Mice may hold key to obesity
Robyn Shelton
Sentinel Medical Writer
December 4, 2006
LA JOLLA, Calif. -- He went into the experiment hoping to learn more about the brain.
He came out with a stunning clue to the nation's obesity crisis.
Gen-Sheng Feng, from the Burnham Institute for Medical Research, hopes his work will some day lead to a drug that can help the 127 million Americans who are overweight.
For now, though, Feng and his colleagues are still exploring the implications of their discovery.
They started out breeding mice with the aim of removing a gene for a key protein in the animals' brains. The larger goal was to see how the mice developed without it.
Five weeks later, it was obvious. The critters were fat -- really fat -- despite eating smaller amounts of food than normal-sized mice.
Feng's team concluded that the protein, called Shp2, plays a critical role in metabolism and weight control in the brain.
Ever since, his laboratory at Burnham has been studying the molecular underpinnings of obesity.
Similar research will be carried out in Orlando as early as the spring, when Burnham plans to set up shop in donated laboratory space while its new building is constructed at Lake Nona.
Burnham eventually plans to conduct research in Orlando that could touch on many illnesses: cancer, Alzheimer's, infectious diseases and others. But an early focus will be obesity and one of its most dangerous complications, diabetes.
The work is meant to complement ongoing research at the institute's campus in California, where Feng and others study the cellular processes, proteins, genes and molecular changes that occur in people suffering from the conditions.
The obesity epidemic
Feng sees his experiments with mice as paving the way to treatments for one of the biggest health threats of the 21st century.
Tapping on the keyboard in his office, the scientist pulls up charts on his computer that show the escalating rise in U.S. obesity rates.
More than 64 percent of American adults -- an estimated 127 million people -- are overweight. Approximately 60 million of those are obese, and 9 million are severely obese.
The extra pounds lead to numerous health risks, including heart disease, high blood pressure, osteoarthritis, certain cancers, kidney disease, infertility, lower-back pain, sleep apnea and stroke.
In particular, doctors are worried about obesity's link to the skyrocketing rate of Type 2 diabetes, which largely is caused by excess weight and lack of exercise. Nearly 19 million Americans have this form of the disease, including a growing number of overweight children.
"Obesity is a strong risk factor for so many other chronic illnesses, the concern is that more people will be experiencing these illnesses even earlier [in life]," said Dianna Densmore from the Centers for Disease Control and Prevention in Atlanta. "You essentially have a growing epidemic of what are actually preventable chronic illnesses."
Scientists are working to understand every angle of the crisis.
Its causes are numerous and complex -- encompassing everything from societal influences such as inactivity and larger portion sizes to the chemistry inside our brains.
Feng thinks the Shp2 protein may be a key link.
A graduate of Indiana University, Feng worked at a hospital in Toronto and taught at IU before being recruited to Burnham in 2000. Years earlier, he and other scientists actually discovered the gene for Shp2, which is deeply involved in cell growth.
But scientists suspected it plays other roles in the body as well.
Mighty fat mice
In particular, Feng's team wanted to learn how Shp2 influenced the forebrain, a region that controls basic functions such as the sleep-wake cycle and regulation of body temperature.
So using an approach common in biology, the scientists bred mice that are missing the gene for the protein of interest. In this case, the researchers used advanced techniques that strictly eliminated the genetic code for Shp2 from cells in the forebrain.
The mice in these experiments even have a name -- knockouts -- which refers to the elimination of a single gene from their DNA. Each gene holds the code, or recipe, that's necessary to make a specific protein. No gene, no protein.
By seeing how the knockouts differ from normal mice, researchers can infer what the protein does. For example, knockout mice with stunted limbs suggest that the protein is critical for normal growth of the legs. If the mutant critters are blind, the protein probably plays a role in eyesight.
In Feng's experiment, the knockouts packed on the weight. Some were twice as fat as normal mice of the same age.
Even more astonishing to researchers, the animals gained weight despite eating smaller amounts of food than their genetically complete brothers.
Without Shp2, their metabolism was clearly out of whack. They also had high blood sugar, high triglycerides and abnormal levels of a hormone called leptin.
Leptin -- long studied in the fight against weight gain -- is secreted by fat tissue. Researchers say the hormone serves as a signal to the brain when the body has enough fat.
In the past, scientists had suspected that some people didn't produce enough leptin to get the message across. But medical trials with leptin therapies have been disappointing.
Now, Feng said, the suspicion is that the body becomes resistant to leptin. So even if the hormone is present in adequate levels, people no longer respond to it, similar to the way that Type 2 diabetics become resistant to insulin. The question then becomes: How do you restore the body's sensitivity to leptin?
Feng thinks that Shp2 might help leptin do its job more effectively.
"If you diminish the message by deleting the gene [for Shp2], then maybe you can amplify" it by enhancing the protein, Feng explained.
His laboratory now is doing research for potential drugs that might turn up the volume on Shp2 in the brain, and consequently, curb weight gain. The molecular biologist expects obesity to occupy much of his scientific work from here to retirement.
"This is such a serious problem," said Feng, speaking softly, carefully. "For the rest of my life, this is what I would like to do. This is my hope: [to] contribute to the treatment of obese patients."
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