Abstract：
OBJECTIVE: To show that electroacupuncture stimulation (ES) remodels sympathetic innervation in brown adipose tissue (BAT) via the bone morphogenic protein 8B (BMP8B)-neuregulin 4 (NRG4)-ErbB4 axis, with somatotopic dependence.
METHODS: We established a high-fat diet (HFD) model with C57BL/6J mice to measure the thermogenesis and metabolism of BAT. In addition, the sympathetic nerve activity (SNA) was measured with the electrophysiological technique, and the immunostaining of c-Fos was used to detect the central nervous system sources of sympathetic outflows. Finally, the key role of the BMP8B-NRG4-ErbB4 axis was verified by peripheral specific antagonism of ErbB4.
RESULTS: ES at the forelimb and abdomen regions significantly up-regulate SNA, whereas ES at the hindlimb region has a limited regulatory effect on SNA but still partially restores HFD-induced BAT dysfunction. Mechanistically, ES at the forelimb and abdomen regions driving catecholaminergic signals in brown adipocytes depends on neural activities projected from the ventromedial nucleus of the hypothalamus (VMH) to the spinal cord intermediolateral column (IML). Notably, the peripheral suppression of ErbB4 in BAT inhibits the thermogenesis and metabolic function of BAT, as well as significantly hindering the SNA activation and metabolic benefits induced by ES.
CONCLUSIONS: These results suggest that ES appears to be an effective approach for remodeling sympathetic innervation in BAT, which is closely related to neuronal activity in the VMH and the NRG4-ErbB4 signaling pathway.
METHODS: We established a high-fat diet (HFD) model with C57BL/6J mice to measure the thermogenesis and metabolism of BAT. In addition, the sympathetic nerve activity (SNA) was measured with the electrophysiological technique, and the immunostaining of c-Fos was used to detect the central nervous system sources of sympathetic outflows. Finally, the key role of the BMP8B-NRG4-ErbB4 axis was verified by peripheral specific antagonism of ErbB4.
RESULTS: ES at the forelimb and abdomen regions significantly up-regulate SNA, whereas ES at the hindlimb region has a limited regulatory effect on SNA but still partially restores HFD-induced BAT dysfunction. Mechanistically, ES at the forelimb and abdomen regions driving catecholaminergic signals in brown adipocytes depends on neural activities projected from the ventromedial nucleus of the hypothalamus (VMH) to the spinal cord intermediolateral column (IML). Notably, the peripheral suppression of ErbB4 in BAT inhibits the thermogenesis and metabolic function of BAT, as well as significantly hindering the SNA activation and metabolic benefits induced by ES.
CONCLUSIONS: These results suggest that ES appears to be an effective approach for remodeling sympathetic innervation in BAT, which is closely related to neuronal activity in the VMH and the NRG4-ErbB4 signaling pathway.
摘要：
目的：显示电针刺激（ES）通过骨形态发生蛋白8B（BMP8B）-神经调节蛋白4（NRG4）-ErbB4轴重塑棕色脂肪组织（BAT）的交感神经支配，有躯体依赖性。
方法：我们用C57BL/6J小鼠建立了高脂饮食（HFD）模型，以测量BAT的产热和代谢。此外,交感神经活动（SNA）用电生理技术测量，c-Fos免疫染色用于检测交感神经流出的中枢神经系统来源。最后,BMP8B-NRG4-ErbB4轴的关键作用通过ErbB4的外周特异性拮抗作用得到证实.
结果：前肢和腹部区域的ES显著上调SNA，尽管后肢区域的ES对SNA的调节作用有限，但仍部分恢复HFD诱导的BAT功能障碍。机械上,前肢和腹部区域的ES驱动棕色脂肪细胞中的儿茶酚胺能信号，取决于从下丘脑（VMH）的腹内侧核投射到脊髓中外侧柱（IML）的神经活动。值得注意的是,BAT中ErbB4的外周抑制抑制BAT的产热和代谢功能，以及显著阻碍ES诱导的SNA激活和代谢益处。
结论：这些结果表明，ES似乎是重塑BAT交感神经支配的有效方法，这与VMH中的神经元活性和NRG4-ErbB4信号通路密切相关。
方法：我们用C57BL/6J小鼠建立了高脂饮食（HFD）模型，以测量BAT的产热和代谢。此外,交感神经活动（SNA）用电生理技术测量，c-Fos免疫染色用于检测交感神经流出的中枢神经系统来源。最后,BMP8B-NRG4-ErbB4轴的关键作用通过ErbB4的外周特异性拮抗作用得到证实.
结果：前肢和腹部区域的ES显著上调SNA，尽管后肢区域的ES对SNA的调节作用有限，但仍部分恢复HFD诱导的BAT功能障碍。机械上,前肢和腹部区域的ES驱动棕色脂肪细胞中的儿茶酚胺能信号，取决于从下丘脑（VMH）的腹内侧核投射到脊髓中外侧柱（IML）的神经活动。值得注意的是,BAT中ErbB4的外周抑制抑制BAT的产热和代谢功能，以及显著阻碍ES诱导的SNA激活和代谢益处。
结论：这些结果表明，ES似乎是重塑BAT交感神经支配的有效方法，这与VMH中的神经元活性和NRG4-ErbB4信号通路密切相关。
