Way to Shrink, Grow Fat Is Found

Researchers found that laboratory mice subjected to daily stress and also fed a high-fat diet for a few weeks became obese.
Researchers found that laboratory mice subjected to daily stress and also fed a high-fat diet for a few weeks became obese. (Georgetown University Medical Center)
By Rob Stein
Washington Post Staff Writer
Monday, July 2, 2007

Scientists reported yesterday that they have uncovered a biological switch by which stress can promote obesity, a discovery that could help explain the world's growing weight problem and lead to new ways to melt flab and manipulate fat for cosmetic purposes.

In a series of experiments on mice, researchers showed that the neurochemical pathway they identified promotes fat growth in chronically stressed animals that eat the equivalent of a junk-food diet.

The international team also showed that blocking those signals can prevent fat accumulation and shrink fat deposits and that stimulating the pathway can strategically create new deposits -- possibly offering new ways to remove fat as well as to mold youthful faces, firmer buttocks and bigger breasts.

"It's very exciting," said Zofia Zukowska of Georgetown University's Department of Physiology and Biophysics, who led the research, published online by the journal Nature Medicine. "This could be revolutionary."

While cautioning that the safety and effectiveness of the approach remain to be proven in people, other researchers said the findings reveal new clues about the basic biology of fat and why obesity has been increasing so quickly, particularly in Western countries.

"There is a lot of uncontrollable stress right now in our societies. There's also a lot of inexpensive high-fat food," said Mary F. Dallman of the University of California at San Francisco, who co-wrote a commentary accompanying the research. "This could help explain the obesity epidemic."

The researchers have applied for a patent and have begun negotiating with drug companies to license the technology. They predicted that studies in people could begin within two years.

Previous studies have indicated that whereas acute stress can make some people lose weight, chronic stress, such as long-term job insecurity, might cause some to put on pounds.

To explore this, Zukowska and her colleagues subjected mice to chronic stress -- either standing in cold water an hour a day or being caged with a more aggressive alpha mouse for 10 minutes a day -- and then gave them standard feed or a high-fat, high-sugar diet similar to the junk-food fare many consume.

After two weeks, only the mice that were both stressed and fed the junk-food diet gained a significant amount of weight. They accumulated about twice as much fat in their bellies as non-stressed mice that consumed the same diet.

"This tells me it's not just the stress. It's the combination of stress and the high-fat, high-sugary rich diet -- that is the humongous combo. There is some kind of interaction going on," Zukowska said.

Moreover, the stressed-out junk-food eaters put on the worst kind of fat -- deposited around the abdomen and laced with hormones and other chemical signals that promote illness. After three months, the animals became obese and developed the constellation of health problems that obese humans often get -- high blood pressure, early diabetes, high cholesterol -- an increasingly common condition known as metabolic syndrome.

"By treating the mice the way humans are treated, which is introducing a chronic stress from which they cannot escape and introducing this abundance of food, we mimicked what happens in American society," Zukowska said.

When the researchers examined the animals' fat tissue, they discovered sharply elevated concentrations of a substance called neuropeptide Y (NPY), a chemical messenger produced by nerves in the body, including those in fat. They also had far higher levels of a molecular partner NPY needs to work, known as the neuropeptide Y2R receptor.

"This tells us that NPY and this receptor trigger the whole process of stress-induced obesity," Zukowska said. She noted that other recent studies found that humans with defective NPY receptors are resistant to obesity, whereas those with excessive NPY are prone to it.

After confirming the role of NPY in fat formation in additional studies in genetically engineered mice, the researchers showed in laboratory experiments that NPY induces the growth of immature fat cells, coaxes mature fat cells to get bigger and promotes blood vessels necessary to sustain fat tissue.

The researchers also demonstrated that injecting a substance that blocks NPY prevented mice from accumulating fat -- even if they were stressed and ate a high-fat diet -- and could shrink fat deposits by 40 percent to 50 percent within two weeks.

"It just melts the fat. It's incredible," said Zukowska, noting that the technique could offer an alternative or supplement to liposuction.

On the flip side, when researchers inserted pellets containing NPY under the skin of mice and three monkeys, they were able to stimulate fat growth, suggesting that the approach could replace skin fillers and other cosmetic and reconstructive surgical techniques.

"This has tremendous potential applications for both cosmetic and reconstructive surgery," said Stephen B. Baker, a Georgetown University professor of plastic surgery who helped conduct the research.

Detailed studies of the mice and preliminary findings from the monkeys found no signs of adverse side effects.

"We think we have hit on the natural mechanism that mammals use to grow fat, and reversing that process is the most natural thing," Zukowska said.

"It just has tremendous potential applications," she said. "I have never seen anything like this."

Others cautioned that much more research would be needed to confirm that the same system works in people, and to learn whether blocking or stimulating NPY receptors is safe.

"You might have side effects you wouldn't want, which is always the problem with a substance in the body that does many different things," said Bruce McEwen of Rockefeller University in New York.

It is unlikely that anything will ever be a panacea for weight gain or will replace eating well and exercising regularly, others warned.

"I wouldn't want people to not to make an effort to control their weight or lose weight while waiting for this magical solution to fix the whole thing," said Louis J. Aronne of the Weill Medical College of Cornell University. "This is very promising, but the average person shouldn't say, 'I can eat whatever I want and wait for that shot to take it all away.' "

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