The Role of a Novel Obesity-Risk Variant on Hypothalamic Regulation of Energy Homeostasis

目前肥胖的流行需要改进策略来预防和治疗日益严重的肥胖症。 毁灭性的疾病。最近，我们的合作小组研究了易患肥胖症的萨摩亚人和 在一个假定的转录调节因子(CREBRFR457Q)中发现了一个错义变体，它会增加BMI和 肥胖症。人们对CREBRF知之甚少，对其肥胖风险变异的机制更是知之甚少 影响人类的这些表型。因为食物的摄入量、能量消耗和脂肪储存 在外周和大脑之间协调，我们在小鼠模型中检查了CREBRF的表达 在整个胚胎发育和成年过程中，下丘脑中的含量都受到调节 以特定于细胞的方式进食状态。因此，这项提案的总体目标是了解如何 CREBRF及其肥胖风险变体有助于能量动态平衡的中央调节，以及更多 具体地说，对弓状核POMC和AgRP神经元的发育和功能 在营养应激期间，下丘脑以性别特有的方式。我们的中心假设是CREBRF及其 肥胖风险变异影响关键下丘脑的增殖、分化和随后的激活/输出 控制食物摄入量、能量消耗和体重的神经元。这一假设得到了 以下是初步数据：1)表达CREBRFR457Q变异体的人体重指数增加，肥胖， 2)缺乏CREBRF的小鼠体重和摄食量减少，3)野生型CREBRF相反 在POMC和AgRP神经元中调节对禁食的反应；4)CREBRF在胚胎中表达 并诱导下丘脑与神经发生相对应。中心假设将使用以下工具进行检验 可用的细胞模型和小鼠模型可实现以下两个具体目的：1)确定影响 CREBRF及其肥胖风险变体对胚胎下丘脑发育的影响；2)确定其影响 CREBRF及其肥胖危险变异体对关键成人下丘脑神经元基因表达的影响 不同进食状态下的能量平衡。这项研究具有创新性，因为它使用了一个多学科的 阐明一种新的人类肥胖风险变异的机制的方法和最新技术 在一个知之甚少的基因中影响能量平衡的中枢调节。这项研究具有重要的意义 因为它与风险等位基因高发的人群直接相关，而且很可能 揭示能量动态平衡的一般调节和更常见的发病机制的新见解 人类的肥胖。这些发现预计将产生广泛的翻译影响，因为它们将提供 对一个相对未知的基因的基本理解，并揭示可以作为靶点的新机制 以针对性别的方式预防和/或治疗肥胖。此外，此NIDDK R21将支持 为随后的R01提案生成影响较大的出版物和初步数据，进一步审查 CREBRF在下丘脑发育、能量平衡和其他疾病相关过程中的作用。

The current obesity epidemic warrants improved strategies for preventing and treating this increasingly devastating disease. Recently, our collaborative group examined the obesity-prone Samoan population and identified a missense variant in a putative transcriptional regulator (CREBRFR457Q) that increases BMI and adiposity. Little is understood about CREBRF and even less for the mechanisms by which its obesity-risk variant influence these phenotypes in humans. Because food intake, energy expenditure, and fat storage are orchestrated between the periphery and the brain, we examined in murine models that CREBRF was expressed and enriched in the hypothalamus throughout embryonic development and in adulthood is regulated during feeding state in a cell-specific manner. Therefore, the overall objective of this proposal is to understand how CREBRF and its obesity-risk variant contribute to the central regulation of energy homeostasis and, more specifically, to the development and function of POMC and AgRP neurons in the arcuate nucleus of the hypothalamus during nutritional stress in a sex-specific manner. Our central hypothesis is that CREBRF and its obesity-risk variant influence proliferation, differentiation, and subsequent activation/output of key hypothalamic neurons that control food intake, energy expenditure, and body weight. This hypothesis is supported by the following preliminary data: 1) humans expressing the CREBRFR457Q variant have increased BMI and adiposity, 2) mice lacking CREBRF have reduced body weight and food intake, 3) wild type CREBRF is reciprocally regulated in POMC and AgRP neurons in response to fasting, and 4) CREBRF is expressed in the embryonic hypothalamus and induced corresponding with neurogenesis. The central hypothesis will be tested using available cell and mouse models to achieve the following two specific aims: 1) to determine the impact of CREBRF and its obesity-risk variant on embryonic hypothalamic development, and 2) to determine the impact of CREBRF and its obesity-risk variant on gene expression in key adult hypothalamic neurons that regulate energy balance during various feeding states. This research is innovative because it uses a multidisciplinary approach and state-of-the-art techniques to elucidate mechanisms by which a novel human obesity-risk variant in a poorly understood gene influences the central regulation of energy homeostasis. This research is significant because it is directly relevant to populations with a high prevalence of the risk allele and because it is likely to reveal novel insights into the general regulation of energy homeostasis and pathogenesis of more common obesity in humans. These findings are expected to have broad translational impact because they will provide fundamental understanding for a relatively unknown gene and reveal novel mechanisms that can be targeted for prevention and/or treatment of obesity in a sex-specific manner. Additionally, this NIDDK R21 will support the generation of high-impact publications and preliminary data for subsequent R01 proposals further examining the role of CREBRF on hypothalamic development, in energy homeostasis, and other disease-relevant processes.