Genetic factors of overweight and obesity
How do genes affect obesity?
SUMMARY: Science shows that genetics plays a role in obesity. Genes can directly cause obesity in disorders such as Bardet-Biedl syndrome and Prader-Willi syndrome. However genes do not always predict future health. Genes and behavior may both be needed for a person to be overweight. In some cases multiple genes may increase one�s susceptibility for obesity and require outside factors; such as abundant food supply or little physical activity.
Obesity is a complex disease resulting from the interactions of a wide variety of hereditary and environmental factors. The combined progress in quantitative genetics, genomics and bioinformatics has contributed to a better understanding of the genetic and molecular basis of obesity.
Clustering of cases within a family, the congruence of body weight for monozygotic twins, and the discovery of genes associated with obesity are all arguments reinforcing the genetic dimension of obesity
It is now well established that overweight and the different forms of obesity are conditions tending to concentrate within a family. Obesity risk is two to eight times higher for a person with a family history as opposed to a person with no family history of obesity, and an even higher risk is observed in cases of severe obesity. Heritability of obesity may vary depending on the phenotype studied, however it tends to be higher for phenotypes linked to adipose tissue distribution (40-55%) and for weight or body fat excess (5-40%). Weight gain and adiposity increase with age, an effect also influenced by heredity.
Occurrences of monogenic types of obesity are evidence that obesity may be caused by genetic mutations, however, as yet, only 78 cases worldwide have been attributed to mutations of seven distinct genes. The most common forms of obesity are probably the result of variations within a large number of genes. Sequence variations within a pool of 56 different genes have been reported as being related to obesity phenotypes, however, only ten of those genes showed positive results in at least five different studies.
Beside these rare cases, many individuals have a genetic predisposition that may lead to obesity. Researchers have found many obesity susceptibility genes and the combination of an obesogenic environment and a genetic predisposition will almost inescapably result in the development of obesity. However, it is possible to be obese without having a genetic predisposition.
In brief, current knowledge brings to the conclusion that genetic factors may be involved in the etiology of obesity and, exclusive of very rare severe obesity cases, the genes involved are probably genes that interact with environment factors related to energy intake and expenditure to increase the risk of obesity.
Identification of those genes will help clarify the etiology of obesity and its metabolic consequences, the metabolic complications of obesity, as well as identify at-risk individuals or groups in terms of their genetic profile with the goal of developing personalized prevention and treatment strategies.
For more information on the genetics and obesity visit Obesity and Genetics: A Public Health Perspective.
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 directions
Epigenetics. 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.
|Gene symbol||Gene name||Gene product’s role in energy balance|
|ADIPOQ||Adipocyte-, C1q-, and collagen domain-containing||Produced by fat cells, adiponectin promotes energy expenditure|
|FTO||Fat mass- and obesity-associated gene||Promotes food intake|
|LEP||Leptin||Produced by fat cells|
|LEPR||Leptin receptor||When bound by leptin, inhibits appetite|
|INSIG2||Insulin-induced gene 2||Regulation of cholesterol and fatty acid synthesis|
|MC4R||Melanocortin 4 receptor||When bound by alpha-melanocyte stimulating hormone, stimulates appetite|
|PCSK1||Proprotein convertase subtilisin/kexin type 1||Regulates insulin biosynthesis|
|PPARG||Peroxisome proliferator-activated receptor gamma||Stimulates lipid uptake and development of fat tissue|
For additional information about genes that have been studied for association with obesity, visit the HuGE Navigator.
Centers for Disease Control and Prevention
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For more information on obesity and genomics for consumers, please see our Genomic Resources Guide.