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Genetic Factors  & Obesity

Genetic Factors

Most of the public, including doctors believe people are overweight because they eat too much, eat the wrong foods, and exercise too little. But there may be other reasons. Can people be genetically predisposed to weight gain? Can one’s metabolism affect weight gain? Can drugs or the environment change one’s metabolism and cause weight gain? The links presented here may contain some useful answers to these questions.

Obesity and Genetics

Obesity as a major public health problem

Obesity is an increasingly important health problem in the United States and also worldwide. The rates of obesity (defined as body mass index (BMI) > 30.0) have nearly doubled in the U.S. population from approximately 15 percent in 1980 to an estimated 27 percent in 1999 (1). Although our society has made great strides in reducing other threats to health such as smoking, we have been unable to stem the rising tide of obesity in the population. This trend is particularly disturbing because obesity is central to the development of many chronic diseases such as type 2 diabetes, heart disease, hypertension and cancer. Clearly, the increase in rates of obesity is a matter of major public health concern.

image of rich food, obese man, weighing in, heart attack victim, dna strand

Obesity as a complex metabolic condition

Obesity is characterized by an excessively high amount of body fat or adipose tissue. This condition is common, but the condition varies from individual to individual. At one end of the spectrum, a healthy weight can be attained by cutting down on certain foods, taking smaller portions, and embarking on a regimen of regular exercise. For individuals in this population, a moderate change in diet and exercise are the proper interventions because they work.

At the other end of the spectrum, there is another population of overweight people who do not respond as well to these interventions. Everyone knows someone who tries diligently to lose weight but who experiences limited success or loses weight only to gain it back over time. In fact, more than 80% of those who lose weight will gradually regain it unless a weight maintenance program is implemented over the long-term (2). What is different about these people compared to those who either stay thin or lose weight readily and keep it off with relatively minor lifestyle changes? One difference may be genetic risk factors that affect energy metabolism and result in an inborn susceptibility to gain weight.

Genetics as a risk factor for obesity

Obesity is a condition that results from an environment of caloric abundance and relative physical inactivity that is modulated by a susceptible genotype. Although rare obesity syndromes caused by mutations in single genes have been described, by far the greatest proportion of obesity in humans is not due to mutations in single genes. Genetic predisposition may not be health destiny, but studies indicate that inherited genetic variation is an important risk factor for obesity. Evidence from twin, adoption and family studies strongly suggests that biological relatives exhibit similarities in maintenance of body weight. Genetic factors also are beginning to be implicated in the degree of effectiveness of diet and physical activity interventions for weight reduction.

These genetic risk factors tend to be familial, but are not inherited in a simple manner; they may reflect many genetic variations, and each variation may contribute a small amount of risk and may interact with environmental elements to produce the clinical condition of obesity. An active area of research is determining associations between various obesity-related phenotypes with variations in candidate genes or through linkage studies with anonymous markers spread over the human genome. Learning how genetic variations affect susceptibility to become or remain obese will lead us to a greater understanding of how obesity occurs and, hopefully, how better to prevent and treat this condition.

You can’t change your genes, but you can change your behavior

Does this mean that those with a susceptible genotype are destined to a life of futile efforts to achieve a healthy weight? This need not be the case. We can’t change our genes, but we can change our behavior. Small victories in weight loss—often as little as 10% of total body mass--can result in positive effects on health and well-being, even if an ideal weight remains elusive. Also, the positive effects of regular physical activity include lower blood pressure and increased cardiorespiratory fitness' even in people who are significantly overweight. In the longer term, understanding the genetic variations that influence energy metabolism may help us to understand the underlying biological factors that affect weight gain and energy expenditure and develop interventions that capitalize on these insights. Finally, to recognize that obesity may be due to a metabolic condition rather than a flaw in character is important both for the people who are affected and for society as a whole.

The public health messages to prevent overweight emphasize a nutritious diet and daily physical activity. Many who follow this advice from the outset are able to maintain a healthy weight, even with a genetic susceptibility to gain weight. However, these lifestyle interventions have a range of uptake and effectiveness, especially if obesity is already present. For people who are already overweight, the public health interventions aimed at the general population are not a complete solution. Insights from genetics and molecular biology in controlling appetite and activity may provide more effective drug therapies for treatment of affected individuals. As we continue to emphasize the importance of diet and exercise as major factors that affect long-term health, public health needs to also seek new approaches—such as considering genetic factors in risk factor assessment and intervention design--to more thoroughly address this complex problem.

