Introduction: The Genetics of Obesity

Genes influence every aspect of human physiology, development, and adaptation. Obesity is no exception. Yet little is known to date regarding the specific genes that contribute to obesity and the scale of gene–environment interactions.

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 rare, single-gene forms of obesity. However, scientists are still in the dark about the genetic underpinning of common obesity, which is influenced by dozens, if not hundreds, of genes. This article briefly outlines the contributions of genes and gene–environment interactions to the development of obesity.

Obesity Caused by Mutations in a Single Gene (Monogenic Obesity)

Several rare forms of obesity result from spontaneous mutations in single genes, so-called monogenic mutations. Such mutations, which display a Mendelian pattern of inheritance, have been discovered in genes coding for leptin (LEP), the leptin receptor (LEPR), pro-opiomelanocortin (POMC), and the melanocortin-4 receptor (MCR4), among others. (1) These genes play essential roles in appetite control, food intake, and energy homeostasis.

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)

Common Obesity (Multigenic Obesity)

In the 21st century, obesity is an equal opportunity health problem affecting rich and poor, educated and uneducated, Westernized and non-Westernized societies. Long before obesity became an epidemic, however, body fat levels varied from person to person, 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 so-called “common obesity” is thought to be controlled by several genes (multigenic).

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 twins, 0.32 for dizygotic 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 between monozygotic twins and its attenuation with lesser degrees of shared genes suggest a strong genetic influence on BMI.

Genome-Wide Association Studies

A genome-wide association (GWA) 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 variations, called single-nucleotide polymorphisms (SNPs), are often related to disease risk.

dnaequip (dna-equip.jpg)

In 2007, researchers using GWA studies identified the first obesity-related SNPs in the fat mass and obesity-associated (FTO) gene on chromosome 16. (4, 5) Fasting and feeding both regulate expression of this gene in the hypothalamus. The second obesity-associated SNP that researchers identified lies on chromosome 18, close to the MC4R gene (the same gene responsible for a rare form of monogenic obesity). (6) This polymorphism has also been associated with height and increased food intake. (6, 7)

To date, GWA studies have identified more than 25 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)

Gene-Environment Interactions

In a population, the frequency of different genes remains constant for many generations, and it takes a long time for a new mutation, or polymorphism, to spread through the population. Thus, genetic changes are unlikely to explain the rapid spread of obesity around the globe. Data from migration studies, studies of populations that have undergone Westernization in the absence of migration, and long-term cohort studies suggest that population-wide increases in obesity can occur in the absence of changes in gene frequencies. (1) The rapid spread of obesity in the United States (12) and around the globe (13) suggests that environmental changes over the past 40 years have played a key role in triggering the recent surge of overweight and obesity. (14)

thriftygene (thriftygene.jpg)

One intriguing explanation for why humans might be genetically susceptible to obesity was proposed by James Neel in his "thrifty gene" hypothesis. (15)

It postulates that the human species evolved under the continual threat of famine, and natural selection thus favored genes for the highly efficient use of insulin. This allowed for the parsimonious use of glucose during times of little food, and efficient storage of extra calories as fat during periods when food was more abundant.

Unfortunately, so-called thrifty genes remain activated even in an environment with constantly plentiful food, leading to obesity, while insulin efficiency becomes insulin resistance, leading to type 2 diabetes.

So far, this remains little more than a hypothesis, as GWA and other studies have not yielded evidence to support it. (16)

As is the case for the search for obesity-related genes, work on obesity-related gene–environment interactions is still in its infancy. Progress is unlikely to be linear and forward, as illustrated by early research on interactions between FTO gene polymorphisms and physical activity.

In 2008, Andreasen and colleagues demonstrated that low physical activity accentuated the effect of an FTO SNP on body fat accumulation in 17,508 Danes. (17) Although this finding is in line with the widespread epidemiologic association between low physical activity and high BMI, subsequent work has yielded contradictory results.

