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Skinny genes: How DNA shapes weight-loss success Add to ...

Stephen Scherer is a nice guy: smart, funny, very easy to like - unless you're eating lunch with him.

He can put away a cream soup and a platter of penne with Italian sausage and wash it all down with a large Coke. And even though he's 47, and driving his son to hockey is the closest he comes to rigorous daily exercise, he's still as trim as a teenager. Which is why, if you're the type to pay by the pound for any extra indulgence, you might be tempted at some point during the meal to stab him with your fork.

But you can't blame him. Dr. Scherer simply has skinny genes.

A leading geneticist at the Hospital for Sick Children in Toronto, he recently analyzed his own DNA and discovered that he inherited a rare genetic quirk from his mother that seems to give him a speedy metabolism, allowing him, he suspects, "to eat like a pig and never gain weight."

"I've been the same weight for about 20 years. It never fluctuates more than a few pounds," he says. "I think I probably would exercise more if I knew I needed to."

Most of us haven't been as lucky in the DNA draw. Almost two-thirds of Canadians have tried losing weight during the past five years, but most fail to keep it off, according to a survey released this month by the Heart and Stroke Foundation. Yet a growing body of research has found that much of our success in losing weight, whether it's resisting the urge to overeat or exercising, is shaped by our genes. Studies suggest that genetics account for 60 to 84 per cent of a person's body mass index. The most compelling results come from work on identical twins, who not only share identical genomes, but also nearly identical weight profiles - even when they are raised in different environments.

"We know that genetics plays the dominant role in determining body mass index," says Arya Sharma, one of the country's foremost obesity researchers at the University of Alberta. "I can tell your risk of obesity by looking at your parents."

After running DNA scans on thousands of people over the past few years, researchers have uncovered about 50 gene variants related to the propensity to gain weight. Each one of these variants can moderately influence body mass, but some of us lug around more of them than others.

"Exercise will not help everyone lose weight," Dr. Sharma says. Although slimming down is just one of many reasons to exercise, he notes that "the more genetically predisposed you are to gaining weight, the more effort it's going to take to override those genes.

"Just go out on to the street and pick out 100 people at random - give them the same food to eat, the same amount of exercise, and some will gain weight and some will lose it. Even whether or not you like exercising is very strongly genetically determined."

But before anyone concludes that diet and exercise are futile weapons in the war on weight, researchers have also found that the simple eat-less, move-more strategy can overcome the known genetic susceptibilities for excess weight. Some people just have to move much, much more and eat far, far less to see results.

"There is no gene related to obesity we know about so far that cannot be overridden by lifestyle choices," says Robert Hegele, who has studied and discovered many of the genetic underpinnings of cardiovascular conditions at the University of Western Ontario. "In my career of 25 years, I've only met about five people for whom diet and exercise do very little."

Dr. Hegele says this holds true even for people who carry two copies of the FTO gene, the most significant obesity-related gene identified to date.

Researchers, who discovered it in diabetes studies with mice in 2007, originally nicknamed it the "fatso gene" because it spanned a large stretch of DNA code. Only later did they learn it plays a major role in becoming fat. Acting on the brain's hypothalamus, the FTO gene seems to fuel appetite even after a person is full, increasing the risk of obesity by as much as 70 per cent. What's more, almost half of all people of European descent carry it.

A recent European study of 752 teenagers found those who carry the FTO gene had more body fat than non-carriers unless they exercised for an hour each day. A study of Amish adults in Pennsylvania found that carriers needed three to four hours a day of moderate exercise to keep the weight off.

Even so, large population studies show that while the gene hinders weight loss, it actually has a mild effect, relatively speaking. People who carry two copies of FTO tend to weigh only about six to seven pounds more than those who do not carry any copies. The difference is only three to five pounds at Dr. Hegele's clinic, where there are also patients without the gene who weigh 300 pounds.

"We're just at the kindergarten stage of understanding how to integrate genetic testing into risk prediction in the clinic," Dr. Hegele says. After learning that they carry the FTO gene, "a few patients see the glass as being half empty and react fatalistically: They think there's nothing to be done and so they are not inclined to act. ... Others do become motivated, but they are not the majority."

