Investigating sex-specific metabolic effects of disrupted selenocysteine lyase and selenocysteine tRNA in Agrp hypothalamic neurons

项目总结/摘要 硒是人体必需的抗氧化微量元素，广泛用作膳食补充剂 健康硒因其在抑制氧化应激和调节甲状腺功能和男性中的作用而闻名 生育过去的研究表明，硒蛋白表达的改变与代谢性疾病的风险增加有关。 综合征（MetS）。胞内Sec分解酶Sec裂解酶（Scly）的整体敲除（KO） 增加小鼠对MetS和饮食诱导的肥胖症（DIO）的易感性，伴随着降低 硒蛋白在下丘脑的表达，能量稳态的关键介质。令人惊讶的是， 下丘脑刺豚鼠相关肽（Agrp）阳性神经元中的靶向Scly KO可防止DIO 以及瘦素抵抗，这一效应可能受到男性甲状腺激素功能的影响。Agrp小鼠 硒代半胱氨酸-tRNA（Trsp）的神经元特异性缺失，其是硒蛋白表达所必需的， 显示出与在Scly-Agrp KO小鼠中观察到的代谢作用相似的代谢作用。这些结果仅限于女性 然而，作为雄性Trsp-Agrp KO小鼠的小鼠显示与对照没有显著差异。 这项建议的总体目标是阐明代谢表型的机制， Scly-Agrp KO小鼠和Trsp-Agrp KO小鼠中观察到的性别差异。核心假设是， Agrp神经元依赖于硒的利用，通过性别特异性机制介导高脂饮食诱导的变化。 具体地说，这项提议调查了Scly的缺失保护Agrp神经元发育的可能性。 早期瘦素抵抗，以防止下游下丘脑瘦素抵抗和限制体重增加， 维持棕色脂肪组织的产热。本项目还将检验Trsp缺失的假设， 导致Agrp神经元的进行性神经变性，这影响了 下丘脑神经原性机制导致观察到的代谢表型。这些假设将 使用这些小鼠模型以及体内表型分析、组织分析和离体分析的组合进行测试。 下丘脑脑切片的电生理学研究。 该奖学金将在硒领域经验丰富的导师和先驱的指导下进行， 和一位在神经科学方面有广泛背景的有成就的共同导师。建议个性化 培训计划包括具体的教育和职业发展活动，并受益于 一个由科学家组成的协作社区，实施一个密集的团队指导计划。预计 本文提出的实验将阐明硒利用和硒蛋白的重要作用 在代谢疾病病理学中，提供了关于中枢神经系统之间相互作用的新信息， 和全身能量代谢，并可能潜在地确定关键目标的利益， 代谢紊乱的治疗策略或治疗方法。

PROJECT SUMMARY/ABSTRACT Widely used as a dietary supplement, the antioxidant trace element selenium (Se) is essential for human health. Se is known for its role in curbing oxidative stress and in the regulation of thyroid function and male fertility. Past studies have associated altered selenoprotein expression with increased risk for metabolic syndrome (MetS). Whole-body knockout (KO) of the intracellular Sec decomposition enzyme Sec lyase (Scly) in mice increases susceptibility to MetS and diet-induced obesity (DIO), accompanied by decreased selenoprotein expression in the hypothalamus, a key mediator of energy homeostasis. Surprisingly, mice with targeted Scly KO in agouti-related peptide (Agrp)-positive neurons of the hypothalamus are protected from DIO and leptin resistance, an effect that may be influenced by thyroid hormone function in males. Mice with Agrp neuron-specific deletion of the selenocysteine-tRNA (Trsp), which is essential for selenoprotein expression, display metabolic effects similar to those observed in Scly-Agrp KO mice. These results are specific to female mice, however, as male Trsp-Agrp KO mice show no significant differences from controls. The overall goal of this proposal is to elucidate the mechanisms that underlie the metabolic phenotype of Scly-Agrp KO mice and the sex differences observed in Trsp-Agrp KO mice. The central hypothesis is that Agrp neurons depend on Se utilization to mediate high-fat diet-induced changes via sex-specific mechanisms. Specifically, this proposal investigates the possibility that loss of Scly protects Agrp neurons from developing early leptin resistance to prevent downstream hypothalamic leptin resistance and limit weight gain by maintaining brown adipose tissue thermogenesis. This project will also test the hypothesis that loss of Trsp causes progressive neurodegeneration of Agrp neurons, which impacts sex-specific differences in hypothalamic neurogenic mechanisms to result in the metabolic phenotypes observed. These hypotheses will be tested using these mouse models and a combination of in vivo phenotyping, tissue analysis, and ex vivo electrophysiology on live hypothalamic brain slices. This fellowship will take place under the guidance of an experienced mentor and pioneer in the Se field, and an accomplished co-mentor with an extensive background in neuroscience. The proposed individualized training plan includes specific educational and career development activities, and benefits from the expertise of a collaborative community of scientists implementing an intensive team mentoring program. It is anticipated that the experiments proposed herein will shed light on the important roles of Se utilization and selenoproteins in metabolic disease pathology, provide new information on the interplay between the central nervous system and whole-body energy metabolism, and may potentially identify key targets of interest for preventative strategies or therapeutic treatments for metabolic disorders.