Molecular characterization in human neurons of genes associated with severe obesity identified from consanguineous pedigrees.

从近亲谱系中鉴定出的与严重肥胖相关的人类神经元基因的分子特征。

• 批准号: MR/S026193/1
• 负责人: Giles Yeo
• 金额: $ 129.2万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS026193%2F1
• 关键词: Molecular; characterization; human; neurons; genes

Obesity is a growing public health problem. While it has undoubtedly been driven by the changing environment, there is a large heritable component underlying the variation in body-weight within the population. Genetic studies point to the brain, in particular a region called the hypothalamus, as having a crucial role in modulating appetite. For example, mutations of single genes in the hypothalamic leptin melanocortin pathway leads to severe, early-onset obesity. Around 10% of severe human obesity currently has a clear identified cause, with the majority of mutations sitting within the genes encoding the melanocortin pathway. Thus, much of the genetic aetiology of severe obesity remains to be uncovered, identification of which could reveal novel pathways and potential therapeutic targets. However, studying the disease in inbred populations increases the chances of finding disease causing mutations. Using this approach, we have identified mutations in two new genes, ADCY3 and ROCK1, that are associated with severe obesity. In this proposal, we will study both these genes in detail. Given the role of the brain in the regulation of body-weight and food intake, we will characterize these genes in human neurons. We need to understand not only the function of these genes in normal cells but also the consequences of loss of function for the neuronal populations in which they are expressed. Although murine models have been hugely helpful in the past to overcome the difficulties of inaccessibility of the human hypothalamus, we believe studying human tissue from the relevant regions is essential to get a fuller understanding of the role of these genes. An existing collaboration with the Cambridge Brain Bank, allows us access to fresh and fixed human donor brain samples. The access to this precious material, coupled with recent developments in single cell sequencing and mapping technologies provides us with a timely opportunity to study where these genes are expressed in the human hypothalamus. Additionally, we have recently acquired the ability to generate, genetically manipulate and differentiate human stem-cells into hypothalamic neurons. This will allow us to directly examine the impact of these obesity associated mutations in the context of a relevant human cell. Using high-throughput DNA sequencing approaches, we will also continue our search for other new obesity candidates. Our current proposal is a collaborative venture between two UK centres of excellence in the study of the genetics of obesity. The group of Froguel, from Imperial College London, brings a large collection of severely obese children from highly consanguineous Pakistani pedigrees; and the group of Coll, O'Rahilly and Yeo, from the MRC Metabolic Diseases Unit at the University of Cambridge, who bring bespoke functional expertise and access to human hypothalamic samples. Our aim is to uncover novel appetite control pathways and reveal new potential therapeutic targets in order to tackle obesity.

肥胖是一个日益严重的公共卫生问题。虽然这无疑是由环境变化造成的，但人群中体重的变化有很大的遗传因素。遗传学研究表明，大脑，特别是下丘脑区域，在调节食欲方面发挥着至关重要的作用。例如，下丘脑瘦素黑皮质素通路中单个基因的突变会导致严重的早发性肥胖。目前，大约 10% 的人类严重肥胖症有明确的病因，其中大多数突变位于编码黑皮质素通路的基因内。因此，严重肥胖的许多遗传病因学仍有待揭示，对其进行鉴定可以揭示新的途径和潜在的治疗靶点。然而，在近交群体中研究这种疾病增加了发现引起疾病的突变的机会。利用这种方法，我们发现了与严重肥胖相关的两个新基因 ADCY3 和 ROCK1 的突变。在本提案中，我们将详细研究这两个基因。鉴于大脑在体重和食物摄入调节中的作用，我们将描述人类神经元中的这些基因。我们不仅需要了解这些基因在正常细胞中的功能，还需要了解它们表达的神经元群体功能丧失的后果。尽管小鼠模型在过去对于克服人类下丘脑难以接近的困难非常有帮助，但我们相信研究相关区域的人体组织对于更全面地了解这些基因的作用至关重要。与剑桥脑库的现有合作使我们能够获得新鲜且固定的人类捐赠者大脑样本。这种珍贵材料的获得，加上单细胞测序和绘图技术的最新发展，为我们提供了一个及时的机会来研究这些基因在人类下丘脑中的表达位置。此外，我们最近获得了生成、基因操纵人类干细胞并将其分化为下丘脑神经元的能力。这将使我们能够直接检查这些肥胖相关突变在相关人类细胞中的影响。利用高通量 DNA 测序方法，我们还将继续寻找其他新的肥胖候选者。我们目前的提案是两个英国肥胖遗传学研究卓越中心之间的合作项目。来自伦敦帝国理工学院的弗罗格尔团队带来了大量来自高度血缘关系的巴基斯坦血统的严重肥胖儿童；剑桥大学 MRC 代谢疾病部门的 Coll、O'Rahily 和 Yeo 团队带来了定制的功能专业知识并获得了人类下丘脑样本。我们的目标是发现新的食欲控制途径并揭示新的潜在治疗靶点以解决肥胖问题。

项目成果

Biallelic mutations in P4HTM cause syndromic obesity

P4HTM 双等位基因突变导致综合征性肥胖

• DOI: 10.2337/figshare.22577353.v1
• 发表时间: 2023
• 作者: Froguel P

A survey of the mouse hindbrain in the fed and fasted state using single-nucleus RNA sequencing

使用单核 RNA 测序对进食和禁食状态下的小鼠后脑进行调查

• DOI: 10.1101/2021.03.11.434948
• 发表时间: 2021
• 作者: Dowsett G

A program of successive gene expression in mouse one-cell embryos

• DOI: 10.1016/j.celrep.2023.112023
• 发表时间: 2023-01-31
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Asami, Maki;Lam, Brian Y. H.;Perry, Anthony C. F.
• 通讯作者: Perry, Anthony C. F.

The vagus nerve mediates the physiological but not pharmacological effects of PYY3-36 on food intake.

迷走神经介导 PYY3-36 对食物摄入的生理作用，但不介导药理作用。

• DOI: 10.1016/j.molmet.2024.101895
• 发表时间: 2024
• 期刊: Molecular metabolism
• 影响因子: 8.1
• 作者: Alonso AM

Human embryonic genome activation initiates at the one-cell stage.

• DOI: 10.1016/j.stem.2021.11.012
• 发表时间: 2022-02-03
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Asami M;Lam BYH;Ma MK;Rainbow K;Braun S;VerMilyea MD;Yeo GSH;Perry ACF
• 通讯作者: Perry ACF