The reactions are further complicated in that genes related to weight confer only a predisposition, Dr. Hegele says. This means they might be mitigated not only by efforts to stay fit, but also by other genes - and the vast majority of genes involved in weight gain have yet to be identified.

Many of these genes are thought to be involved in the complex connections between our minds and bellies. For example, research from McGill University suggests that weight struggles and obesity should be considered neurobiological disorders - mediated by a small but powerful group of hormones that can push us to feast when we're full, slow our metabolism and zap the motivation to climb on that treadmill.

Most weight-loss efforts fail because the solutions fail to take the root causes into account, says Dr. Sharma, who is also scientific director of the Canadian Obesity Network. Those causes are the product of an individual's genes and experience - and there is no "one-size-fits-all" solution.

"It comes down to seeking professional help," to tailor a personal plan, Dr. Sharma says. For instance, not everyone has experienced exercise as a positive endeavour and DNA, he says, is a blueprint shaped very much by experience.

"There is no point in prescribing an obesity treatment to people to do things they do not enjoy - people don't like doing things they are not good at. If you're not a natural-born athlete, … taking up regular running, for example, is going to be very difficult."

So how does such a person tackle long-term weight loss?

Those not inclined to take up a vigorous exercise regimen should do "whatever it is that they can enjoy," Dr. Sharma suggests. "Even small bouts of activity - using the stairs, standing rather than sitting in meetings, parking farther away - can help manage weight."

After all, some research has found that a natural-born fidgeter can slay up to 700 calories a day, doing little more than spontaneous muscle contractions and sitting up straight.

Many people can also limit weight gain just by watching how and when they eat, Dr. Sharma adds.

If a person needs, say, 2,000 calories a day but consumed only 400 by dinnertime, he says, the additional 1,600 calories needed is bound to come by way of a huge dinner and dangerous couch-side snacking. Yet if you didn't eat breakfast, or much of a lunch, the body's furnace shifts into starvation mode by evening, he says, meaning that it will cling to every calorie consumed.

Worse, starving people eat very fast, outpacing the brain's ability to register that they have had enough. "It takes 20 to 40 minutes for brains to realize they're full," Dr. Sharma says. "But in 20 minutes you can do a lot of damage."

Spreading calorie intake more evenly throughout the day helps "keep the furnace burning all day long," he says.

Yet biology can be a flawed and unfair beast, and some people simply have a furnace that burns hotter and faster than others. "I have patients who live well - better than I do," Dr. Sharma says, "and they are still 300 pounds; and there are lots of thin people out there who have crappy diets and don't exercise at all, and no one labels them lazy."

Indeed, studies have found that there are those who can consume as many as 1,000 extra calories a day, but, thanks to the gift of inheritance, they just melt away. Dr. Scherer just happens to be one of the lucky ones.

The brain-belly connection: Hormones play a big role

Hormones play a major role in our mental motivation to eat or not to eat. Neurobiology research suggests that people who struggle with weight may well have genes that disrupt these substances, making food as addictive as a drug in some cases.

There's the neurotransmitter dopamine, which - with sex, drugs and food - can excite the brain's reward circuit with a shot of pleasure that reinforces the desire for more. There's the appetite suppressant leptin, which fat tissue secretes to signal the brain when you're full. There's insulin, the sugar-busting hormone that regulates energy and glucose metabolism. And there's ghrelin, the stomach's hunger hormone that can spark the brain's yearning to eat with the mere image of a Big Mac.

One 2008 study suggests that ghrelin levels rise with stress, making the stressed more likely to overeat. Another recent experiment found ghrelin powerful enough to make people crave more food even after a full meal. And at McGill's Montreal Neurological Institute, researchers have shown that ghrelin triggers certain brain regions to respond to visual food cues with an almost hedonistic desire, explaining why it's dangerous to shop for groceries on an empty stomach and how a steady stream of junk-food advertising can hinder weight loss.



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