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

目前的肥胖流行需要改进的策略，以预防和治疗这一日益增加的 毁灭性的疾病最近，我们的合作小组研究了有肥胖倾向的萨摩亚人口， 在一个假定的转录调节因子（CREBRFR 457 Q）中发现了一个错义变体，该变体增加了BMI， 肥胖症人们对CREBRF知之甚少，对其肥胖风险变异体的机制更是知之甚少。 影响人类的这些表型因为食物摄入、能量消耗和脂肪储存 我们在小鼠模型中检测了CREBRF在外周和大脑之间的表达， 并在整个胚胎发育和成年期在下丘脑中富集， 以细胞特异性的方式饲养状态。因此，本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稳态的中枢调节， 特别是，POMC和AgRP神经元在弓状核的发育和功能， 下丘脑在营养应激中以性别特异性的方式。我们的中心假设是，CREBRF及其 肥胖风险变异影响下丘脑关键神经元的增殖、分化和随后的激活/输出 控制食物摄入、能量消耗和体重的神经元。这一假设得到了 以下初步数据：1）表达CREBRFR 457 Q变体的人具有增加的BMI和肥胖， 2)缺乏CREBRF的小鼠体重和食物摄入量减少，3）野生型CREBRF是 CREBRF在POMC和AgRP神经元中响应于禁食而受到调节，以及4）CREBRF在胚胎中表达。 下丘脑和诱导相应的神经发生。中心假设将使用 现有的细胞和小鼠模型，以实现以下两个具体目标：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，以及2）确定 CREBRF及其肥胖风险变体对调节下丘脑神经元基因表达的影响 在不同的进食状态下能量平衡。这项研究是创新的，因为它使用了多学科 方法和最先进的技术来阐明一种新的人类肥胖风险变异 在一个知之甚少的基因影响中央调节能量稳态。这项研究意义重大 因为它与风险等位基因高流行率的人群直接相关，并且因为它可能 揭示了新的见解，一般调节能量稳态和发病机制更常见的 肥胖症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了解，并揭示了新的机制，可以针对 以性别特异性方式预防和/或治疗肥胖。此外，这款NIDDK R21将支持 产生高影响力的出版物和初步数据，用于随后的R 01提案， CREBRF在下丘脑发育、能量稳态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.