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，影响着美国超过 1300 万儿童 个人的生活方式和遗传倾向可能会在世界范围内达到流行的程度。 导致食物摄入和能量消耗之间不平衡，导致脂肪组织过多。 遗传力估计范围为 40-85%，表明当前的行为和行为具有很强的遗传成分。 药物治疗效果有限，凸显了研究遗传因素的重要性 儿童肥胖的病因学为制定新的治疗策略提供了许多重要信号。 肥胖的全基因组关联研究（GWAS）位于已经确定的基因附近，例如 MC4R 和 BDNF 通过我的实验室在儿童肥胖 GWAS 方面的国际领导地位，它已成为 显然，儿童肥胖的遗传特征虽然与成人非常相似，但存在显着的差异 FAIM2 基因座在儿科环境中更为明显，因此在很大程度上受到了影响。 迄今为止，我们对 FAIM2 基因座的精细定位工作已确定 rs7132908 可能是因果关系。 该基因组区域中的非编码变体位于 FAIM2 的 3' 非翻译区中。 使用人类干细胞来源的下丘脑神经元注释为候选顺式调节元件的区域。 模型中，我们观察到 rs7132908 区域和 FAIM2 启动子之间存在物理接触，利用 高分辨率全基因组启动子聚焦的 Capture-C，确实暗示 FAIM2 作为效应基因 该细胞模型与下丘脑弓状核的神经群具有生物学相关性。 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 表达主要限于中枢神经系统的神经元。 研究发现脑组织中 FAIM2 的表达与儿童体重之间存在显着关联 弓状核中的 Faim2 基因表达对营养状况做出反应，在限制后增加。 这表明 FAIM2 可能在代谢激素的下游发挥作用。 我的项目的目标是表征 rs7132908 的顺式调节活性和 FAIM2 在 下丘脑弓形核神经元与肥胖的发病机制有关，我对 FAIM2 感到困惑。 表达受 rs7132908 调节，并且 FAIM2 在神经元对代谢的反应中发挥作用 在我的第一个目标中，我将描述 rs7132908 风险等位基因对 FAIM2 体外表达的影响。 在我的第二个目标中，我将研究弓状核中 FAIM2 失调的后果。 总而言之，这些发现将为我们迈出第一步。 了解 FAIM2 基因座如何导致儿童肥胖倾向，并可能识别新的 药理学目标，以满足更强有力的儿童肥胖治疗的需求。