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Genetic Studies Yield New Insights into Obesity

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Silhouettes of peopleToday, we hear a great deal about which foods to eat and which to avoid to maintain a healthy body. Though we know that one of the strongest contributors to body weight is heredity, there has been less specific information available about the genetics underlying obesity. But research in this area is progressing at a phenomenal pace, and new genomic discoveries are helping to bring into better focus how our bodies store fat and how the complex interplay of genetics, diet, behavior, and other factors determine whether we can readily maintain a healthy body weight, or whether it takes a lot of work to do so.

Two papers in Nature provide lots of fresh clues into the genetic factors involved in predisposing to obesity. Researchers in the international Genetic Investigation of ANthropometric Traits (GIANT) Consortium, more than 500 strong and  including some of the members of my own NIH research lab (including me), examined the genomes of more than half a million people to look for genes and regions of chromosomes that play a role in body fat distribution and obesity. They turned up over 140 genetic locations that, like low-intensity voices in a choir of many, contribute to these traits. Further analyses of the specific genes located in these regions suggest the possibility that the programming behind how fat cells form may influence their distribution, a discovery that could lead to exploitable findings down the road.

In the first study, the researchers focused on genes that influence the waist-to-hip ratio, a standard measure of fat distribution in the body [1]. People whose waistlines are larger than their hip circumference have more belly fat around their abdominal organs, placing them at more risk for cardiovascular disease and diabetes than those whose extra pounds are deposited on their hips and thighs. To identify genetic factors that play a role in this ratio, GIANT researchers co-led by Karen Mohlke, a geneticist at the University of North Carolina in Chapel Hill (whom, I am proud to say, trained with me as a postdoctoral fellow at NIH 15 years ago), examined the genomes of more than 224,000 individuals. The researchers discovered more than 49 locations throughout the genome that are linked to this trait. Of these, 33 were previously undiscovered.

Genes in or near the 49 locations identified in this study were linked to fat cell development, blood vessel formation, skeletal growth, glucose control, and insulin resistance. Many of these associated sites showed a larger effect in women than men, which suggests that fat distribution differs by gender, perhaps helping to explain why men and women gain weight in different ways.

The second paper focused on body mass index (BMI), a common measurement derived from a formula that combines height and weight to gauge overall body fat [2]. Previous studies suggest that about 50 percent of BMI is genetic. Elizabeth Speliotes, a geneticist-physician at the University of Michigan in Ann Arbor, and her army of colleagues examined the genomes of more than 339,000 individuals and discovered 97 sites in the genome that influence obesity, of which 56 were new discoveries. The greater the number of these BMI-boosting sites a person carries, the greater their BMI will tend to be—but this is not destiny. Genetic risk factors are not predetermining, they are predisposing.

Some genes in or near the 97 locations play a role in appetite regulation and feeding behavior. That’s to be expected. Others are involved in processes we know less about, such as energy expenditure and physical activity. But the big surprise is that most of the pathways uncovered by this genetic approach to obesity seem to act in the brain and peripheral nerves. They are linked to the development of neurons and basic functions like signaling. How variations in such genes contribute to obesity remains to be understood. We knew, of course, that the brain is critical in determining appetite, but the prominence of the nervous system genes in predisposing to obesity was unexpected.

Among the new discoveries are many that provide fresh targets for new weight loss treatments, as well as insights into known ones. For example, a glutamate receptor identified in this study may help identify unknown glutamate pathways that affect body weight and reveal why an anti-seizure drug (Topiramate), which affects glutamate levels, also causes weight loss.

Some genetic changes that promote obesity also elevate risk of high cholesterol, cardiovascular disease, and diabetes—but not equally so. Two people with the same BMI may have different underlying causes of obesity and in turn different risks of developing metabolic diseases. In the future, our genetic information may be used to define obesity subtypes, which could then be matched to a specific treatment.

We still have a long way to go to understand the genetics of obesity. Despite this extensive list of genetic factors uncovered here, these account for just an estimated 2.7 percent of the variation for BMI. What we’re finding is that complex traits like obesity probably involve hundreds of low-volume genetic risk factors, each with a small effect that remains difficult to detect with our current techniques. What’s more, just as musical notes can be combined in myriad ways, these low-intensity genes will be expressed in different combinations in different people. But we’re pushing the research needle in the right direction. We know that a normal-sized person who has 104 BMI-increasing genetic markers will on average be 20-plus pounds heavier than someone of a similar build who has less than 78 BMI-increasing genetic markers. These types of findings provide optimism that better times are ahead to provide new approaches to prevent or control obesity.

References:

Genetic Studies of Body Mass Index Yield New Insights for Obesity Biology. Locke AE, Speliotes EK, et al. Nature 2015 Feb 12;518(7538):197-206.

New Genetic Loci Link Adipose and Insulin Biology to Body Fat Distribution. Shungin D, Mohlke KL, et al. Nature 2015 Feb 12;518(7538):187-196.

Links:

Calculate Your Body Mass Index (National Heart, Lung, and Blood Institute/NIH)

Overweight and Obesity Statistics (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

Speliotes Laboratory (University of Michigan, Ann Arbor)

Mohlke Laboratory (University of North Carolina at Chapel Hill)

NIH support: National Institute of Diabetes and Digestive and Kidney Diseases; National Human Genome Research Institute; National Cancer Institute; National Heart, Lung, and Blood Institute; National Institute of Mental Health; National Institute on Aging; National Institute of Allergy and Infectious Diseases; The Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Neurological Disorders and Stroke; National Institute of General Medical Sciences, National Institute on Drug Abuse; National Institute of Environmental Health Sciences; National Center for Research Resources; National Center for Advancing Translational Sciences; National Institute of Arthritis and Musculoskelatal and Skin Diseases; National Eye Institute; Fogarty International Center; and NIH Common Fund

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