Angiotensin receptor G protein signal switching in AgRP neurons in cardiometabolic control

AgRP 神经元中血管紧张素受体 G 蛋白信号转换在心脏代谢控制中的作用

• 批准号: 10658260
• 负责人: Justin L Grobe
• 金额: $ 63.84万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658260
• 关键词: Age; American; Angiotensin II; Angiotensin II Receptor; Angiotensin Receptor; Angiotensin Type 1a Receptor; Angiotensins; Animal Model; Animals; Area; Autocrine Communication; Basal metabolic rate; Behavioral Mechanisms; Biology; Blood Pressure; Body Weight decreased; Brain; Brain region; Cardiovascular system; Cell Nucleus; Cells; Cellular biology; Clinical; Consumption; Data; Development; Diet; Disinhibition; Electrolytes; Electrophysiology (science); Energy Metabolism; Exhibits; Fatty acid glycerol esters; Female; Functional disorder; Funding; GTP-Binding Proteins; Genetic; High Prevalence; Homeostasis; Hormones; Human; Hypertension; Hypothalamic structure; Intervention; Ion Channel; Leptin; Liquid substance; Maintenance; Mediating; Metabolic Control; Metabolism; Methods; Modality; Modeling; Molecular; Molecular Biology; Mus; National Health and Nutrition Examination Survey; Neurons; Neurosecretory Systems; Obesity; Overweight; Pathogenesis; Pathway interactions; Peptides; Phenotype; Physiological; Physiology; Process; Publishing; Receptor Activation; Receptor Signaling; Renin-Angiotensin System; Resistance; Risk Factors; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Signaling Protein; Smoking; Stimulus; Structure of nucleus infundibularis hypothalami; Sympathetic Nervous System; System; Thinness; Tissues; Transgenic Animals; Viral; Weight; Work; attenuation; blood pressure control; blood pressure elevation; cardiometabolism; cardiovascular health; cell type; comorbidity; desensitization; diet-induced obesity; excessive weight gain; feeding; genetic manipulation; improved; in vivo; in vivo evaluation; innovation; insight; male; mortality; neural circuit; neurotransmission; novel; obese person; paracrine; pharmacologic; protein activation; receptor; response; synergism; transcriptome; transcriptome sequencing

Project Summary / Abstract NHANES data indicate that 47.3% of Americans have high blood pressure (hypertension), 71.3% are overweight, and there is strong overlap between these groups. Hypothalamic pathways controlling blood pressure are tightly intertwined with pathways controlling resting metabolic rate (RMR). With prolonged obesity, cardiovascular- stimulating autonomic responses and blood pressure responses remain intact, but RMR control progressively desensitizes (a process termed “RMR adaptation”). RMR adaptation is thought to contribute to the resistance of the body to maintaining weight loss, and the propensity of the body to regain mass. Thus, there is a critically unmet need to understand the basic hypothalamic neurocircuitry that coordinately controls blood pressure and RMR in healthy conditions, and how this system selectively desensitizes during obesity. The renin-angiotensin system (RAS) within the brain is well known to contribute to blood pressure control through actions in multiple brain regions, and our team recently discovered that the RAS within the arcuate nucleus of the hypothalamus (ARC) is critically involved in the control of RMR. In particular, the angiotensin II (ANG) type 1A receptor (AT1A) in neurons of the ARC that express Agouti-related peptide (AgRP) are required for control of RMR but not blood pressure in response to leptin, ANG, and other stimuli. The objective of the current proposal is therefore to clarify the molecular signaling pathways within AgRP neurons that are utilized by the AT1A receptor to control RMR. Preliminary data indicate that in the lean state, (i) only a subset of AgRP neurons express AT1A, (ii) these AT1A signal via a Gi second messenger, and (iii) such signaling causes inhibition of the cell, ultimately to disinhibit melanocortin signaling in pre-autonomic target regions and thus increase RMR. Excitingly, we have discovered that following prolonged high fat feeding, a subset of AT1A-expressing AgRP neurons of the ARC spontaneously exhibit “G protein signal switching” and begin to couple to Gq instead of Gi second-messengers, which results in stimulatory effects of ANG on these cells. We therefore propose the general hypotheses that (i) in the lean state, AT1A-expressing AgRP neurons are importantly involved in RMR control, and that AT1A signals via Gi, but that (ii) after diet-induced obesity, the alteration in AT1A second-messenger cascade from Gi to Gs in these cells is causal for the development of RMR adaptation. Aim 1 will define the ‘normal’ signaling cascade of AT1A in AgRP neurons in lean animals, while Aim 2 will dissect the mechanistic contribution of G protein signal switching in these cells in the development of RMR adaptation. These studies will utilize an array of novel transgenic animal models, viral delivery methods, cutting-edge cardiometabolic phenotyping approaches, and chemogenetic methods. Completion of the project will greatly increase fundamental understanding of RMR control and adaptation biology, and provide the first in vivo evaluation of the pathophysiological significance of G protein signal switching downstream of ANG receptors in a single cell type in cardiometabolic physiology.

