by Laurie Fruth
You've tried them all - the grapefruit diet, the liquid diet, even the highly touted protein diet. You've sweated out miles on the treadmill, trudged up the stairs instead of riding the elevator, and grunted through too many sit-ups to count. And you just can't seem to shed that extra weight you hate.
For most people, excess weight is only a nuisance that, at best, makes their clothes fit too tight and, at worst, forces them to dredge up some nagging self-esteem issues that they'd rather forget.
But for 25 percent of the American population, fat is more than just an annoyance or matter of vanity - it's a serious health risk. The clinically obese are at far greater risk of developing diabetes, cancer, and heart disease than the rest of the population. And as the medical profession warns that the problem is reaching epidemic proportions nationally, scientists are taking a fresh look at its causes - and why some of us become obese while others merely carry around a few extra pounds. Many scientists are no longer blaming the condition exclusively on eating behavior.
UNLV biological sciences professor Deborah Hoshizaki is one of those scientists. She believes that at least part of the cause of obesity - and fat cell production in general - can be traced to the genes that regulate the development of cells in our bodies. She and a team of biology graduate students and post-doctoral researchers are investigating the genetic programming that controls how cells develop and determines which ones become fat cells.
"What people need to realize is that, yes, if you eat too much, you're going to gain weight. But that's just a small part of the problem," Hoshizaki explains. "For many years it was thought that you're born with a certain number of fat cells that either grow or diminish according to your eating behavior and metabolic rate. But as it turns out, that's not true. We can always make more fat cells."
Of course, making more fat cells isn't the problem - it's getting rid of the ones we have. But, as the thinking often goes in scientific research, if you can find out how and why a condition develops, you can often discover how to make it stop developing. Hoshizaki believes that her work may someday make this possible.
She and her team have already identified two genes that play a critical role in the development of fat cells and are in the process of cloning a third. But in order to conduct their research, they have had to examine cells before they've matured, which has made working with human cells unfeasible; hence, their research subjects are not exactly what you might expect.
"We have used fruit flies because we're looking at the very earliest stages of development - stages that you can't see in humans," Hoshizaki says. "And with the exception of some very early events in the creation of an embryo, the rules that govern embryo development in the fruit fly are the same rules that govern embryo development in humans."
Because the genetic rules are essentially the same for humans and fruit flies, Hoshizaki believes her research will pave the way for future studies on human subjects.
"We have colleagues in France who are interested in doing human studies, and they call and say, 'So, do you have it?' They're waiting for us to identify the genes that control fat cell development in the fruit fly so that they can begin to look for the same genes in humans."
But they may have to wait a while longer. The process of finding the genes is not simply a matter of looking at a gnat under a microscope. As Hoshizaki explains, every single cell in a fruit fly's body contains the same genetic material or DNA. But only a portion of that genetic information is needed for a cell to become what nature intended it to be. The researchers must discover which genes tell a cell to activate or "turn on" the specific portion of the DNA sequence that will program it to become a fat cell rather than a heart cell or muscle cell.
To find that gene, scientists in Hoshizaki's lab have performed their own brand of detective work. They have scoured the scientific literature for clues. They have asked "what if" questions of each other and carefully designed experiments to pursue theories. They have analyzed and criticized their own work and the work of their colleagues. And eventually, after months of long hours in the lab, they have made some amazing discoveries.
Perhaps their most striking one has been the discovery of "serpent" -
a gene in the fruit fly that, when defective or mutated, causes the
embryo to take on a snake-like appearance. (They become defective or
mutated as a result of any number of spontaneous causes, such as exposure
to chemicals or radiation.) Hoshizaki and Stephen Hayes, a post-doctoral
fellow working in her lab, found that when the gene becomes defective,
the cell cannot turn on the fat cell program and fat cells do not form in
the embryo. Hence, a functional serpent gene is necessary for fat cell
development.
Once Hayes and Hoshizaki successfully demonstrated that serpent was one of the genes needed to "turn on" the fat cell program, they continued their investigation by asking an important "what if" question: What would happen if they "turned on" the serpent gene in cells that were not originally destined to become fat cells?
"We were curious as to what would happen if we took the serpent gene and activated it in a third of the cells of an embryo. In other words, we activated serpent in a much larger number of cells than normal," Hoshizaki said. "What we found was amazing. We discovered that the serpent gene was not only necessary for making a fat cell, but also that it alone could also reprogram a cell to become a fat cell."
