Investigating the role of the FAIM2 locus in predisposition to childhood obesity

研究 FAIM2 位点在儿童肥胖易感性中的作用

• 批准号: 10770983
• 负责人: Sheridan Hope Littleton
• 金额: $ 3.52万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10770983
• 关键词: 3' Untranslated Regions; ATAC-seq; Address; Adipose tissue; Adult; Affect; Alleles; Apoptotic; Appetite Stimulants; Behavior Therapy; Body mass index; Brain-Derived Neurotrophic Factor; CRISPR/Cas technology; Cell model; Central Nervous System; Child; Childhood; Chromosome Mapping; Complex; Desire for food; Development; Disease; Eating; Energy Metabolism; Enzyme-Linked Immunosorbent Assay; Epidemic; Etiology; Exposure to; Food Energy; Food deprivation (experimental); Gene Expression; Gene set enrichment analysis; Genes; Genetic; Genetic Predisposition to Disease; Genomic Segment; Goals; Heritability; Heterozygote; Hormone secretion; Hypothalamic structure; Immunofluorescence Immunologic; In Vitro; Individual; Insulin; Integral Membrane Protein; International; Knock-out; Leadership; Leptin; Life Style; Maps; Meta-Analysis; Metabolic hormone; Methods; Modeling; Molecular; Morphology; Neurons; Neuropeptides; Nutritional status; Obesity; Pathogenesis; Peptides; Pharmacological Treatment; Phenotype; Population; Predisposition; Pro-Opiomelanocortin; Proteins; Publishing; Regulation; Regulatory Element; Research; Resolution; Risk; Rodent; Role; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Structure of nucleus infundibularis hypothalami; Testing; Tissues; United States; Untranslated RNA; Variant; Weight; Western Blotting; adult obesity; alpha-Melanocyte stimulating hormone; body system; brain tissue; cell type; comorbidity; energy balance; food restriction; genetic signature; genome wide association study; genome-wide; ghrelin; human stem cells; in vivo; increased appetite; mRNA Expression; mouse model; neural; neuropeptide Y; neurophysiology; novel; novel therapeutic intervention; obesity development; obesity in children; obesity treatment; pharmacologic; promoter; response; risk variant; transcriptome; transcriptome sequencing

ABSTRACT Childhood obesity is a complex, polygenic disease affecting over 13 million children in the United States and reaching epidemic proportions around the world. An individual’s lifestyle and genetic predisposition may cause an imbalance between food intake and energy expenditure, resulting in excess adipose tissue. Heritability estimates that range from 40-85% indicate a strong genetic component. Current behavioral and pharmacological treatments have only modest results, highlighting the importance of investigating the genetic etiology of childhood obesity for the development of new treatment strategies. Many of the top signals from genome-wide association studies (GWAS) of obesity reside near already well-established genes, such as MC4R and BDNF. Through my lab’s international leadership of GWAS of childhood obesity, it has become clear that the genetic signature of obesity in children is very similar to adults, although there is a significant exception. The FAIM2 locus is much more pronounced in the pediatric setting and thus has been largely overlooked to date. Our fine-mapping efforts at the FAIM2 locus have identified rs7132908 as the likely causal non-coding variant in this genomic region. rs7132908 resides in the 3’ untranslated region of FAIM2 and is in a region annotated as a candidate cis-regulatory element. Using a human stem cell-derived hypothalamic neuron model, we have observed a physical contact between the rs7132908 region and the FAIM2 promoter utilizing high-resolution genome-wide promoter-focused Capture-C, indeed implicating FAIM2 as the effector gene at this locus. This cell model is biologically relevant as neural populations of the hypothalamic arcuate nucleus have been implicated in childhood obesity by tissue enrichment analysis, gene set enrichment analysis and rodent studies. FAIM2 encodes the transmembrane protein ‘Fas apoptotic inhibitory molecule 2’ and its expression is largely restricted to neurons of the central nervous system. A transcriptome-wide association study identified a significant association between FAIM2 expression in brain tissue and childhood body mass index. Faim2 gene expression in the arcuate nucleus responds to nutritional status, increasing after restricted food intake or food deprivation. This suggests that FAIM2 may function downstream of metabolic hormones. The goal of my project is to characterize the cis-regulatory activity of rs7132908 and the function of FAIM2 in hypothalamic arcuate nucleus neurons as they relate to the pathogenesis of obesity. I hypothesize that FAIM2 expression is regulated by rs7132908 and that FAIM2 functions in the neuronal response to metabolic hormones. In my first aim, I will characterize the effect of the rs7132908 risk allele on FAIM2 expression in vitro and in vivo. In my second aim, I will investigate the consequences of FAIM2 dysregulation in arcuate nucleus neurons responding to metabolic hormones. Taken together, these findings will provide a first step toward understanding how the FAIM2 locus contributes to childhood obesity predisposition and may identify novel pharmacological targets to answer the demands for more robust childhood obesity treatment.

抽象的 儿童肥胖是一种复杂的多基因疾病，影响了美国超过1300万儿童 并在世界范围内达到流行比例。一个人的生活方式和遗传倾向可能 导致食物摄入和能量消耗之间的不平衡，导致过量的脂肪组织。 遗传力估计，范围为40-85％，表示强大的遗传成分。当前的行为和 药理学治疗只有适中的结果，强调了研究通用的重要性 儿童期为制定新治疗策略的病因。来自 肥胖的全基因组关联研究（GWAS）靠近已经建立的基因附近，例如 MC4R和BDNF。通过我实验室的国际童年对象的国际领导，它已经成为 很明显，儿童肥胖的遗传特征与成年人非常相似，尽管有重要的 例外。 Faim2基因座在儿科环境中更为明显，因此在很大程度上是 迄今为止被忽略。我们在FAIM2基因座进行的精细映射工作已将RS7132908确定为可能的催化 该基因组区域中的非编码变体。 RS7132908居住在Faim2的3’未翻译区域中，位于 区域注释为候选顺式调节元件。使用人类干细胞衍生的下丘脑神经元 模型，我们观察到使用RS7132908区域与FAIM2启动子之间的物理接触 高分辨率全基因组以启动子为重点的捕获C，确实将FAIM2作为效应子基因 这个基因座。该细胞模型在生物学上与下丘脑弓形核的神经种群相关 通过组织富集分析，基因集富集分析和 啮齿动物研究。 FAIM2编码跨膜蛋白“ FAS凋亡抑制分子2”及其 表达在很大程度上仅限于中枢神经系统的神经元。整个转录组的关联 研究确定了FAIM2在脑组织中的表达与儿童体重之间存在显着关联 指数。 Faim2基因在弧形对营养状况的反应中的表达，在受限之后增加 食物摄入或剥夺食物。这表明FAIM2可能在代谢骑马的下游起作用。 我项目的目的是表征RS7132908的顺式调节活动和FAIM2的功能 下丘脑弓形神经元与肥胖的发病机理有关。我假设Faim2 表达受RS7132908的调节，FAIM2在对代谢的神经元反应中起作用 激素。在我的第一个目标中，我将表征RS7132908的影响等位基因对FAIM2表达的影响 和体内。在我的第二个目标中，我将研究弧形核中FAIM2失调的后果 对代谢激素反应的神经元。综上所述，这些发现将为迈向 了解FAIM2基因座如何有助于儿童肥胖症，并可能识别出新颖的 药理学目标是回答对更健壮的儿童肥胖治疗的需求。