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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

基本信息

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
项目类别：
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

项目摘要

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