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.

中文翻译：

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弓状血管紧张素：整合心脏代谢控制的机制：2022 年 COH 职业中期卓越研究奖。


美国心脏协会已将肥胖确定为心血管疾病（包括高血压）持续改善的主要障碍。尽管药物、运动、饮食和手术都会导致体重减轻，但很少有受试者能长期保持体重减轻。静息代谢率 （RMR） 的功能失调的综合控制 （即适应） 似乎是这种体重维持失败的基础，但对生理和病理生理学 RMR 控制的神经生物学知之甚少。在这里，我们回顾了最近对下丘脑弓状核内 Ang-II（血管紧张素 II）信号传导对 RMR 的细胞和分子控制的见解。在 agouti 相关肽神经元的独特子集中，AT1R （Ang-II 1 型受体） 与 RMR 的综合控制有关。此外，这种神经元类型内 AT1R 的自发 G 蛋白信号转换似乎是 RMR 适应发病机制的基础，它定性地改变了细胞对 AT1R 激活的反应，这些反应来自 β-arrestin-1/Gαi （异源三聚体 G 蛋白，α i 亚型） 介导的对 Gαq （异源三聚体 G 蛋白，α q 亚型） 介导的刺激反应介导的刺激反应。我们得出结论，肥胖的治疗方法可能受到介导能量平衡正常综合控制的信号机制的可塑性的阻碍。由于第二信使耦合的质变，在正常生理状态下会增加 RMR 的相同刺激可能会降低肥胖期间的 RMR。 了解调节受体（如 AT1R）及其各种第二信使信号级联之间相互作用的机制将为 RMR 适应的发病机制提供新的见解，并可能为肥胖和高血压的新治疗方法提供新的见解。