Inter-generational risk factors for obesity: a path to prevention in LMICs based on a modifiable epigenetic signature in the POMC gene

肥胖是一个重大的全球公共卫生问题，在包括冈比亚在内的低收入和中等收入国家(LMIC)具有日益严重的破坏性影响。肥胖干预通常是昂贵和无效的；因此，预防是关键。预计LMIC将受到肥胖症和T2糖尿病(T2D)预计增加的最大打击。由于LMIC的卫生保健资源匮乏，肥胖症和T2D的病死率比富裕国家高得多，构成了现在和未来卫生预算的主要负担。BMI(身体质量指数)具有高度的遗传性(在家庭中运行)，尽管遗传变异在个人体重变异中所占比例很小。表观遗传机制(如DNA甲基化)可能解释了许多缺失的遗传性。可变甲基化区域(VMR)是基因组中的区域，显示出个体之间甲基化的巨大差异；这种变异可能通过改变基因表达而导致个体之间的特征(例如体重)的差异。肥胖是一种过度消费的疾病。一个复杂的荷尔蒙通路网络调节食欲和饱腹感，POMC(阿片黑素皮质素原)荷尔蒙调节大脑的饱腹感反应。它是能量平衡和肥胖风险的关键调节器。在儿童和成人中，POMC内含子2/外显子3边界的可变甲基化区域(VMR)的DNA甲基化增加与BMI相关。POMC甲基化影响POMC基因的表达，从而在POMC甲基化和肥胖之间提供联系。以前已经表明，POMC甲基化是在早期胚胎中建立的，并在冈比亚人受孕时受到季节性营养变化的影响。研究还表明，儿童POMC VMR的甲基化与父亲的甲基化有关，而不是与母亲的甲基化有关。因此，假设1)POMC的超甲基化(通过抑制饱腹感)将促进收获季节更快的体重增加，并防止饥饿季节的体重下降，2)后代的POMC甲基化受到母亲受孕前后营养的影响，3)后代的POMC甲基化与父亲的相关，而不是母亲的外周血细胞甲基化。我们将利用我们久负盛名的冈比亚季节性“自然实验”，即降雨的季节性变化(雨季和旱季)在食物的可获得性和构成、成年人的工作模式以及儿童的传染病和生长模式方面造成了深刻的反差。这导致个人体重和身体成分在一年中出现季节性变化，例如，冈比亚妇女的平均体重在6月至10月期间波动近4公斤。该项目将在一年多的时间里每月跟踪500对母子，检查他们的体重、BMI和身体成分与他们在研究开始时的POMC甲基化的关系。100对母子组合还将在一年中的三个时间点(季节的高峰期，4月至10月至4月)进行DXA(双能X射线吸收法)扫描和一顿丰盛的早餐(参与者可以自由地吃下她们想吃的早餐，以衡量饱腹感)。了解POMC的表观遗传调控及其对体重和肥胖易感性的影响，可以为育龄妇女设计营养干预措施，降低她们后代的肥胖风险。在考虑未来对LMIC的干预之前，评估POMC VMR甲基化对不同环境下BMI的影响是很重要的。如果发现这些表观遗传标记在营养上是可改变的，并进一步影响婴儿和儿童的体重调节，这将开启旨在优化人类胎儿发育和终身健康结果的定向干预的新篇章。

Obesity is a major global public health issue with increasing damaging effects in low and middle-income countries (LMIC) including The Gambia. Obesity interventions are generally expensive and ineffective; therefore, prevention is key. LMICs are predicted to be the hardest hit by the projected increases in obesity and T2 diabetes (T2D). Due to poorly resourced health care in LMICs the case-fatality rates for obesity and T2D are much higher than in affluent nations and constitute a major burden for health budgets now and more so in the future.BMI (body mass index) is highly heritable (runs in families), though genetic variants account for a small proportion of individual body weight variability. Epigenetic mechanisms (e.g. DNA methylation) may explain much of the missing heritability. Variably Methylated Regions (VMR) are regions in the genome that show substantial variation between individuals in their methylation; this variation may contribute to variations in characteristics (e.g. body weight) between individuals by altering gene expression.Obesity is a disorder of over consumption. A complex network of hormonal pathways regulates appetite and satiety, with POMC (pro-opiomelanocortin) hormone that mediates satiety responses in the brain. It is a key regulator of energy balance and obesity risk. Increased DNA methylation at a variably methylated region (VMR) at the POMC intron2/exon3 boundary is correlated with BMI in children and adults. POMC methylation influences the amount of POMC gene expression, thus provides a link between POMC methylation and obesity. It has been shown previously that POMC methylation is established in the early embryo and is influenced by seasonal nutritional changes at conception in Gambians. It has also been shown that children's methylation at POMC VMR is associated with the father's methylation not the mother's.It is therefore hypothesised that 1) POMC hypermethylation (by dampening satiety) will promote more rapid weight gain in the harvest season and protect against weight loss in the hungry season, 2) offspring POMC methylation is influenced by the mother's nutrition around time of conception and 3) offspring POMC methylation is correlated with father's, but not mother's, peripheral blood cell methylation. We will exploit our well-established Gambian seasonal 'experiment of nature', whereby seasonal changes in rainfall (wet and dry seasons) creates profound contrasts in the availability and composition of food, in work patterns among adults, and in infectious disease and growth patterns in children. This leads to seasonally driven variations in individual's weight and body composition over the year e.g. in Gambian women on average weight fluctuates by nearly 4 kg between June and October. The project will follow up 500 mother and child pairs monthly over a year to examine their weight, BMI and body composition in relation to their POMC methylation taken at the start of the study. A subset of 100 mother and child pairs will also have DXA (Dual energy X-ray Absorptiometry) scans and an ab libitum breakfast (participants are freely permitted to consume as much breakfast as they wish as a measure of satiety) at three time points (at peaks of seasons; April-October-April) over the year.Understanding epigenetic regulation of POMC and how this influences body weight and susceptibility to obesity, could enable the design of nutritional interventions for women of child-bearing age that would mitigate obesity risk in their offspring. It is important to assess the effect of methylation at POMC VMR on BMI in diverse settings before considering future interventions in this LMIC. If it is found that these epigenetic marks are nutritionally modifiable and further that they influence weight regulation in infants and children, this would open a new chapter in directed interventions designed to optimise human foetal development and life-long health outcomes.