的必要性。 行为和肝脏能量代谢。 尽管副交感神经胆碱能神经元在调节 肝葡萄糖通过胰岛素依赖和非依赖两种方式输出，目前尚不清楚， 葡萄糖感知是该DMV-肝脏神经回路的重要生理触发。到 为了解决这一主要差距，目标2中的研究将确定DMV肝脏的葡萄糖感知是否 投射胆碱能神经元控制肝脏的胆碱能紧张。 虽然高脂肪喂养会提高肝脏交感神经活性，但饮食诱导的肥胖 (DIO)减少副交感运动神经元的动作电位放电。因此，我们已经开始 以探测肝胆碱能系统是否受到营养状态的调节。我们 初步研究表明，高脂肪喂养上调了GI偶联的毒蕈碱乙酰胆碱， 2型受体（M2 R）和4型受体（M4 R）在肝脏中的表达。因此，目标3中的研究将 检验饮食诱导的肝胆碱能系统改变破坏整个 身体能量稳态和肝脏能量代谢，导致胰岛素抵抗， DIO中肝脂肪变性。