Skinny Genes: Are Some People Born to Be Thin?

Jealous of that friend who stays slim without breaking a sweat while you toil away on the elliptical just to balance out a single cookie?The difference in your bodies may lie in your genes, but having the so-called “skinny gene” may not be as desirable as it sounds.

The skinny on the science:
Genes are sections of DNA that instruct proteins, cells and other molecules to perform all the vital tasks in your body, from forming your organs to carrying oxygen through your blood to helping you digest that cookie. All people have essentially the same sets of genes. In fact, you share up to 99.9 percent of your genetic makeup with pretty much everyone else on the planet. But, our small genetic variations influence the differences in our hair color, our susceptibility to certain diseases, and the ease with which we lose or gain weight.

Variations in genes linked to body mass index (BMI) can make a person prone to extreme thinness or obesity. In the past four years, researchers have identified at least 52 genes that relate to body weight regulation. One recent study, from the Medical Research Council’s Epidemiology Unit in Cambridge, U.K., found that a variation of one of them, a gene called IRS1, is linked to a low percentage of body fat.

For that study, the researchers analyzed the DNA of over 75,000 people in the study, and are working on more studies that up their sample size to 300,000. They expect the new studies will reveal even more BMI-related genes.But while having “skinny genes” would seem desirable to many people who struggle with their weight, it may not be as great as it sounds because thin doesn’t always mean healthy. People with the IRS1 variation may have lower body fat, but the researchers found that they still had high blood sugar and cholesterol levels.  When the researchers dug further, they found that while the IRS1 variants had lower levels of subcutaneous fat, which lies directly under the skin, they also had a higher rate of so-called visceral fat, which is packed around the organs. People with the “lean” variation of IRS1, particularly men, thus have higher risk of diseases that are usually associated with being overweight, including type 2 diabetes and heart disease.

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“It’s sort of unexpected. Normally you’d expect that genes that lower your fat percentage would also lower your risk for these diseases because being lean still is typically healthy. But this gene clearly showed an opposite pattern,” says Dr. Ruth Loos, a former group leader in MRC’s Epidemiology Unit and senior author of the study. (Loos is now a researcher at Mount Sinai School of Medicine in New York.)“We can only speculate about mechanisms, but maybe this gene causes a fat storage problem—the fat isn’t sufficiently stored subcutaneously and it looks for other ways to be stored,” adds Dr. Loos.

Extreme thinness:
More recently, researchers from University Hospital in Lausanne and Imperial College London, in collaboration with a wide network of scientists and clinicians, looked at the DNA of over 95,000 people and found a 28-gene region that also relates to BMI: an extra copy of the region indicated extreme thinness, while a deletion of the region increased the risk of morbid obesity (typically, there are two copies of all genes—one from the mother and one from the father—but genetic mutations sometimes delete a gene or make too many copies of it).

One in 2,000 of the test subjects in the general population had a duplicate copy of the gene, putting them at risk of being severely underweight. Of these, men with the duplication were 23 times more likely than their normal counterparts to be underweight. Women fared a little better, at five times more likely to be underweight.The same region of 28 genes is associated with brain disorders such as autism, which may be linked to a deletion of the region, and schizophrenia, which may be linked to duplications.

As of now, it is unclear which gene or genes out of the 28 relate directly to BMI (it’s also premature to guess whether the same genes that affect BMI are linked to the psychiatric disorders, or if they just happen to reside in the same region of DNA). Dr. Jacques Beckmann, a geneticist at the University Hospital in Lausanne, Switzerland and one of the authors of the study, is working with his team to narrow it down, both to see which genes are responsible for the extreme thinness and obesity, and whether or not they are linked to these other disorders.They are also working to understand the mechanisms that are causing the increased or decreased weight:“We are trying to research to see how this affects the patients, their attitudes towards food and what kind of food, but beyond that we don’t know,” says Beckmann. “And that is one of the reasons we would like to know what gene is responsible because then we could perhaps take this gene in a given pathway and know how it is participating.”

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The road to body weight treatments?
It’s too early to know if or when the research will have a direct impact on public health—far more research has to be done in order to fully understand the underlying mechanisms that work to make people with these genetic variations so thin (and, alternatively, how those with other variations become obese).  But, the researchers have some ideas of what might be going on.Explains Dr. Loos: “We currently know very little about the ‘physiology’ of those newly identified genes for BMI. Preliminary evidence suggests that at least some of them might influence body weight through a function in the brain, such as sensations of hunger and appetite, feelings of reward. But, these are very preliminary results and it will likely take many years before we will have greater insight.”

Eventually, understanding these mechanisms could lead to treatments for extreme thinness or obesity, and prenatal genetic screening may help doctors combat weight issues early on. “Hopefully a therapy will come, but this could take many more years,” adds Dr. Beckmann, “But the better we understand the disease process, the better we will be able one day to help people.”

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