In a study of 704 healthy Old Order Amish individuals, Rampersaud and colleagues identified 26 FTO SNPs associated with BMI. In stratified analyses of two FTO SNPs, their associations with BMI were restricted to subjects with low physical activity scores. (18) In the ongoing Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study, meanwhile, Ruiz and colleagues demonstrated that the effect of an FTO SNP on body fat parameters was much lower in adolescents who met the daily physical activity recommendations than in those who did not. (19) Yet a similar study in Swedish and Finnish adults found no interaction between physical activity and this FTO SNP on BMI. (20)

Most humans probably have some genetic predisposition to obesity, depending on their family history and ethnicity. But triggering the expression of an obesity-related phenotype generally requires some change in diet, lifestyle, or other environmental factors. Candidates for such change include the following:

Read more about the influence of thefood environment on obesity.

Implications for the Future

A better understanding of the genetic contributions to obesity—especially common obesity—and gene–environment interactions should lead to important advances in treating and preventing this widespread and problematic condition. Early applications include the following:

To date, however, the benefits from this genetic work remain largely theoretical, and will almost certainly stay that way until personalized, gene-based medicine becomes part of clinical practice. (Visit the U.S. Dept. of Health and Human Services website for more information on the promise of personalized health careOpens in New Window.)

In a broader sense, identifying obesity-related genes and gene–environment interactions will generate a better understanding of the pathophysiology of obesity and the causal pathways that lead to obesity. Such information could someday yield promising strategies for preventing and treating obesity.

References

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 RevOpens in New Window. 2006; 27:710–18.

3. Maes HH, Neale MC, Eaves LJ. Genetic and environmental factors in relative body weight and human adiposity. Behav GenetOpens in New Window. 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 GenetOpens in New Window. 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. ScienceOpens in New Window. 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 GenetOpens in New Window. 2008; 17:3502–8.

8. O'Rahilly S. Human genetics illuminates the paths to metabolic disease. NatureOpens in New Window. 2009; 462:307–14.

9. Speliotes EK, Willer, C.J., Berndt, S.I., et al. Association analyses of 249,796 individuals reveal eighteen new loci associated with body mass index. Nat Genet. In press.

10. Heid IM, Jackson A.U., Randall J.C. Meta-analysis identifies 13 novel loci associated with waist–hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet. In press.

11. Walley AJ, Asher JE, Froguel P. The genetic contribution to non-syndromic human obesity. Nat Rev GenetOpens in New Window. 2009; 10:431–42.

12. Sherry B, Blanck HM, Galuska DA, Pan L, Dietz WH. Vital Signs: State-Specific Obesity Prevalence Among Adults, United States, 2009. Morbidity and Mortality Weekly ReportOpens in New Window. 2010; 59:1–5.

13. Popkin BM. Recent dynamics suggest selected countries catching up to US obesity. Am J Clin NutrOpens in New Window. 2009; 91:284S-288S.

14. Qi L, Cho YA. Gene–environment interaction and obesity. Nutr RevOpens in New Window. 2008; 66:684–94.

15. Neel JV. Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"? Am J Hum GenetOpens in New Window. 1962; 14:353–62.

16. Southam L, Soranzo N, Montgomery SB, et al. Is the thrifty genotype hypothesis supported by evidence based on confirmed type 2 diabetes- and obesity-susceptibility variants? DiabetologiaOpens in New Window. 2009; 52:1846–51.

17. Andreasen CH, Stender-Petersen KL, Mogensen MS, et al. Low physical activity accentuates the effect of the FTO rs9939609 polymorphism on body fat accumulation. DiabetesOpens in New Window. 2008; 57:95–101.

18. 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 MedOpens in New Window. 2008; 168:1791–7.

19. 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 MedOpens in New Window. 2010; 164:328–33.

20. 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.DiabetologiaOpens in New Window. 2009; 52:1334–8.

21. Kelesidis T, Kelesidis I, Chou S, Mantzoros CS. Narrative review: the role of leptin in human physiology: emerging clinical applications. Ann Intern MedOpens in New Window. 2010; 152:93–100.

What are you waiting for? Trim down and slip into your favorite clothes you thought you’d never wear again.

