Acaso estos genes me hacen ver gordo(a)?Contributed by: Anonymous · Views: 1,457
Contributed by: Anonymous · August 16, 2008 @ 12:09 PM MDT · Views: 1,457
Do these genes make me look fat?By Madeline Fisher
Two mice in James Ntambi’s lab illustrate the power of genes
in controlling fat. While both mice eat the same fat-laden diets,
the mouse on the right lacks a gene that is critical to how the body
stores fat from food. Without this gene, this mouse can eat what
amounts to a cheeseburger and fries every day and gain no fat.
Ntambi has found that substances in some foods change how this
gene functions in our bodies.
Photo: Wolfgang Hoffmann
It’s hardly a secret that America is fat. Take a look around any bar, mall or fast-food joint, and you’ll quickly find evidence of our collective corpulence. Spilling out of our seats and our relaxed-fit jeans, we cram together at tables to down mountainous plates of food and bucket-sized drinks. Doors have been widened to accommodate us, and chairs reinforced. Even our pets have grown plump, and, more tragically, our children.
According to the Centers for Disease Control and Prevention, one-third of Americans have progressed to that dangerous state of flabbiness known as obesity. Another third are overweight. This means that, all told, hundreds of millions of us now carry too many pounds, and with them, a greater risk for obesity-related illnesses, including diabetes, heart disease and some cancers, just to name a few.
Nutritional sciences professor Eric Yen and graduate student Stephanie Lamb examine liver cells, which the lab studies to understand how our bodies assemble and store fat from food. Yen is exploring how variations in a gene involved in metabolism may explain why people can eat the same foods but put on different amounts of weight.
Photo: Wolfgang Hoffmann
As it turns out, there is. Though we tend to see food as the cause of our flab, it’s the way food interacts with our intricate network of genes that ultimately dictates whether we pack on pounds. In the past several years, scientists have discovered dozens of obesity-related genes, including ones that control the size of our fat cells, our metabolic rate and how quickly we feel full. And while the story that’s emerging from these genes is wildly complicated, it may also finally produce solid answers to a crisis that has reached epidemic proportions.
At least that’s the hope of James Ntambi. A CALS professor of biochemistry and nutritional sciences, Ntambi has been working to unlock the secrets of how food interacts with our genes for more than 20 years. It’s a curiosity that began as an undergraduate student at Makerere University in his native Uganda. Ntambi can recall lingering outside the biochemistry department to pore over wall charts that detailed the body’s metabolic pathways. Eventually he turned his attention to fat cells — specifically, how the small, precursor fat cells we’re all born with transform over time into fat-storing adipose tissue. In the late1980s, Ntambi began to study a gene called SCD, which seemed to dramatically increase its activity during this conversion process, making him wonder about its potential link to obesity. He has been following that hunch ever since.
We now know that SCD encodes an enzyme that converts certain saturated fatty acids into unsaturated forms. These unsaturated fats are the building blocks of many types of lipids, including triglyceride, the main component of body fat. In the lab, Ntambi’s team showed that mice that lack the SCD gene are completely unable to store fat from food or make new fat from carbohydrate. Instead, they burn calories like crazy. Even when they eat the equivalent of a hamburger and fries at every meal, these mice gain virtually no fat.
Ntambi’s research with these miracle mice has sent drug companies scrambling to find chemicals capable of inhibiting the SCD genes in our bodies, which would supposedly allow us to eat fatty foods without storing extra fat. But intriguingly, Ntambi has found that certain foods and other biological molecules do the same thing. For example, omega-3 and omega-6 fatty acids — also known as fish oils because of their abundance in fish — naturally suppress SCD. In lab studies, fish oils cut the activity of the gene significantly, helping tip the body’s metabolism away from fat synthesis and storage and toward calorie burning. This is likely one reason fish are so highly touted in diets. (The American Heart Association recommends that people eat foods high in fish oils at least twice a week.) They actually alter a key gene’s operation.
“We’ve always had nutritional experts who tell us about diets,” says Ntambi, “but now we’re telling them how the diets work.”
Growing up on a Ugandan coffee and cotton plantation, Ntambi never imagined that he would study fat. When he entered graduate school at Johns Hopkins University, he put his interest in metabolism aside and pledged to study “an African disease.” He began investigating the parasites that cause African sleeping sickness, as well as a related scourge of cattle called ngana, all the while making plans to continue the research back home in Uganda.He laughs heartily now at the memory, because of course things didn’t turn out that way.
Instead, after earning his doctorate in 1985, Ntambi was invited to do what turned out to be his fateful research on human fat cells. His new post charged him to identify and clone the genes in mice that switch on as fat cells grow, which led him to SCD. In 1988, he became the first person to clone SCD, and soon afterward, he began examining the foods and other factors that affect the gene’s activity.
What Ntambi has discovered since is that, while molecules such as fish oils inhibit SCD and promote energy expenditure, many others do the opposite. For example, the hormones insulin and estrogen, the vitamins A and D, and the simple sugars glucose and fructose all boost SCD’s activity dramatically, suggesting that when they’re present, they encourage the body to make fat. And two of these substances — glucose and fructose — are more present within us now than ever before.
One of the chief reasons is the emergence of high fructose corn syrup, a sweetener made from corn. Low corn prices in the 1980s made the sweetener a low-cost alternative to cane sugar, leading soft-drink giants Coca-Cola and Pepsi to begin using it. At the same time, Americans were growing wary of fat in their diets, and the food industry responded with an array of reduced-fat products, many of them stoked with corn syrup to boost their flavor. Now, corn-based sweeteners are in everything from fruit drinks to baked goods to supposedly healthy items such as yogurt.
