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

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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.