Back to Home Page: www.mediplex.in

Back to Weight Loss Section: http://www.mediplex.in/wt/index_wt.html

Back to SLIMPLEX MEDICINE: http://www.mediplex.in/slimplex/faq.html#diet
Back to Height Increase Section for Kids: http://www.mediplex.in/ht/index_ht.html

 

 

Back
Related to : Weight Loss, Fat Loss, Fast Weight Loss, Weight Loss diets, Inch Loss, fastest way to lose weight, best way to lose weight healthy, healthy way to lose weight quickly, lose weight, best way to lose weight quickly and safely, simple way to lose weight fast,good diet to lose weight fast, safe weight loss pills,

http://mediplex.in/wt/index_weightloss.html

 

Related to : Weight Loss, Fat Loss, Fast Weight Loss, Weight Loss diets, Inch Loss, fastest way to lose weight, best way to lose weight healthy, healthy way to lose weight quickly, lose weight, best way to lose weight quickly and safely,simple way to lose weight fast,good diet to lose weight fast, safe weight loss pills,

http://mediplex.in/wt/index_weightloss.html

 

Related to : Weight Loss, Fat Loss, Fast Weight Loss, Weight Loss diets, Inch Loss, fastest way to lose weight, best way to lose weight healthy, healthy way to lose weight quickly, lose weight, best way to lose weight quickly and safely,simple way to lose weight fast,good diet to lose weight fast, safe weight loss pills,

http://mediplex.in/wt/index_weightloss.html

 

Related to : Weight Loss, Fat Loss, Fast Weight Loss, Weight Loss diets, Inch Loss, fastest way to lose weight, best way to lose weight healthy, healthy way to lose weight quickly, lose weight, best way to lose weight quickly and safely,simple way to lose weight fast,good diet to lose weight fast, safe weight loss pills,

http://mediplex.in/wt/index_weightloss.html

 

Related to : Weight Loss, Fat Loss, Fast Weight Loss, Weight Loss diets, Inch Loss, fastest way to lose weight, best way to lose weight healthy, healthy way to lose weight quickly, lose weight, best way to lose weight quickly and safely,simple way to lose weight fast,good diet to lose weight fast, safe weight loss pills,

http://mediplex.in/wt/index_weightloss.html

 

Related to : Weight Loss, Fat Loss, Fast Weight Loss, Weight Loss diets, Inch Loss, fastest way to lose weight, best way to lose weight healthy, healthy way to lose weight quickly, lose weight, best way to lose weight quickly and safely,simple way to lose weight fast,good diet to lose weight fast, safe weight loss pills,

http://mediplex.in/wt/index_weightloss.html

 

Related to : Weight Loss, Fat Loss, Fast Weight Loss, Weight Loss diets, Inch Loss, fastest way to lose weight, best way to lose weight healthy, healthy way to lose weight quickly, lose weight, best way to lose weight quickly and safely,simple way to lose weight fast,good diet to lose weight fast, safe weight loss pills,

http://mediplex.in/wt/index_weightloss.html

 

Related to : Weight Loss, Fat Loss, Fast Weight Loss, Weight Loss diets, Inch Loss, fastest way to lose weight, best way to lose weight healthy, healthy way to lose weight quickly, lose weight, best way to lose weight quickly and safely,simple way to lose weight fast,good diet to lose weight fast, safe weight loss pills,

http://mediplex.in/wt/index_weightloss.html

 

Related to : Weight Loss, Fat Loss, Fast Weight Loss, Weight Loss diets, Inch Loss, fastest way to lose weight, best way to lose weight healthy, healthy way to lose weight quickly, lose weight, best way to lose weight quickly and safely,simple way to lose weight fast,good diet to lose weight fast, safe weight loss pills,

http://mediplex.in/wt/index_weightloss.html

 

Related to : Weight Loss, Fat Loss, Fast Weight Loss, Weight Loss diets, Inch Loss, fastest way to lose weight, best way to lose weight healthy, healthy way to lose weight quickly, lose weight, best way to lose weight quickly and safely,simple way to lose weight fast,good diet to lose weight fast, safe weight loss pills,

http://mediplex.in/wt/index_weightloss.html

 

Related to : Weight Loss, Fat Loss, Fast Weight Loss, Weight Loss diets, Inch Loss, fastest way to lose weight, best way to lose weight healthy, healthy way to lose weight quickly, lose weight, best way to lose weight quickly and safely,simple way to lose weight fast,good diet to lose weight fast, safe weight loss pills,

http://mediplex.in/wt/index_weightloss.html

 

Related to : Weight Loss, Fat Loss, Fast Weight Loss, Weight Loss diets, Inch Loss, fastest way to lose weight, best way to lose weight healthy, healthy way to lose weight quickly, lose weight, best way to lose weight quickly and safely,simple way to lose weight fast,good diet to lose weight fast, safe weight loss pills,

http://mediplex.in/wt/index_weightloss.html

 

