Arcuate ERa Signaling in Central Control of Female Bone Metabolism

项目摘要/摘要 在这个修订的R01应用中，我们将询问中枢神经系统中的雌激素信号是如何控制的 以性别依赖的方式进行骨骼代谢。众所周知，外周雌激素影响骨质疏松。 无论是老鼠还是人类。作为了解小鼠雌激素神经回路如何影响的努力的一部分 在女性新陈代谢中，我们发现弓状核(ARC)中的雌激素信号。 下丘脑通常会抑制雌性小鼠的皮质和松质骨量。消融雌激素 在三种交叉和独立的小鼠模型中，受体α(Era)导致显著的高骨量 雌性小鼠的群体表型；雄性骨骼不受影响。突变的雌性动物表现出异常密集的 骨小梁和皮质骨，其强度超过其他已报道的小鼠模型。立体定位法- 脑Era的引导缺失证实了这种骨表型的中心起源，并解偶联了这一 由于循环中的雌二醇、睾酮或瘦素的变化而产生的表型。我们的工作定义了中心 调节骨骼新陈代谢，以及生殖和能量平衡，作为一种基本性- 生理学上的差异。这些数据也为大脑是一个主要决定因素的概念提供了证据 改善女性的骨代谢，从而扩大下丘脑的能量把关功能 用于非经典新陈代谢组织的支出，如骨骼。虽然我们的研究是最早的 临床前阶段，了解我们的模型如何构建大量致密和强壮的骨骼 改变目前治疗荷尔蒙和年龄相关性骨丢失的合理设计。为什么以及如何 女性ARC神经元通常会抑制骨代谢，这仍然是一个谜。在以下三个目标中，我们 试图解开这个谜团。我们将定义并确认哪些ARC神经元调节这一脑骨 连接，询问通过化学遗传学和药理学操纵这些神经元是否模仿高骨 或使突变体的骨表型正常化，然后开始确定分子 这种性别相关的高骨表型的基础。

Project Summary/Abstract In this revised R01 application we will ask how estrogen signaling in the central nervous system controls bone metabolism in a sex dependent manner. It is well known that peripheral estrogen affects bone in both mice and humans. As part of our efforts to understand how estrogen neural circuits in mice affect female metabolism, we discovered that estrogen signaling in the arcuate nucleus (ARC) of the hypothalamus normally suppresses cortical and trabecular bone mass in female mice. Ablating estrogen receptor alpha (ERa) in three intersectional and independent mouse models leads to a striking high bone mass phenotype in female mice; male bones are unaffected. Mutant females exhibit exceptionally dense trabecular and cortical bones, whose strengths surpass other reported mouse models. Stereotaxic- guided deletion of brain ERa confirmed the central origin of this bone phenotype and uncoupled this phenotype from changes in circulating estradiol, testosterone, or leptin. Our work defines central regulation of bone metabolism, alongside reproduction and energy balance, as a fundamental sex- difference in physiology. These data also offer proof for the concept that the brain is a major determinant of female bone metabolism, thus expanding the gatekeeper function of the hypothalamus in energy expenditure to non-classical metabolic tissues, such as bone. Although our research is in the earliest pre-clinical stages, understanding how our models build massively dense and strong bones could transform current rational design of therapeutics for hormonal and age-related bone loss. Why and how female ARC neurons normally inhibit bone metabolism remain a mystery. In the following three aims, we seek to unravel this puzzle. We will define and then confirm which ARC neurons mediate this brain-bone connection, ask if manipulating these neurons via chemogenetics and pharmacology mimics high bone phenotype or normalizes the bone phenotype in mutants, and then begin determining the molecular basis for this sex-dependent high bone phenotype.