Do these genes make me look fat?
Scientists are probing the complex relationship between our DNA and our diets to unravel the root causes of obesity. But for those seeking a simple solution to the worldwide fat epidemic, their answers may be hard to swallow.
By Madeline Fisher
Based on everything he knows about SCD, Ntambi doesn’t think this bodes well for our waistlines. Some of his latest results in mice show that an excess of sugary and starchy foods acts directly on the SCD gene in the liver to boost the making of fat. Indeed, swigging Big Gulp soft drinks and gobbling king-size candy bars may ramp up SCD so much that the body’s natural energy balance is lost, swinging instead toward ever-increasing levels of fat storage.
“A lot of processed carbohydrate is not good,” says Ntambi. “That’s basically what we are saying.”
Why then, when being obese takes such a toll on our health, does the body seem bent on tucking away every last calorie as fat? To answer that question, we may need to look back millions of years to our ancestral roots, to times when people were never quite sure where their next meal was coming from.
“Actually, the particular challenge we are having now—too much food—is quite new,” says Eric Yen, an assistant professor of nutritional sciences who joined the CALS faculty last fall. “Throughout evolution, selection was usually the other way around: Individuals were selected who could store energy when food was around so that they could survive when it wasn’t.”
Those lucky people didn’t just survive; they also passed their fat-storing capabilities onto their children through their genes. SCD may have been one of those genes. Yen believes the gene and enzyme he studies, called MGAT, could be another.
“It looks like the main job of this enzyme is to preserve the energy we get from dietary fat so that we don’t waste it,” he says. He explains that the body normally absorbs around 92 percent of the fat we eat; any amount less than that signals disease. In contrast, we take up only 15 to 85 percent of the cholesterol in our food, depending on body needs. “Fat is a very precious nutrient,” he says.
Dietary fat consists mainly of triglyceride, which also happens to be the major component of the fat we store. But triglyceride is too large a molecule to make the transition from food item to body fat directly. Instead, digestive enzymes must first break it down into fatty acids and glycerol molecules for passage across the intestinal wall. Once these building blocks have shuttled inside special cells lining the small intestine, they are assembled once more into triglyceride for packaging and shipping to the rest of the body.
Within these cells, MGAT carries out a step in the reassembly of triglyceride, but its role is also turning out to be more complex than this simple action implies. Similar to Ntambi’s experiments with mice missing the SCD gene, Yen and his colleagues engineered mice to lack MGAT in all tissues, and then placed them on a high-fat diet to see what would happen. Much to their surprise, mice without MGAT took up the same amount of fat as control mice, although they did so more slowly. What they didn’t do was store the extra calories they absorbed. Instead, their energy expenditure rose, along with their body temperatures. A mere delay in absorption, in other words, led them to waste the energy from fat as body heat.
“It’s just fascinating to me: Why would slowing down fat absorption change our energy metabolism?” says Yen. “That’s very counterintuitive because we used to think that one calorie equals one calorie. Fat is fat, and once it gets in (the body), it should behave the same as any other calorie. But it doesn’t seem like that’s the end of the story. I think there may be many layers of complexity that we’re just figuring out.”
At the same time, Yen is also hoping to uncover how MGAT functions in different individuals. He suspects the gene may contain subtle mutations that cause the MGAT enzyme to work less efficiently in certain people than in others, possibly helping to explain why some individuals never grow plump even when they eat lots of fatty foods.
“A lot of the emphasis of our work may be to look at variations in this gene,” Yen says. “Can those variations account for the differences we see in how obese people get on similar diets?”
Teasing out those differences may not only help us to better understand obesity as a disease, he adds, but could also lead to improved dietary guidelines for preventing the problem in the first place. “In the past, the main challenge of any public health field has been to create a simple message that people can remember, such as, ‘Don’t eat fat and you’ll be lean,’” he says. “But people are not simple. So lots of times we give out dietary guidelines that don’t really make sense for certain people.”
Here lies one of the difficulties in explaining the relationship between genes and obesity. While people are largely similar on a genetic level—we have more than 99 percent of our DNA in common—the structure and deployment of those genes is wildly variable. Even with the same blueprint, our bodies make unique modifications that can trivialize blanket assessments of how we function. Take, for example, the case of type 2 diabetes, a disease that is often closely associated with obesity. There is good reason for that: Of the 20 million Americans who suffer from type 2 diabetes, roughly 80 percent are also obese. And yet, the vast majority of obese people don’t go on to develop the disease.
Tags: DNA, Genetics, obesity
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