Obesity-Promoting Genes in an Obesity-Promoting World
Genes influence every aspect of human physiology, development, and adaptation. Obesity is no exception. Yet relatively little is known regarding the specific genes that contribute to obesity and the scale of so-called “genetic environment interactions” the complex interplay between our genetic makeup and our life experiences.
A 2014 study found that consumption of fried food could interact with genes related to obesity, underscoring the importance of reducing fried food consumption in individuals genetically predisposed to obesity. (21)The search for human obesity genes began several decades ago. Rapid advances in molecular biology and the success of the Human Genome Project have intensified the search. This work has illuminated several genetic factors that are responsible for very rare, single-gene forms of obesity. Emerging research has also begun to identify the genetic underpinnings of so-called “common” obesity, which is influenced by dozens, if not hundreds, of genes. In addition, research into the relationship between certain foods and obesity is shedding more light on the interaction between diet, genes, and obesity.
What’s increasingly clear from these early findings is that genetic factors identified so far make only a small contribution to obesity risk—and that our genes are not our destiny: Many people who carry these so-called “obesity genes” do not become overweight, and healthy lifestyles can counteract these genetic effects. This article briefly outlines the contributions of genes and gene–environment interactions to the development of obesity.
Several rare forms of obesity result from spontaneous mutations in single genes, so-called monogenic mutations. Such mutations have been discovered in genes that play essential roles in appetite control, food intake, and energy homeostasis—primarily, in genes that code for the hormone leptin, the leptin receptor, pro-opiomelanocortin, and the melanocortin-4 receptor, among others. (1)
Obesity is also a hallmark of several genetic syndromes caused by mutation or chromosomal abnormalities, such as Prader–Willi and Bardet–Biedl syndromes. In these syndromes, obesity is often accompanied by mental retardation, reproductive anomalies, or other problems. (2)
In the 21st century, obesity is a health problem affecting rich and poor, educated and uneducated, Westernized and non-Westernized societies. Body fat level varies from person to person, however, and some people have always tended to carry a bit more body fat than others. Evidence from animal models, human linkage studies, twin studies, and association studies of large populations suggests that this variation in our susceptibility to obesity has a genetic component. But rather than being controlled by a single gene, susceptibility to common obesity is thought to be affected by many genes (polygenic).
Twin studies offer some insight into the genetics of common obesity. Based on data from more than 25,000 twin pairs and 50,000 biological and adoptive family members, the estimates for mean correlations for body mass index (BMI) are 0.74 for monozygotic (“identical”) twins, 0.32 for dizygotic (“fraternal”) twins, 0.25 for siblings, 0.19 for parent–offspring pairs, 0.06 for adoptive relatives, and 0.12 for spouses. (3) The strong correlation for BMI between monozygotic twins and its attenuation with lesser degrees of shared genes suggest a strong genetic influence on BMI. However, this conclusion is based on the assumption that identical and fraternal twins have the same degree of shared environment—and it’s an assumption that may not hold in practice.
A genome-wide association study scans hundreds of thousands of genetic markers across thousands of individuals’ complete sets of DNA to find gene variations that may be related to a particular disease. These studies can be used to find gene variations that play a role in common, complex diseases such as obesity. Often, a change in just one small section of the DNA that encodes for a gene can make a difference in the gene’s action. These tiny DNA variations, called “gene variants” or “single-nucleotide polymorphisms” (SNPs), are often related to disease risk.
In 2007, researchers using genome-wide association studies identified the first obesity-related gene variants in the so-called “fat mass and obesity-associated” (FTO) gene on chromosome 16. (4, 5) These gene variants are fairly common, and people who carry one have a 20 to 30 percent higher risk of obesity than people who do not. The second obesity-associated gene variant that researchers identified lies on chromosome 18, close to the melanocortin-4 receptor gene (the same gene responsible for a rare form of monogenic obesity). (6, 7)
To date, genome-wide association studies have identified more than 30 candidate genes on 12 chromosomes that are associated with body mass index. (8–10) It’s important to keep in mind that even the most promising of these candidate genes, FTO, accounts for only a small fraction of the gene-related susceptibility to obesity. (11)
Genetic changes are unlikely to explain the rapid spread of obesity around the globe. (1) That’s because the “gene pool”—the frequency of different genes across a population—remains fairly stable for many generations. It takes a long time for new mutations or polymorphisms to spread. So if our genes have stayed largely the same, what has changed over the past 40 years of rising obesity rates? Our environment: the physical, social, political, and economic surroundings that influence how much we eat and how active we are. Environmental changes that make it easier for people to overeat, and harder for people to get enough physical activity, have played a key role in triggering the recent surge of overweight and obesity. (12)
Work on obesity-related gene–environment interactions is still in its infancy. The evidence so far suggests that genetic predisposition is not destiny—many people who carry so-called “obesity genes” do not become overweight. Rather, it seems that eating a healthy diet and getting enough exercise may counteract some of the gene-related obesity risk.
In 2008, for example, Andreasen and colleagues demonstrated that physical activity offsets the effects of one obesity-promoting gene, a common variant of FTO. The study, conducted in 17,058 Danes, found that people who carried the obesity-promoting gene, and who were inactive, had higher BMIs than people without the gene variant who were inactive. Having a genetic predisposition to obesity did not seem to matter, however, for people who were active: Their BMIs were no higher or lower than those of people who did not have the obesity gene. (15)
Subsequent work on the relationship between the FTO gene, physical activity, and obesity yielded contradictory results. (16–18) To arrive at a more definitive answer, investigators recently combined and re-analyzed the data from 45 studies in adults and 9 studies in children—nearly 240,000 people in all. (19) They found that people who carried the obesity-promoting FTO gene variant had a 23 percent higher risk of obesity than those who did not. But once again, being physically active lowered the risk: Active adults who carried the obesity-promoting gene had a 30 percent lower risk of obesity than inactive adults who carried the gene.