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.
This paradox plays out strikingly when you compare diabetes risks among people of different cultures or geographic regions. Among the Pima Indians of Arizona, for instance, one-half of all adults have diabetes, one of the highest rates of diabetes in the world. While obesity is epidemic among the Pima community, another factor seems to be at play, says Alan Attie, a biochemistry professor who studies diabetes. Attie points out that while white Americans are considered to be at risk for diabetes when they have a body mass index (BMI) of 30 or above, the figure is much lower for the Pima Indians. A much lower level of obesity puts them at risk for developing the disease.
The same is true of people who live in southern India: Scientists estimate that southern Indians need only hit a BMI of 23 to be in the same danger as a white American with a BMI of 30. So while a six-foot-tall, 175-pound Caucasian male would need to gain about 50 pounds to be considered at high risk for diabetes, a southern Indian man of the same weight and height would already be there.
“So that tells you something about genetics,” says Attie. “There clearly are some genetic factors that are normally silent when you’re lean, but that interact with obesity to bring on diabetes. And they’re much worse in certain groups of people.”
Much like Ntambi and Yen, Attie has been probing this idea in experiments with genetically engineered mice. His lab houses two groups of mice, both of which are morbidly obese. But only one is susceptible to type 2 diabetes. He is now searching for the genes that account for the disparity.
But even as we’re uncovering genetic differences in how we process foods, the foods themselves are growing more homogenous, a trend that could greatly complicate efforts to prevent obesity-related diseases such as diabetes. On the street in Taipei, Taiwan, where Yen grew up, for example, six American fast food outlets have sprung up since he graduated from high school. And Taipei is not alone: As Western staples and processed foods spread around the globe, we’re only beginning to learn what effect those diets will have on populations that have historically not consumed them. Already, obesity rates have been climbing in Asia and other parts of the world, and this has Attie worried about the implications for diabetes. “Although we talk a lot about the diabetes epidemic in the United States and Europe, the diabetes epidemic that is anticipated in Asia is going to be much worse,” he says.
This global transformation is proving significant for Africa, as well. When Ntambi left behind his studies of African sleeping sickness to investigate obesity, he never imagined that someday he’d again be working on an African disease. Sadly, though, that’s exactly what obesity and diabetes have become.
“When I was growing up in Africa, I never saw many obese people. Now I do,” says Ntambi, who travels back every year to Uganda to teach and do research. “So something must be changing, and I think it’s lifestyle and diet.”
Ntambi believes Ugandans, like many Westerners, have grown fatter as they’ve become more affluent, which brings access to more food and time-saving technologies that encourage a sedentary lifestyle.
“It’s a paradox,” he says. “In Africa, when you buy a car or when you have a TV, it’s a sign of prosperity and you would be proud. But if you misuse that technology, it’s going to turn around and affect your health.”
To be sure, recent years have seen a massive investment in research to address this global epidemic. Ntambi’s work with SCD, as well as Yen’s research on MGAT, have pointed two possible routes toward intervention. Based on the knowledge that inhibiting genes such as these change how our bodies store fat and burn energy, several drug companies are now trying to develop a pill that would tilt our metabolic balance away from cherishing fat.
While a weight-loss pill is a tantalizing idea, however, things aren’t quite that simple. For one thing, while mice don’t naturally express MGAT in the liver, people do, and Yen imagines that a drug targeted at MGAT could cause liver side effects not evident from mouse studies. Chemically inhibiting SCD also has potential downsides. Mice lacking the gene suffer from dry eyes and severe skin problems, and their levels of saturated fatty acids rise — with unknown consequences. What’s more, deleting SCD causes the metabolic rates of mice to skyrocket, suggesting that drugs aimed at the gene could possibly affect longevity.
“So, it’s tricky,” says Attie, who has collaborated with Ntambi on several studies of the gene. “But we’ll know. There are a lot of drug companies working on SCD.”
Side effects aside, there is perhaps a bigger reason not to pin all of our hopes on a miracle drug for obesity. Such drugs are bound to be expensive — and therefore out of reach for much of the world’s population, says Ntambi. He has seen it before with diabetes in Uganda.
“Diabetes can be managed by diet, exercise and, of course, by insulin. But insulin is very expensive in developing countries,” he says. “So someone may be diabetic, but not really have access to insulin, or individuals can become diabetic and they don’t know it.”
That’s why, when Ntambi was packing last December for a six-month sabbatical in Uganda, he packed some 3,000 donated kits for monitoring blood glucose levels. During his visit, he handed them out for free so that people could check their blood sugar and get appropriate medical attention. He also hoped, along the way, to educate as many people as possible on ways to prevent obesity and diabetes, since for many Ugandans, changes in lifestyle and diet are likely the best — and possibly only — solutions for good health.
“We’re not saying that you shouldn’t eat a high-carbohydrate or a high-fat diet,” says Ntambi. “You can eat what you like, if you enjoy it, as long as you’re able to have energy balance in the body. The energy coming in has to be counteracted by the energy that is going out.” And in nutrition, that’s as simple as it gets: Expend more energy than you take in, and you’ll shed pounds. We’ve heard it before, but the science of genetics is reinforcing its essential truth by showing us exactly why it works this way. The only question is: Will we listen?
Courtesy: University of Wisconsin-Madison