在肥胖期间，Agouti 相关肽神经元中的血管紧张素 AT 受体信号转换介导代谢率适应。

Angiotensin AT receptor signal switching in Agouti-related peptide neurons mediates metabolic rate adaptation during obesity.

机构信息

Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.

出版信息

Cell Rep. 2023 Aug 29;42(8):112935. doi: 10.1016/j.celrep.2023.112935. Epub 2023 Aug 2.

Resting metabolic rate (RMR) adaptation occurs during obesity and is hypothesized to contribute to failed weight management. Angiotensin II (Ang-II) type 1 (AT) receptors in Agouti-related peptide (AgRP) neurons contribute to the integrative control of RMR, and deletion of AT from AgRP neurons causes RMR adaptation. Extracellular patch-clamp recordings identify distinct cellular responses of individual AgRP neurons from lean mice to Ang-II: no response, inhibition via AT and Gαi, or stimulation via Ang-II type 2 (AT) receptors and Gαq. Following diet-induced obesity, a subset of Ang-II/AT-inhibited AgRP neurons undergo a spontaneous G-protein "signal switch," whereby AT stop inhibiting the cell via Gαi and instead begin stimulating the cell via Gαq. DREADD-mediated activation of Gαi, but not Gαq, in AT-expressing AgRP cells stimulates RMR in lean and obese mice. Thus, loss of AT-Gαi coupling within the AT-expressing AgRP neuron subtype represents a molecular mechanism contributing to RMR adaptation.

静息代谢率（RMR）适应发生在肥胖过程中，据推测它有助于体重管理的失败。Agouti 相关肽（AgRP）神经元中的血管紧张素 II（Ang-II）1 型（AT）受体有助于 RMR 的综合控制，而 AgRP 神经元中 AT 的缺失会导致 RMR 适应。细胞外膜片钳记录鉴定出来自瘦鼠的单个 AgRP 神经元对 Ang-II 的不同细胞反应：无反应、通过 AT 和 Gαi 抑制，或通过 Ang-II 2 型（AT）受体和 Gαq 刺激。在饮食诱导肥胖后，一部分 Ang-II/AT 抑制的 AgRP 神经元会发生自发的 G 蛋白“信号转换”，其中 AT 通过 Gαi 停止抑制细胞，而是通过 Gαq 开始刺激细胞。在表达 AT 的 AgRP 细胞中，通过 DREADD 介导的 Gαi 激活，但不是 Gαq 激活，会刺激瘦鼠和肥胖鼠的 RMR。因此，表达 AT 的 AgRP 神经元亚型中 AT-Gαi 偶联的丧失代表了导致 RMR 适应的分子机制。