So, serpent, when activated, can turn a cell that was supposed to become a muscle cell into a fat cell.
"When we tell people about that discovery, they often laugh and say, 'I've been doing that all my life!' But, in truth, cells don't change once they've matured. They may get bigger or smaller, but they don't change in fundamental nature.
"Up to that point, we were operating from the notion that the destiny of these cells was pretty much sealed by their genetic programming from the very beginning. That is why this discovery is so incredible. It indicates that serpent is the master control gene for triggering the development of fat cells. It is the only gene we've discovered so far that completely determines whether a cell turns into a fat cell or not."
As important as this discovery was, the researchers realized they must go a step further and attempt to answer the larger question that looms before them: What causes the serpent gene to be activated in some cells and not in others?
The challenge of answering that question sparked the interest of UNLV graduate student Jennell Miller when she began working with Hoshizaki more than two years ago. Miller, who is pursuing her doctorate in biological sciences, has since identified two other genes called AbdB and Ubx that determine whether the serpent gene is turned on in cells. Miller explains that the AbdB gene produces a protein that activates the serpent gene. On the other hand, the Ubx gene may be having the opposite effect.
"In some parts of the embryo, we have AbdB turned on but the serpent gene is not turned on. We believe that Ubx may be repressing the serpent gene in these areas," Miller says, explaining that their examination of this aspect of the study is still in progress.
However, if Hoshizaki, Miller, and Hayes can find out more precisely
how these three genes interact to produce fat cells, perhaps they and
their colleagues can begin to unravel the mystery of why fat cell
generation becomes a runaway problem in some fruit flies and not in
others. The next step, of course, would then be for their colleagues to
extrapolate from their findings how the same process might occur in
humans.
Though the researchers are excited by the strides they have made so far, they recognize their work is far from done. The ongoing process of collecting embryos, staining slides, and decoding DNA sequences is extremely time-consuming, and they acknowledge they've chosen a challenging field to study. They've also found that working long hours on such a specialized research project presents some other non-scientific challenges as well.
"It can be lonely," Miller admits. "It's hard to talk to people outside the lab about what you're working on, so you find yourself socializing primarily with other scientists. And this can lead to some interesting conversations. I was in an elevator one day with a lab friend and some other people. Without thinking, I said to my friend, 'Oh, I hope my embryos turned out okay.' Then I noticed the strange looks I was getting from other people in the elevator."
But both Miller and Hoshizaki are committed to spreading the word about their research and increasing awareness of the problems associated with obesity. This spring, they are presenting two series of lectures on obesity - and, as Hoshizaki describes it, "how fat cells talk to the brain" - for local physicians and families of obese children.
Though their lectures are not specifically focused on their own research, Hoshizaki says they offer her and her graduate students the opportunity to apply their scientific knowledge in a different setting, as well as a chance to do a bit of public service.
"I strongly believe that the more the general public understands how we do science - how we make observations, how we collect data, how we use models - the better informed they will be when it comes to making decisions about health issues. We do this public service because we want the scientific community and the general public to know that UNLV is a resource," Hoshizaki says.
Toward this end, Hoshizaki and two local physicians recently presented a University Forum lecture at UNLV on the biological and clinical aspects of obesity. Also, she consults regularly with the physicians who run a clinic that treats overweight children between the ages of 5 and 17; she keeps them up to date on the latest literature about the scientific research being done on fat cell development.
Meanwhile, the researchers themselves have authored several articles on their findings in the scientific journals Development and Mechanisms of Development, and their investigation of the fat cell continues.
Though Hoshizaki does not intend to extend her research into human testing of her theories, she is interested in developing methods and establishing a facility in Las Vegas for diagnosing genetic defects that cause childhood obesity. She plans to seek grant funding in the community to pursue the idea.
"No one knows to what extent obesity is inherited," Hoshizaki says. "But the data we're collecting at the local clinics suggests that the genetic contribution to obesity is much greater than we imagined. For that reason, we are very interested in developing diagnostic tools to determine which genes are responsible.
"Through my work with the clinics, I have met children and their families whose lives have been so adversely affected by obesity," she says. "It's been truly compelling to meet these people. It has demonstrated to me that we need to offer some diagnostic services locally. This is very important because it will determine the best clinical treatment for this very serious disease."