项目摘要 /摘要 NHANES的数据表明47.3％的美国人患有高血压（高血压），71.3％超重， 这些群体之间存在强烈的重叠。控制血压的下丘脑途径紧密 与控制静息代谢率（RMR）的途径交织在一起。长时间肥胖，心血管 - 刺激自主反应和血压反应保持完整，但RMR控制逐渐 脱敏（一种称为“ RMR适应”的过程）。 RMR适应被认为有助于 身体保持体重减轻的身体，以及身体保持质量的承诺。那是一个批判性的 未满足的需要了解基本的下丘脑神经路，该下丘脑神经通路可以协调控制血压和 在健康条件下的RMR，以及该系统在肥胖期间如何有选择地脱敏。肾素 - 血管紧张素 众所周知，大脑内部的系统（RAS）通过多个行动来促进血压控制 大脑区域，我们的团队最近发现下丘脑的弧形核内的RAS （ARC）与RMR的控制至关重要。特别是，血管紧张素II（ANG）1A型受体（AT1A） 在表达Agouti相关肽（AGRP）的弧神经元中，RMR需要控制，但不需要血液 响应瘦素，ANG和其他刺激的压力。因此，当前建议的目的是澄清 AT1A受体使用的AGRP神经元内的分子信号通路来控制RMR。 初步数据表明在瘦状态下，（i）仅AGRP神经元的一部分表达AT1A，（ii）这些AT1A 通过GI第二使者信号，（iii）此类信号导致细胞的抑制，最终导致dissib抑制 自治靶区域中的黑色皮质素信号传导，从而增加RMR。令人兴奋的是，我们发现了 长时间高脂肪进食后，弧的表达AT1A的AGRP神经元的子集 暴露了“ G蛋白信号转换”，然后开始夫妇与GQ，而不是GI第二次介绍者，结果 在ANG对这些细胞的刺激作用中。因此，我们提出了（i）在精益中的一般假设 状态，表达AT1A的AGRP神经元重要地参与了RMR对照，并且通过GI信号，AT1A信号， 但是（ii）在饮食引起的肥胖症之后，AT1A第二届级别级联的变化从gi到gs 细胞是RMR适应发展的因果。 AIM 1将定义AT1A的“正常”信号级联 在瘦动物中的AGRP神经元中，AIM 2将剖析G蛋白信号的机械贡献 在RMR适应的发展中切换这些细胞。这些研究将利用一系列新颖 转基因动物模型，病毒输送方法，尖端的心脏代谢表型方法和 化学发生方法。该项目的完成将大大增加对RMR的基本理解 控制和适应生物学，并提供对病理生理意义的体内评估 G蛋白信号在心脏代谢生理学中单细胞类型中的ANG受体下游转换。