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Stress plus bad diet equals belly fat

A hormone triggers deposits in mice, scientists say. It may help human trouble spots.

July 02, 2007|Thomas H. Maugh II | Times Staff Writer

The fat on your belly may be there because of stress in your everyday life, and researchers think they may know how to get rid of it.

Studies of mice and monkeys show that repeated stress -- and a high-fat, high-sugar diet -- release a hormone, neuropeptide Y, that causes a buildup of abdominal fat, researchers from Georgetown University reported Sunday.

Manipulating levels of that hormone could melt fat from areas where it is not desired and accumulate it where it is needed, the researchers say in the journal Nature Medicine.

"These are eye-opening findings," said neuroscientist Arshad Khan of USC, who was not involved in the research.

Khan continued: "There are different kinds of fat, and where it is located matters."

Mary F. Dallman of UC San Francisco said in an editorial in the same journal: "A large gap in our understanding of how chronic stressors lead to abdominal obesity has been filled.... Their results were remarkable and have profound implications for new drug development."

Plastic surgeons are particularly looking forward to further results from the study, said Dr. Stephen Baker of Georgetown University Hospital, himself a plastic surgeon and a coauthor of the report. The study could lead to safe and effective replacements for unapproved chemicals, like Lipodissolve, used by some doctors to dissolve local fat deposits.

It could also reduce or eliminate the need for extremely expensive fat replacements used in breast and facial reconstruction and in other surgeries, he said. "In the longer term, we might even be able to use it to prevent obesity. This is the real deal."

The team hopes to begin human studies within two years.

The research began with a simple study of mice. Dr. Zofia Zukowska of Georgetown and her colleagues divided mice into four groups: Two received a conventional diet, and two received a diet high in fat and sugar. Then one group from each diet was forced to stand in cold water for an hour every day, "like the Northern European experience of waiting for a bus with wet feet," she said.

The remaining groups were exposed to an aggressive alpha male for 10 minutes each day, "like having a bad boss."

For the mice on the normal diet, "it really didn't matter whether they were stressed or not," she said. "They didn't have much difference in weight. If anything, the stressed ones weighed less."

But the stressed mice on the "fast food" diet accumulated twice as much belly fat in the first two weeks as those that were not stressed. Over three months, they became grossly obese.

Biopsies of the fat showed increased levels of neuropeptide Y, or NPY, a hormone discovered nearly 25 years ago. In the brain, NPY stimulates appetite. In the periphery of the body, it is a growth factor that stimulates enlargement of cells and the production of new blood vessels to supply nourishment.

Zukowska and graduate student Lydia Kuo, who did much of the work, found that the hormone not only enlarged fat cells, but stimulated the production of new fat cells and blood vessels to support them.

"It makes sense that, in a stressed environment, an animal would want to make and store fat for a future 'fight-or-flight' response," said neuroscientist Adrian J. Dunn of the Louisiana State University Health Sciences Center, who was not involved in the study. "Unfortunately, in modern society, we are not doing much fighting or fleeing," and the fat remains.

A buildup of abdominal fat is a prime contributor to a condition called metabolic syndrome, which affects 60 million Americans, according to the Centers for Disease Control and Prevention. Metabolic syndrome sharply increases an individual's risk of diabetes, heart disease and stroke.

"It seems a pity that it is this particular depot that is increased with stressors and comfort foods," Dallman and Dr. James P. Warne wrote in their commentary.

Zukowska's team then attempted to mimic the process of fat formation by implanting NPY in a slow-release tablet under the skin of mice and monkeys. In each, she said, the production of new fat was stimulated around the tablet.

Next, the team implanted human fat in nude mice, which have an inhibited immune system and are unable to fight off such transplants. Normally, this fat is reabsorbed by the animal within a couple of weeks, Baker said. But when they implanted NPY along with it, 99% of the fat was retained after three months.

The opposite also works. When the researchers implanted a slow-release tablet of a small molecule that blocks the cellular receptor for NPY, the fat buildup did not occur. Similarly, implanting the molecule in a fat deposit causes the fat "to just melt away," Zukowska said. "It's incredible."

Within two weeks the fat deposit in the mice had shrunk by half.

The team hopes to obtain similar results in humans. The hormone and the receptor are nearly identical in mice, monkeys and humans.

Furthermore, Baker said, there is a Northern European population that, due to a genetic abnormality, secretes excessive amounts of NPY when stressed. That population is unusually susceptible to obesity and diabetes. In contrast, a Swedish population with a genetic mutation that lessens the receptor's efficacy is resistant to obesity.

NPY has been injected into humans with no apparent side effects, but its long-term effects have not been studied, Zukowska cautioned. The receptor blockers have never been used in humans, she added, so nothing is known about their safety.

Dunn cautioned against building up hopes prematurely. "Things sometimes work in animals, but then we get side effects in humans, or other things go wrong," he said.

thomas.maugh@latimes.com

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