Forebrain-hypothalamic estrogen receptor alpha in non-alcoholic fatty liver disease

项目总结： 大约70%的美国成年人被认为超重或肥胖，这增加了他们患糖尿病的风险 代谢并发症，如非酒精性脂肪肝(NAFLD)。NAFLD包括一系列 脂肪性(即肝脏甘油三酯增加)导致II型糖尿病风险增加的肝脏疾病， 胰岛素抵抗和肥胖相关死亡率。性二型性是明确确立的，其发病率 男性NAFLD显著高于绝经前女性。保护女性的机制 脂肪肝的死因仍不清楚。虽然大多数调查都是以肝脏为中心的，但我们的 最近的研究表明，穹隆下器(SFO)的内质网应激是一种前脑 感知循环因素的脑室周围区域，在雄性小鼠肥胖期间介导肝脏脂肪变性。 重要的是，SFO有密集的兴奋性投射到下丘脑室旁核(PVN)， 一种在自主神经和内分泌控制中起关键作用的整合核，具有直接的脊髓 投射到肝脏。我们令人兴奋的数据表明，投射到下丘脑室旁核的SFO神经元被激活 称为SFO®PVN神经元)导致肝交感神经流出增加，伴随着 非酒精性脂肪肝的发展。此外，抑制这一前脑-下丘脑环路或移除 肝脏交感神经足以挽救肥胖介导的NAFLD。结合使用创新的 影像、分子、神经解剖学和综合生理学方法，我们将以这些发现为基础 并解决了这样一个中心假设，即SFO®PVN投射神经元中的雌激素信号可以预防 非酒精性脂肪肝在女性中的发展。给出：1)积累雌激素信号预防 内质网应激；2)雌激素受体α(ERA)在SFO®PVN投射上表达 神经元，在目标1中，我们将综合评估雌激素是否对高脂饮食诱导的 SFO®室旁核投射神经元的内质网应激。与此相一致，在目标2中，我们将审查 SFO®PVN投射神经元中的雌激素信号是否对肥胖诱导的肝脏有保护作用 交感神经过度活动与非酒精性脂肪肝通过内质网应激机制。剖析两者之间的联系 中枢神经系统雌激素信号和内质网应激在肝交感神经调控中的作用 外流和NAFLD的发展将促进我们对有助于 非酒精性脂肪肝的性别差异。这些发现还可能有助于确定治疗和治疗的新靶点 预防这种情况的预防。此外，优雅的跨部门病毒靶向策略的组合，高 分辨率显微镜方法，直接记录交感神经流出到肝脏，并全面 组织/分子肝脏分析提供了一种新的、综合的方法来洞察性行为 非酒精性脂肪肝的发育呈二型性。

PROJECT SUMMARY: Approximately 70% of American adults are considered overweight or obese putting them at increased risk for metabolic complications such as non-alcoholic fatty liver disease (NAFLD). NAFLD encompasses a spectrum of steatogenic (i.e. increased liver triglycerides) liver disorders that lead to an increased risk for type II diabetes, insulin resistance and obesity-related mortality. Sexual dimorphism is clearly established, with the incidence of NAFLD being significantly higher in males than premenopausal females. The mechanisms that protect females from fatty liver remain unclear. While the majority of investigations have taken a liver-centric perspective, our recent findings indicate that endoplasmic reticulum stress in the subfornical organ (SFO), a forebrain circumventricular region that senses circulating factors, mediates hepatic steatosis during obesity in male mice. Importantly, the SFO has dense excitatory projections to the paraventricular nucleus of the hypothalamus (PVN), an integrative nucleus that plays a critical role in autonomic and endocrine control and has direct spinal projections to the liver. Our exciting data indicate that activation of SFO neurons that project to the PVN (hereafter referred to as SFO®PVN neurons) results in elevations in hepatic sympathetic outflow that are accompanied by the development of NAFLD. Furthermore, inhibition of this forebrain-hypothalamic circuit or removal of the hepatic sympathetic nerves is sufficient to rescue obesity-mediated NAFLD. Using a combination of innovative imaging, molecular, neuroanatomical, and integrative physiological approaches, we will build upon these findings and address the central hypothesis that estrogen signaling in SFO®PVN projecting neurons protects against NAFLD development in females. Given: 1) Accumulating evidence that estrogen signaling protects against endoplasmic reticulum stress; and 2) Estrogen receptor alpha (ERa) is expressed on SFO®PVN projecting neurons, in Aim 1 we will comprehensively evaluate whether estrogen protects against high fat diet-induced endoplasmic reticulum stress in SFO®PVN projecting neurons. In line with this, in Aim 2, we will examine whether estrogen signaling in SFO®PVN projecting neurons protects against obesity-induced hepatic sympathetic overactivity and NAFLD via endoplasmic reticulum stress mechanisms. Dissecting the links between central nervous system estrogen signaling and endoplasmic reticulum stress in the control of hepatic sympathetic outflow and NAFLD development will advance our understanding of underlying mechanisms that contribute to sex differences in NAFLD. These findings may also help identify new therapeutic targets for treatment and prevention of this condition. Moreover, the combination of elegant intersectional viral targeting strategies, high- resolution microscopy approaches, direct recording of sympathetic outflow to the liver, and comprehensive histological/molecular hepatic analysis provides a novel and integrative approach to gain insight into sexually dimorphic NAFLD development.