A forebrain-hypothalamic ER stress driven circuit mediates hepatic steatosis during obesity.
A forebrain-hypothalamic ER stress driven circuit mediates hepatic steatosis during obesity.
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DOI：
10.1016/j.molmet.2023.101858
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发表时间：
2024-01
影响因子：
8.1
通讯作者：
Young, Colin N.
中科院分区：
文献类型：
--
作者：
Blackmore, Katherine;Houchen, Claire J.;Simonyan, Hayk;Arestakesyan, Hovhannes;Stark, Alyssa K.;Dow, Samantha A.;Kim, Han Rae;Jeong, Jin Kwon;Popratiloff, Anastas;Young, Colin N.
关键词：
非酒精性脂肪性肝病(NAFLD)影响三分之一的成年人，并导致晚期肝脏损伤和心脏代谢性疾病。虽然最近的证据表明，大脑参与了NAFLD，但参与这一反应的下游神经回路和神经分子机制仍不清楚。在这里，我们研究了一个独特的前脑-下丘脑回路在NAFLD中的作用。用化学方法激活和抑制投射到小鼠下丘脑室旁核的穹隆下器周围神经元(sFo→pvn)，研究sfo→pvn信号在非酒精性脂肪肝中的作用。新的扫描电子显微镜技术、组织学方法、分子生物学技术和病毒方法被进一步用于描绘内质网(ER)应激在该回路中在驱动NAFLD中的作用。在瘦肉动物中，→室旁核神经元的急性化学激活足以引起肝脏交感神经依赖的肝脏脂肪变性。相反，抑制这一前脑-下丘脑回路可以挽救肥胖相关的NAFLD。此外，膳食NAFLD与PVN内显著的内质网超微结构改变和内质网应激有关，这种变化在SFO的兴奋信号减少后被钝化。最后，选择性抑制PVN内质网应激可减少肥胖时的肝脏脂肪变性。总而言之，这些发现描述了一种以前未知的前脑-下丘脑-内质网应激回路，它与肝脏脂肪变性有关，这可能为未来NAFLD的治疗策略指明方向。涉及SFO到PVN的神经元回路的激活会导致肝脏脂肪变性。肥胖时抑制sFO→室旁核神经元可减轻肝脏脂肪变性。PVN内质网应激在肥胖期间发生，部分由SFO输入驱动。肥胖期间抑制PVN ER应激可减少肝脏脂肪变性。
Non-alcoholic fatty liver disease (NAFLD) affects 1 in 3 adults and contributes to advanced liver injury and cardiometabolic disease. While recent evidence points to involvement of the brain in NAFLD, the downstream neural circuits and neuronal molecular mechanisms involved in this response, remain unclear. Here, we investigated the role of a unique forebrain-hypothalamic circuit in NAFLD. Chemogenetic activation and inhibition of circumventricular subfornical organ (SFO) neurons that project to the paraventricular nucleus of the hypothalamus (PVN; SFO→PVN) in mice were used to study the role of SFO→PVN signaling in NAFLD. Novel scanning electron microscopy techniques, histological approaches, molecular biology techniques, and viral methodologies were further used to delineate the role of endoplasmic reticulum (ER) stress within this circuit in driving NAFLD. In lean animals, acute chemogenetic activation of SFO→PVN neurons was sufficient to cause hepatic steatosis in a liver sympathetic nerve dependent manner. Conversely, inhibition of this forebrain-hypothalamic circuit rescued obesity-associated NAFLD. Furthermore, dietary NAFLD is associated with marked ER ultrastructural alterations and ER stress in the PVN, which was blunted following reductions in excitatory signaling from the SFO. Finally, selective inhibition of PVN ER stress reduced hepatic steatosis during obesity. Collectively, these findings characterize a previously unrecognized forebrain-hypothalamic-ER stress circuit that is involved in hepatic steatosis, which may point to future therapeutic strategies for NAFLD. Activation of a neuronal circuit involving the SFO to PVN causes hepatic steatosis. Inhibition of SFO→PVN neurons during obesity alleviates hepatic steatosis. PVN ER stress occurs during obesity, driven in part by SFO inputs. Inhibition of PVN ER stress during obesity reduces hepatic steatosis.
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影响因子：
6.1
作者：
Lee SH;Han K;Yang HK;Kim HS;Cho JH;Kwon HS;Park YM;Cha BY;Yoon KH
通讯作者：
Yoon KH
影响因子：
7.2
作者：
Daneman, Richard;Prat, Alexandre
通讯作者：
Prat, Alexandre
影响因子：
3.8
作者：
Almeda-Valdes, Paloma;Cuevas-Ramos, Daniel;Aguilar-Salinas, Carlos Alberto
通讯作者：
Aguilar-Salinas, Carlos Alberto
影响因子：
6.7
作者：
Leite, Nathalie C.;Salles, Gil F.;Cardoso, Claudia R. L.
通讯作者：
Cardoso, Claudia R. L.
影响因子：
4.3
作者：
Liu, Hong;Lu, Hong-Yun
通讯作者：
Lu, Hong-Yun