Thursday, February 14, 2013

Obesity, exercise and epigenetics: no excuses

No excuses. It's the mantra of many a fitness boot camp and weight room. But what if your genes make you more likely to store fat on your body or less likely to lose weight when you exercise?

In the experience of Molly Bray, Ph.D., professor of epidemiology and genetics at UAB, the many obese people she has worked with do not see genetic barriers to weight loss as excuses. To the contrary, learning that their genes are making it harder to lose weight is empowering. New enthusiasm and harder workouts replace the frustration of doing everything your doctor tells you and getting nowhere.

Along with counseling people about genetic components of obesity risk, Bray leads a research effort to understand the mechanisms behind them. As she explained in her presentation at a recent UAB Epigenetics Symposium, some people have versions of genes that contribute to obesity. Risk may be influenced further by epigenetic chemical reactions that determine when genes that control energy use are turned on or off.

To recap for this third podcast in our epigenetics series, the human genetic system is composed of more than genes, the long stretches of DNA that encode instructions for the building of proteins. Proteins are the workhorse molecules that comprise the body's structures and carry its signals. We inherit genes and proteins from our parents largely unchanged, because changes often cause disease or death, even though they are necessary if we are to evolve.

While genes form the basic instructions for human life, they are not very good at changing quickly as our surroundings change. In fact, you and many like you may have to die (say during a plague) before the gene pool gets around to favoring those who happen to have the mutations (slow, random changes in genes) that make some better adapted to survive.

That may explain why we have epigenetic mechanisms: quick, reversible chemical reactions that turn genes on and off, often in response to environmental cues. Research has revealed that many genes are turned on and off epigenetically based on whether or not we eat good food, breathe clean air and exercise, and these changes have consequences for our risk of developing many diseases, including obesity.

Show notes for the podcast:

1:50 Epigenetic changes proceed very rapidly, some believe within 24 hours, said Bray.

2:23 The Human Genome Project, for all it has revealed about the DNA sequence of our genes, could not account for the variation in risk for many diseases going from person to person. Differences in the mechanisms that regulate genes may explain more about this disease risk variability than differences in genes themselves.

3:29 Methylation, the attachment of a methyl group (one carbon plus three hydrogens) to certain spots in the DNA chain, is recognized as a major epigenetic mechanism. It enables other proteins to assemble there in a way that silences or turns off the surrounding gene. Researchers once thought that such methylation marks were made in the womb and persisted throughout life, an idea which gave rise to theories about the fetal origins of adult disease. Then came the discovery of enzymes called demethylases, which remove methyl groups. The field now understands that methylation is an active process, with epigenetic changes occurring throughout life, some of them in response to our diet and excercise patterns.

4:18 One reason that epigenetic changes may be important for each person's obesity risk has to do with a gene called FTO (fat mass and obesity related transcript), said Bray.  Certain versions of this gene are more closely associated with obesity risk than any other gene, with the effect consistently shown in several studies across multiple populations and in people of all ages.

4:55 Researchers theorize that the protein built according to the instructions encoded in the FTO gene may act as a demethylase. Its not known why FTO continues to be associated with obesity, but it could be that an FTO demethylase is turning on or off genes that govern energy balance (e.g. how we burn calories in response to exercise).

5:40 Importantly, regular exercise largely erases the increased risk for obesity associated with the versions of the FTO gene. No one then is doomed by their genes, said Bray, because behavior can change them. A recent, small study showed that a single exercise session changes the methylation status of many genes.

7:24 Bray's lab is currently studying how people respond to exercise. Lack of response to an exercise program can be extremely frustrating, but the answer may be straightforward: work out harder.  Her data shows that clinicians can safely increase exercise intensity for many of these patients, and that current treatment guidelines in this regard may need to change.  People can tolerate harder workouts if that's what it takes, said Bray.

8:06 Genes may influence several aspects of a person's response to exercise, including the tough combination of making you need higher intensity workouts to get results and less able to tolerate them. Exercise for some may not "feel good."

8:22 Generally when people find out that a genetic or epigenetic variation may be affecting their response to exercise, they don't see it as an excuse. They benefit greatly from the insight, and realize they're not "just lazy," Bray said.

9:55 Obesity is associated with inflammation, the out-of-place triggering of the immune response.  Inflammation has been established as one link between obesity and several complex diseases, including cardiovascular disease, diabetes and cancer.  Excercise has been shown to counter inflammation. At the intersection of these processes, many of the methylation changes related to exercise and obesity are happening on genes that govern immune responses and inflammation.


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