Related to : Weight Loss, Fat Loss, Fast Weight Loss, Weight Loss diets, Inch Loss, fastest way to lose weight, best way to lose weight healthy, healthy way to lose weight quickly, lose weight, best way to lose weight quickly and safely,simple way to lose weight fast,good diet to lose weight fast, safe weight loss pills,

http://mediplex.in/wt/index_weightloss.html

 

Related to : Weight Loss, Fat Loss, Fast Weight Loss, Weight Loss diets, Inch Loss, fastest way to lose weight, best way to lose weight healthy, healthy way to lose weight quickly, lose weight, best way to lose weight quickly and safely,simple way to lose weight fast,good diet to lose weight fast, safe weight loss pills,

http://mediplex.in/wt/index_weightloss.html

 

Related to : Weight Loss, Fat Loss, Fast Weight Loss, Weight Loss diets, Inch Loss, fastest way to lose weight, best way to lose weight healthy, healthy way to lose weight quickly, lose weight, best way to lose weight quickly and safely,simple way to lose weight fast,good diet to lose weight fast, safe weight loss pills,

http://mediplex.in/wt/index_weightloss.html

 

Related to : Weight Loss, Fat Loss, Fast Weight Loss, Weight Loss diets, Inch Loss, fastest way to lose weight, best way to lose weight healthy, healthy way to lose weight quickly, lose weight, best way to lose weight quickly and safely,simple way to lose weight fast,good diet to lose weight fast, safe weight loss pills,

http://mediplex.in/wt/index_weightloss.html

 

Related to : Weight Loss, Fat Loss, Fast Weight Loss, Weight Loss diets, Inch Loss, fastest way to lose weight, best way to lose weight healthy, healthy way to lose weight quickly, lose weight, best way to lose weight quickly and safely,simple way to lose weight fast,good diet to lose weight fast, safe weight loss pills,

http://mediplex.in/wt/index_weightloss.html

 

Related to : Weight Loss, Fat Loss, Fast Weight Loss, Weight Loss diets, Inch Loss, fastest way to lose weight, best way to lose weight healthy, healthy way to lose weight quickly, lose weight, best way to lose weight quickly and safely,simple way to lose weight fast,good diet to lose weight fast, safe weight loss pills,

http://mediplex.in/wt/index_weightloss.html

 

Related to : Weight Loss, Fat Loss, Fast Weight Loss, Weight Loss diets, Inch Loss, fastest way to lose weight, best way to lose weight healthy, healthy way to lose weight quickly, lose weight, best way to lose weight quickly and safely,simple way to lose weight fast,good diet to lose weight fast, safe weight loss pills,

http://mediplex.in/wt/index_weightloss.html

 

Related to : Weight Loss, Fat Loss, Fast Weight Loss, Weight Loss diets, Inch Loss, fastest way to lose weight, best way to lose weight healthy, healthy way to lose weight quickly, lose weight, best way to lose weight quickly and safely,simple way to lose weight fast,good diet to lose weight fast, safe weight loss pills,

http://mediplex.in/wt/index_weightloss.html

 

Related to : Weight Loss, Fat Loss, Fast Weight Loss, Weight Loss diets, Inch Loss, fastest way to lose weight, best way to lose weight healthy, healthy way to lose weight quickly, lose weight, best way to lose weight quickly and safely,simple way to lose weight fast,good diet to lose weight fast, safe weight loss pills,

http://mediplex.in/wt/index_weightloss.html

 

Related to : Weight Loss, Fat Loss, Fast Weight Loss, Weight Loss diets, Inch Loss, fastest way to lose weight, best way to lose weight healthy, healthy way to lose weight quickly, lose weight, best way to lose weight quickly and safely,simple way to lose weight fast,good diet to lose weight fast, safe weight loss pills,

http://mediplex.in/wt/index_weightloss.html

 

Related to : Weight Loss, Fat Loss, Fast Weight Loss, Weight Loss diets, Inch Loss, fastest way to lose weight, best way to lose weight healthy, healthy way to lose weight quickly, lose weight, best way to lose weight quickly and safely,simple way to lose weight fast,good diet to lose weight fast, safe weight loss pills,

http://mediplex.in/wt/index_weightloss.html