Most people probably have some genetic predisposition to obesity, depending on their family history and ethnicity. Moving from genetic predisposition to obesity itself generally requires some change in diet, lifestyle, or other environmental factors. Some of those changes include the following:
- the ready availability of food at all hours of the day and in places that once did not sell food, such as gas stations, pharmacies, and office supply stores;
- a dramatic decrease in physical activity during work, domestic activities, and leisure time, especially among children;
- increased time spent watching television, using computers, and performing other sedentary activities; and
- the influx of highly processed foods, fast food, and sugar-sweetened beverages, along with the ubiquitous marketing campaigns that promote them.
Having a better understanding of the genetic contributions to obesity—especially common obesity—and gene–environment interactions will generate a better understanding of the causal pathways that lead to obesity. Such information could someday yield promising strategies for obesity prevention and treatment. But it’s important to remember that overall, the contribution of genes to obesity risk is small, while the contribution of our toxic food and activity environment is huge. As one scientist wrote, “Genes may co-determine who becomes obese, but our environment determines how many become obese.” (20) That’s why obesity prevention efforts must focus on changing our environment to make healthy choices easier choices, for all.
1. Hu F. Genetic predictors of obesity. In: Hu F, ed. Obesity Epidemiology. New York City: Oxford University Press, 2008; 437–460.
2. Farooqi S, O’Rahilly S. Genetics of obesity in humans. Endocr Rev. 2006; 27:710–18.
3. Maes HH, Neale MC, Eaves LJ. Genetic and environmental factors in relative body weight and human adiposity. Behav Genet. 1997; 27:325–51.
4. Dina C, Meyre D, Gallina S, et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet. 2007; 39:724–6.
5. Frayling TM, Timpson NJ, Weedon MN, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007; 316:889–94.
6. Loos RJ, Lindgren CM, Li S, et al. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet. 2008; 40:768–75.
7. Qi L, Kraft P, Hunter DJ, Hu FB. The common obesity variant near MC4R gene is associated with higher intakes of total energy and dietary fat, weight change and diabetes risk in women. Hum Mol Genet. 2008; 17:3502–8.
8. O’Rahilly S. Human genetics illuminates the paths to metabolic disease. Nature. 2009; 462:307–14.
9. Speliotes EK, Willer CJ, Berndt SI, et al. Association analyses of 249,796 individuals reveal eighteen new loci associated with body mass index. Nat Genet. 2010; 42:937-48.
10. Heid IM, Jackson AU, Randall JC. Meta-analysis identifies 13 novel loci associated with waist–hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet. 2010; 42:949-60.
11. Walley AJ, Asher JE, Froguel P. The genetic contribution to non-syndromic human obesity. Nat Rev Genet. 2009; 10:431–42.
12. Qi L, Cho YA. Gene–environment interaction and obesity. Nutr Rev. 2008; 66:684–94.
15. Andreasen CH, Stender-Petersen KL, Mogensen MS, et al. Low physical activity accentuates the effect of the FTO rs9939609 polymorphism on body fat accumulation. Diabetes. 2008; 57:95–101.
16. Rampersaud E, Mitchell BD, Pollin TI, et al. Physical activity and the association of common FTO gene variants with body mass index and obesity. Arch Intern Med. 2008; 168:1791–7.
17. Ruiz JR, Labayen I, Ortega FB, et al. Attenuation of the effect of the FTO rs9939609 polymorphism on total and central body fat by physical activity in adolescents: the HELENA study. Arch Pediatr Adolesc Med. 2010; 164:328–33.
18. Jonsson A, Renstrom F, Lyssenko V, et al. Assessing the effect of interaction between an FTO variant (rs9939609) and physical activity on obesity in 15,925 Swedish and 2,511 Finnish adults. Diabetologia. 2009; 52:1334–8.
19. Kilpeläinen TO, Qi L, Brage S, et al.Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children. PLoS Med. 2011;8:e1001116. Epub 2011 Nov 1.
20. Veerman JL. On the futility of screening for genes that make you fat. PLoS Med. 2011 Nov;8(11):e1001114. Epub 2011 Nov 1.
21. Qi, Q, Chu, AY, Kang, JH, Huang, J, Rose, LM, Jensen, MK, Liang, L, Curhan, GC, Pasquale, LR, Wiggs, JL, De Vivo, I, Chan, AT, Choi, HK, Tamimi, RM, Ridker, PM, Hunter, DJ, Willett, WC, Rimm, EB, Chasman, DI, Hu, FB, Qi, L. (2014). Fried food consumption, genetic risk, and body mass index: gene-diet interaction analysis in three US cohort studies. BMJ 19;348:g1610.
22. Asai M Ramachandrappa S Joachim M Shen Y Zhang R Nuthalapati N Ramanathan V Strochlic, DE Ferket P Linhart K, Ho C Novoselova, TV Garg S Ridderstr
The aim of the Harvard School of Public Health Obesity Prevention Source Web site is to provide timely information about obesity’s global causes, consequences, prevention, and control, for the public, health and public health practitioners, business and community leaders, and policymakers. The contents of this Web site are not intended to offer personal medical advice. You should seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this Web site. The Web site’s obesity prevention policy recommendations are based primarily on a review of U.S. expert guidance, unless otherwise indicated; in other countries, different policy approaches may be needed to achieve improvements in food and physical activity environments, so that healthy choices are easy choices, for all.