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）中的破坏性影响越来越大。肥胖干预措施通常昂贵且无效;因此，预防是关键。预计LMICs将成为肥胖和T2糖尿病（T2 D）预计增加的最严重打击。由于中低收入国家的卫生保健资源不足，肥胖和T2 D的病死率远高于富裕国家，并构成了现在和未来卫生预算的主要负担。BMI（身体质量指数）具有高度遗传性（家族遗传），尽管遗传变异在个体体重变异中所占比例很小。表观遗传机制（例如DNA甲基化）可以解释大部分缺失的遗传性。可变甲基化区域（VMR）是基因组中显示个体之间甲基化的实质性变化的区域;这种变化可能通过改变基因表达而导致个体之间的特征（例如体重）的变化。肥胖是一种过度消费的疾病。一个复杂的激素通路网络调节食欲和饱腹感，POMC（前阿黑皮素）激素介导大脑中的饱腹感反应。它是能量平衡和肥胖风险的关键调节器。在POMC内含子2/外显子3边界处的甲基化区域（VMR）的DNA甲基化增加与儿童和成人的BMI相关。POMC甲基化影响POMC基因表达量，从而提供了POMC甲基化与肥胖之间的联系。先前已经表明，POMC甲基化在早期胚胎中建立，并受到冈比亚人受孕时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，而与母亲的甲基化无关。（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减轻，2）后代POMC甲基化受母亲在受孕时的营养影响，3）后代POMC甲基化与父亲的外周血细胞甲基化相关，但与母亲的外周血细胞甲基化无关。我们将利用我们完善的冈比亚季节性“自然实验”，即降雨的季节性变化（雨季和旱季）在食物的供应和组成、成人的工作模式以及儿童的传染病和生长模式方面产生了深刻的对比。这导致个人的体重和身体成分在一年中随季节变化，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。该项目将在一年内每月随访500对母亲和儿童，以检查他们的体重，BMI和身体成分与研究开始时的POMC甲基化的关系。100对母子对的子集也将进行DXA（双能X线吸收测定法）扫描和自由进食早餐（参与者可以自由地吃尽可能多的早餐，作为饱腹感的衡量标准）（在旺季;了解POMC的表观遗传调控以及这如何影响体重和肥胖易感性，可以为育龄妇女设计营养干预措施，减少其后代的肥胖风险。重要的是要评估在POMC VMR的甲基化对BMI在不同的设置之前，考虑在这个LMIC未来的干预措施。如果发现这些表观遗传标记在营养上是可改变的，并且进一步影响婴儿和儿童的体重调节，这将为旨在优化人类胎儿发育和终身健康结果的定向干预开辟新的篇章。

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.