Do genetics and environmental effects lead to obesity?
In populations sharing the same environment there are both obese and normal weight individuals. This might suggest that some individuals are more susceptible to weight gain than others. This difference could be the result of the individual genetic profile.
In 1997, the Leptin (LPT) gene was the first gene associated with a Mendelian nonsyndromic form of obesity. Since 2007, genome wide scans have been successful in identifying more than 100 loci associated with the common polygenic form of obesity.
The obesity associated single nucleotide polymorphisms, SNPs, that have been identified to date explain less than 3% of the inherited susceptibility to develop an obese phenotype. Studies suggest genetics could play a role in body mass index (BMI) up to 47-80%. This suggests that additional genetic loci or other generic variance remain to be discovered.
Genetic Influences on Obesity
BMI is highly correlated with parental obesity. Children who both parents are obese, have higher risk of being obese when compared with children from non-obese parents. A meta-analysis of 31 twin studies showed that for adults, the BMI variation explained by genetic difference range from 47% to 80%. More recently, a study analyzing 87,782 twin pairs from 45 cohorts also concludes the important role of genetic factors in the variation of BMI. The studies demonstrated that BMIs of adopted children correlate strongly with biological parents, and less with adoptive parents. What is more common than the single nucleotide mutations is polygenic obesity. Due to the human genome project, several studies emerged identifying more than 100 BMI associated weight when comparing a sample composed by normal weight and obese individuals.
Environmental Influences on Obesity
The global rise of obesity may be due to environmental factors such as high food consumption, highly sweetened beverages, less activity, television watching, etc. Several studies found associations between obesity and time spent watching television in both adults and children. From an evolutionary perspective, humans were more active and had limitations on food intake. One study found that low socioeconomic position (SEP) is associated with a 10% higher risk for overweight and 41% risk of obesity. Parental education level is also highly associated with childhood obesity. Higher educational achievement may facilitate better understanding and utilization of available nutritional information. Modern food environments are filled with nutrient poor and energy dense foods. These foods are highly palatable and processed in ways that make it difficult for the body to regulate intake in weight.
Gene Lifestyle Interactions in Obesity
It is hypothesized that interaction effects between genes and environmental factors may account for some of this missing genetic effects. For example, respiratory disorders (e.g. obstructive sleep apnea) or sleep disturbance (e.g. sleep duration, insomnia, or excessive daytime sleepiness) have been identified influencing obesity.
Gene Physical Activity Interactions
Moderate to vigorous physical activity attenuates the effect of fat mass in obesity associated genes (FTO). In other words, increasing physical activity changes the expression of genes to make one less susceptible to obesity. A meta-analysis showed that the effect of FTORS9939609 on BMI, waist circumference, body fat percentage, and obesity risk is approximately 30% lower in physically active than in sedentary adults.
The role for FTO in the regulation of food intake was evidenced by several works which showed the association with increased appetite, energy, dietary fat or protein intake, and reduce satiety. Several other studies have shown that in FTO gene polymorphisms that a high fat diet further accentuated the obesity risk. A high protein diet was found to facilitate weight loss and improvement of body composition whereas the opposite was seen on a low protein diet. A case control study found that high carbohydrate consumption increase risk of obesity in other genotypes. A diet low in fiber appeared to have a BMI increasing effect in another genotype. One other genetic association showed higher rates of adiposity among participants with higher intake of sugar sweetened or higher consumption of fried food. In summary, different FTO Gene polymorphisms respond to different diets.
Other Players Contributing to Obesity Susceptibility
Epigenetics refers to a set of mechanisms regulating gene expression without alteration of the DNA sequence, and involves DNA methylation, histone modifications, and other roles in gene expression. DNA methylation consist of the introduction of methyl groups at the carbon-5 position. Through epigenonic studies it was possible to identify methylation profiles in different genes associated with obesity. Some ways methylation occurs is through foods, alcohols, pollution, etc. This likely even occurs during pregnancy. Our diet compositions changed drastically from the times humans were hunter gatherers. The industrialized food brought new molecules that may influence the transcription of genes.
There is emerging evidence to suggest that diet alters gut microbiota, and this is reflected by differences observed between obese and lean individuals. Furthermore, other studies pointed to the importance of gut microbiota in modulating energy intake.
My Conclusions
Data appears to show that 47 to 80% of obesity is related to genetics. Through the human genome project and other studies we have only found approximately 5% through single nucleotide polymorphisms. This suggest that there are either other genetic factors that we are missing or that there are other contributing factors to gene expression. Epigenetics and other gene expression mechanisms are a common hypothesis at this time. Things such as the diet‘s impact on gene expression, physical activity’s impact on gene expression, environmental factors on gene expression, behavioral impacts on gene expression (sleep disturbances, stress, etc.), and socioeconomic impacts on gene expression could all play a role. It is important for us to understand that it is not simply just an imbalance between energy intake and expenditure. An individualized approach needs to occur to treat the disease of obesity.
Seth Jarrell, MD