Way to Shrink, Grow Fat Is Found -Tests Also Show Link to Stress

[Guest guest]

By Rob Stein

Washington Post Staff Writer

Monday, July 2, 2007; Page A01

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.

Researchers found that laboratory mice subjected to daily stress and also

fed a high-fat diet for a few weeks became obese.

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 town 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 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 B. Baker, a town 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.' "