Department of Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Obesity (Silver Spring). 2024 Jan;32(1):59-69. doi: 10.1002/oby.23895. Epub 2023 Oct 4.
Nonalcoholic fatty liver disease (NAFLD), characterized by excess liver triglyceride accumulation (hepatic steatosis), leads to an increased risk for cardiometabolic diseases and obesity-related mortality. Emerging evidence points to endoplasmic reticulum (ER) stress in the central nervous system as critical in NAFLD pathogenesis. Here, we tested the contribution of ER stress in a circumventricular organ-hypothalamic circuit in NAFLD development during obesity.
C57BL/6J male mice were fed a high-fat diet (HFD) or normal chow. A combination of histological, viral tracing, intersectional viral targeting, and in vivo integrative physiological approaches were used to examine the role of ER stress in subfornical organ to hypothalamic paraventricular nucleus projecting neurons (SFO➔PVN) in NAFLD during diet-induced obesity.
Immunohistochemical analysis revealed marked unfolded protein response activation in the SFO, particularly in excitatory SFO➔PVN neurons of HFD-fed animals. Moreover, intersectional viral inhibition of ER stress in SFO➔PVN neurons resulted in a reduction in hepatomegaly, hepatic steatosis, and a blunted increase in body weight gain during diet-induced obesity, independent of changes in food intake, substrate partitioning, energy expenditure, and ambulatory activity.
These results indicate that ER stress in an SFO➔PVN neural circuit contributes to hepatic steatosis during obesity.
非酒精性脂肪性肝病（NAFLD）的特征是肝脏甘油三酯积累过多（肝脂肪变性），导致代谢性心血管疾病和肥胖相关死亡率增加。新出现的证据表明，中枢神经系统内质网（ER）应激在 NAFLD 发病机制中至关重要。在这里，我们在肥胖期间 NAFLD 发展的一个脑区（下丘脑旁室核）的脑区-下丘脑旁室核投射神经元（SFO➔PVN）中测试了 ER 应激在其中的作用。
C57BL/6J 雄性小鼠喂食高脂肪饮食（HFD）或正常饲料。我们结合组织学、病毒追踪、交叉病毒靶向和体内综合生理方法，研究了 ER 应激在 SFO➔PVN 投射神经元中在肥胖诱导的 NAFLD 中的作用。
免疫组织化学分析显示，HFD 喂养动物的 SFO 中存在明显的未折叠蛋白反应激活，特别是兴奋性 SFO➔PVN 神经元。此外，SFO➔PVN 神经元中 ER 应激的交叉病毒抑制导致肝肿大、肝脂肪变性减少，并且在肥胖诱导的体重增加中体重增加减少，而不影响食物摄入、底物分配、能量消耗和活动。
这些结果表明，SFO➔PVN 神经回路中的 ER 应激有助于肥胖期间的肝脂肪变性。
