Epigenetic Mechanisms of Human Hypothalamic Body Weight Regulation

人类下丘脑体重调节的表观遗传机制

• 批准号: 263507924
• 负责人: Professor Dr. Peter Kühnen
• 金额: --
• 依托单位: Institut für Experimentelle Pädiatrische Endokrinologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/263507924?language=en
• 关键词: Epigenetic; Mechanisms; Human; Hypothalamic; Body

Obesity is one of the major health care problems worldwide in industrial as well as in in low and middle-income countries (LMICS) being responsible for approximately 2 millions death per year. Although twin studies point towards a genetic background up to 70%, monogenic forms of obesity are rare and results of large genome-wide association studies including genome-wide analysis explain less than 25 % of intra-individual body weight variability. One potential explanation for this observation, which has been termed “missing heritability” might be related to epigenetic modifications. We have focused our attention on the DNA methylation of the pro-opiomelanocortin (POMC) gene, which plays a pivotal role in the leptin-melanocortin signaling cascade, one of the main pathways regulating satiety and energy expenditure within the hypothalamus. The results of the first funding period have underlined the role for a POMC DNA hypermethylation as an individual risk factor for the development of obesity. There are evidences that the analyzed POMC region fulfills the criteria for a metastable epiallele, being set during early embryonic development and being influenced by a paternal influence and changes in C1 metabolite status of the mother during conception. Due to POMC methylation differences between rodent and human samples, no appropriate animal model is available at the moment and for this reason our conclusions are based on several reproducible observation in different cohorts. To gain further insights into the mechanism we have started to establish during the first funding period a naïve-pluripotent stem cell based model, in which we will now be able to analyze the functional consequences of POMC hypermethylation in-vitro (work package 1). Additionally we want to broaden our view and analyze a few million CpG sites in laser-microdissected human, postmortem MSH and NPY neurons separately of obese and non-obese individuals, using a post-bisulfite adapter tagging (PBAT) technique (work-package 2). Thereby we will be able to identify intra-and inter-individual differentially methylated regions, which might play a role in epigenetic body weight regulation. Both work packages are designed to achieve the major goal of this grant application and to gain further insights how differences within the individual epigenetic signature are affecting body weight regulation and modifying the individual risk to become obese during lifetime.

肥胖是全球工业以及低收入和中等收入国家 (LMICS) 的主要医疗保健问题之一，每年导致约 200 万人死亡。尽管双胞胎研究指出高达 70% 的遗传背景，但单基因形式的肥胖很少见，并且包括全基因组分析在内的大型全基因组关联研究的结果解释了不到 25% 的个体内体重变异。这一观察结果的一个潜在解释被称为“遗传性缺失”，可能与表观遗传修饰有关。我们将注意力集中在阿片黑皮质素原 (POMC) 基因的 DNA 甲基化上，该基因在瘦素-黑皮质素信号级联中发挥着关键作用，而瘦素-黑皮质素信号级联是调节下丘脑饱腹感和能量消耗的主要途径之一。第一个资助期的结果强调了 POMC DNA 高甲基化作为肥胖发展的个体危险因素的作用。有证据表明，分析的 POMC 区域满足亚稳态表观等位基因的标准，该区域在早期胚胎发育过程中设定，并受到父亲影响和受孕期间母亲 C1 代谢状态变化的影响。由于啮齿动物和人类样本之间的 POMC 甲基化差异，目前没有合适的动物模型，因此我们的结论是基于不同队列中的几个可重复的观察。为了进一步了解该机制，我们在第一个资助期间开始建立一个基于幼稚多能干细胞的模型，我们现在能够在其中分析 POMC 超甲基化的体外功能后果（工作包 1）。此外，我们希望拓宽我们的视野，并使用亚硫酸氢盐后接头标记 (PBAT) 技术（工作包 2），分别分析肥胖和非肥胖个体的激光显微解剖人体、死后 MSH 和 NPY 神经元中的数百万个 CpG 位点。因此，我们将能够识别个体内和个体间差异甲基化区域，这可能在表观遗传体重调节中发挥作用。这两个工作包旨在实现本拨款申请的主要目标，并进一步了解个体表观遗传特征的差异如何影响体重调节并改变个体一生中肥胖的风险。