Angiotensin in the Arcuate: Mechanisms Integrating Cardiometabolic Control: The 2022 COH Mid-Career Award for Research Excellence.

IF 6.9 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE
Hypertension Pub Date : 2024-11-01 Epub Date: 2024-09-24 DOI:10.1161/HYPERTENSIONAHA.124.20524
Samuel B R Lawton, Valerie A Wagner, Pablo Nakagawa, Jeffrey L Segar, Curt D Sigmund, Lisa L Morselli, Justin L Grobe
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引用次数: 0

Abstract

The American Heart Association has identified obesity as a primary impediment to ongoing improvements in cardiovascular diseases, including hypertension. Although drugs, exercise, diets, and surgeries can each cause weight loss, few subjects maintain a reduced weight over the long term. Dysfunctional integrative control (ie, adaptation) of resting metabolic rate (RMR) appears to underlie this failed weight maintenance, yet the neurobiology of physiological and pathophysiological RMR control is poorly understood. Here, we review recent insights into the cellular and molecular control of RMR by Ang-II (angiotensin II) signaling within the arcuate nucleus of the hypothalamus. Within a unique subset of agouti-related peptide neurons, AT1R (Ang-II type 1 receptors) are implicated in the integrative control of RMR. Furthermore, a spontaneous G protein signal switch of AT1R within this neuron type appears to underlie the pathogenesis of RMR adaptation by qualitatively changing the cellular response to AT1R activation from a β-arrestin-1/Gαi (heterotrimeric G protein, α i subtype)-mediated inhibitory response to a Gαq (heterotrimeric G protein, α q subtype)-mediated stimulatory response. We conclude that therapeutic approaches to obesity are likely hampered by the plasticity of the signaling mechanisms that mediate the normal integrative control of energy balance. The same stimulus that would increase RMR in the normal physiological state may decrease RMR during obesity due to qualitative changes in second-messenger coupling. Understanding the mechanisms that regulate interactions between receptors such as AT1R and its various second messenger signaling cascades will provide novel insights into the pathogenesis of RMR adaptation and potentially point toward new therapeutic approaches for obesity and hypertension.

弓形体中的血管紧张素:心血管代谢控制的综合机制
背景:美国心脏协会认为,肥胖是持续改善包括高血压在内的心血管疾病的主要障碍。虽然药物、运动、饮食和手术都能减轻体重,但很少有人能长期保持减轻的体重。静息代谢率(RMR)的综合控制(即适应)功能失调似乎是体重维持失败的原因,但人们对生理和病理生理学RMR控制的神经生物学却知之甚少:方法:综述下丘脑弓状核内血管紧张素 II(Ang-II)信号传导对 RMR 的细胞和分子控制的最新研究成果:结果:在AgRP(激动相关肽)神经元的一个独特亚群中,AT1Rs(Ang-II 1型受体)与RMR的综合控制有关。此外,在这种神经元类型中,AT1R 的自发 G 蛋白信号转换似乎是 RMR 适应性发病机制的基础,它从质量上改变了细胞对 AT1R 激活的反应,即从β-arrestin-1/Gαi 介导的抑制性反应转变为 Gαq 介导的刺激性反应:结论:肥胖症的治疗方法可能会受到介导能量平衡正常综合控制的信号机制可塑性的阻碍。由于第二信使耦合的质变,在正常生理状态下会增加 RMR 的相同刺激在肥胖时可能会降低 RMR。了解调节 AT1R 等受体及其各种第二信使信号级联之间相互作用的机制,将为了解 RMR 适应的发病机制提供新的见解,并有可能为肥胖症和高血压的治疗提供新的方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Hypertension
Hypertension 医学-外周血管病
CiteScore
15.90
自引率
4.80%
发文量
1006
审稿时长
1 months
期刊介绍: Hypertension presents top-tier articles on high blood pressure in each monthly release. These articles delve into basic science, clinical treatment, and prevention of hypertension and associated cardiovascular, metabolic, and renal conditions. Renowned for their lasting significance, these papers contribute to advancing our understanding and management of hypertension-related issues.
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