This page last modified on October 05, 2004



Obesity and Genetics:
What We Know, What We Don’t Know and What It Means

Introduction: Rising rates of obesity seem to be a consequence of modern life, with access to large amounts of palatable, high calorie food and limited need for physical activity. However, this environment of plenty affects different people in different ways. Some are able to maintain a reasonable balance between energy input and energy expenditure. Others have a chronic imbalance that favors energy input, which expresses itself as overweight and obesity. What accounts for these differences between individuals?

What We Know:

What We Don’t Know:

Biological relatives tend to resemble each other in many ways, including body weight. Individuals with a family history of obesity may be predisposed to gain weight and interventions that prevent obesity are especially important.

Why are biological relatives more similar in body weight? What genes are associated with this observation? Are the same genetic associations seen in every family? How do these genes affect energy metabolism and regulation?

In an environment made constant for food intake and physical activity, individuals respond differently. Some people store more energy as fat in an environment of excess; others lose less fat in an environment of scarcity. The different responses are largely due to genetic variation between individuals.

Why are interventions based on diet and exercise more effective for some people than others? What are the biological differences between these high and low responders? How do we use these insights to tailor interventions to specific needs?

Fat stores are regulated over long periods of time by complex systems that involve input and feedback from fatty tissues, the brain and endocrine glands like the pancreas and the thyroid. Overweight and obesity can result from only a very small positive energy input imbalance over a long period of time.

What elements of energy regulation feedback systems are different in individuals? How do these differences affect energy metabolism and regulation?

Rarely, people have mutations in single genes that result in severe obesity that starts in infancy. Studying these individuals is providing insight into the complex biological pathways that regulate the balance between energy input and energy expenditure.

Do additional obesity syndromes exist that are caused by mutations in single genes? If so, what are they? What are the natural history, management strategy and outcome for affected individuals?

Obese individuals have genetic similarities that may shed light on the biological differences that predispose to gain weight. This knowledge may be useful in preventing or treating obesity in predisposed people.

How do genetic variations that are shared by obese people affect gene expression and function? How do genetic variation and environmental factors interact to produce obesity? What are the biological features associated with the tendency to gain weight? What environmental factors are helpful in countering these tendencies?

Pharmaceutical companies are using genetic approaches (pharmacogenomics) to develop new drug strategies to treat obesity

Will pharmacologic approaches benefit most people affected with obesity? Will these drugs be accessible to most people?

The tendency to store energy in the form of fat is believed to result from thousands of years of evolution in an environment characterized by tenuous food supplies. In other words, those who could store energy in times of plenty, were more likely to survive periods of famine and to pass this tendency to their offspring.

How can thousands of years of evolutionary pressure be countered? Can specific factors in the modern environment (other than the obvious) be identified and controlled to more effectively counter these tendencies?

What It Means

For people who are genetically predisposed to gain weight, preventing obesity is the best course. Predisposed persons may require individualized interventions and greater support to be successful in maintaining a healthy weight.

Obesity is a chronic lifelong condition that is the result of an environment of caloric abundance and relative physical inactivity modulated by a susceptible genotype. For those who are predisposed, preventing weight gain is the best course of action.

Genes are not destiny. Obesity can be prevented or can be managed in many cases with a combination of diet, physical activity, and medication.

Drugs that will aid in losing weight or maintaining a healthy weight are being developed and are expected to be available in the next few years.

People who are affected with overweight and obesity are often victims of stigmatization and discrimination. It is time to stop blaming the victim. Many obesity researchers believe that people who struggle with their weight are pushing against thousands of years of evolution that has selected for storing energy as fat in times of plenty for use in times of scarcity. It is time to recognize their struggle, understand their challenges and support their need for lifelong efforts to achieve better healing.



Additional Resources:

Obesity Gene Pinpointed

Genetic Clues to Obesity

Genetic aspects of susceptibility to obesity and related dyslipidemias






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