Genomics and Health
Genes and obesity
What do genes have to do with obesity?Obesity is the result of chronic energy imbalance in a person who consistently takes in more calories from food and drink than are needed to power their body’s metabolic and physical functions. The rapidly rising population prevalence of obesity in recent decades has been attributed to an “obesogenic” environment, which offers ready access to high-calorie foods but limits opportunities for physical activity. The obesity epidemic can be considered a collective response to this environment. Obesity is an important public health problem because it increases the risk of developing diabetes, heart disease, stroke, and other serious diseases.
Even in an obesogenic environment, not everyone becomes obese. Before the genomic research era, studies of family members, twins, and adoptees offered indirect scientific evidence that a sizable portion of the variation in weight among adults is due to genetic factors. For example, a key study that compared the body mass index (BMI) of twins reared either together or apart found that inherited factors had more influence than childhood environment.
One gene or many?Rarely, obesity occurs in families according to a clear inheritance pattern caused by changes in a single gene. The most commonly implicated gene is MC4R, which encodes the melanocortin 4 receptor. Changes in MC4R that diminish its function are found in a small fraction (<5%) of obese people in various ethnic groups. Affected children feel extremely hungry and become obese because of consistent overeating (hyperphagia). So far, rare variants in at least nine genes have been implicated in single-gene (monogenic) obesity.
In most obese people, no single genetic cause can be identified. Since 2006, genome-wide association studies have found more than 50 genes associated with obesity, most with very small effects. Several of these genes also have variants that are associated with monogenic obesity, a phenomenon that has been observed in many other common conditions. Most obesity seems to be multifactorial, that is, the result of complex interactions among many genes and environmental factors.
How do genes control energy balance?The brain regulates food intake by responding to signals received from fat (adipose) tissue, the pancreas, and the digestive tract. These signals are transmitted by hormones—such as leptin, insulin, and ghrelin—and other small molecules. The brain coordinates these signals with other inputs and responds with instructions to the body: either to eat more and reduce energy use, or to do the opposite. Genes are the basis for the signals and responses that guide food intake, and small changes in these genes can affect their levels of activity. Some genes with variants that have been associated with obesity are listed in the Table.
Energy is crucial to survival. Human energy regulation is primed to protect against weight loss, rather than to control weight gain. The "thrifty genotype" hypothesis was proposed to help explain this observation. It suggests that the same genes that helped our ancestors survive occasional famines are now being challenged by environments in which food is plentiful year round.
How can this knowledge help public health?Public health efforts to prevent obesity focus on strategies that promote healthy eating and encourage physical activity. These strategies are employed at the community level, for example by increasing the availability of healthy food and beverage choices in schools and other public service settings. Such strategies are successful when many individual people respond with positive behavior changes.
A systematic review of information about more than 200,000 adults found that carriers of the common FTO gene variant most consistently associated with obesity were able to reduce their risk through physical activity. Knowing that one’s actions can make a difference is important.
Some new directionsEpigenetics. Environmental exposures during critical periods of human development can cause permanent changes in a gene’s activity without changing the sequence of the gene itself. Studying these “epigenetic” effects involves measuring chemical modifications of DNA, RNA, or associated proteins that influence gene expression. Although epigenetics might help explain how early exposures such as infant feeding influence adult obesity, epidemiologic studies using these techniques are still at an early stage.
Table: Selected genes with variants that have been associated with obesity
|Gene symbol||Gene name||Gene product’s role in energy balance|
|LEP||Leptin||Produced by fat cells|
|LEPR||Leptin receptor||When bound by leptin, inhibits appetite|
|INS||Insulin||Produced by pancreas|
|INSR||Insulin receptor||Induces uptake and storage of glucose|
|GHRL||Ghrelin||Produced by stomach|
|GHSR||Growth hormone secretagogue receptor||When bound by ghrelin, stimulates appetite|
|MC4R||Melanocortin 4 receptor||When bound by alpha-melanocyte stimulating hormone, stimulates appetite|
|FTO||Fat mass- and obesity-associated gene||Promotes food intake|
|PPARG||Peroxisome proliferator-activated receptor gamma||Stimulates lipid uptake and development of fat tissue|
|ADIPOQ||Adipocyte-, C1q-, and collagen domain-containing||Produced by fat cells, adiponectin promotes energy expenditure|
- Bell CG, Walley AJ, Froguel P. The genetics of human obesity. Nat Rev Genet. 2005 Mar;6(3):221-34.
- Choquet H, Meyre D. Genetics of Obesity: What have we Learned? Curr Genomics. 2011 May;12(3):169-79.
- Herrera BM, Keildson S, Lindgren CM. Genetics and epigenetics of obesity. Maturitas. 2011 May;69(1):41-9.
- Thompson AL. Developmental origins of obesity: Early feeding environments, infant growth, and the intestinal microbiome. Am J Hum Biol. 2012 May;24(3):350-60.
Centers for Disease Control and Prevention
- Obesity and Genetics, Office of Public Health Genomics, CDC
- Obesity and Genetics: What We Know, What We Don't Know and What It Means
- Overweight and Obesity, Centers for Disease Control and Prevention, CDC
- Family History Tools and Resources, Office of Public Health Genomics, CDC
Other health organizations
For more information on obesity and genomics for consumers, please see our Genomic Resources Guide.