Anti-Fat Injection in Mice Conjures Up an Ice Cream Dream

WASHINGTON, July 3 -- For those who eat to combat stress, researchers here may have made a dream come true -- an injection that makes fat melt away, at least in mice.

In mice subjected to the equivalent of eating a pound of ice cream to get over some murine vicissitudes, blocking a well-known neuropeptide caused excess visceral fat to vanish, according to Zofia Zukowska, M.D., Ph.D., of Georgetown, and colleagues.

They indicated that in a series of experiments stress led to the release of Neuropeptide Y (NPY) from sympathetic nerves, which in turn upregulated NPY and its Y2 receptors (NPY2R) in a process dependent on the presence of glucocorticoids in the abdominal fat, the researchers reported online in Nature Medicine.

This positive feedback response by NPY led to the growth of abdominal fat, resulting in an increase in angiogenesis in white fat tissue, infiltration by macrophages, and proliferation of new adipocytes.

Over time, a feedback loop resulted in abdominal obesity and a metabolic syndrome-like condition in the animals, they said.

But injecting the new fat tissue with a compound that blocks the peptide's Y2 receptors (known as NPY2R) stopped the process and caused established visceral fat to disappear, Dr. Zukowska and colleagues said.

"We couldn't believe such fat remodeling was possible, but the numerous different experiments conducted over four years demonstrated that it is, at least in mice," Dr. Zukowska said.

She added that pilot studies show a similar mechanism exists in monkeys, but noted that a great deal of research remains to be done before the approach can be evaluated in humans.

In the long run, "we are hopeful that these findings might eventually lead to control of metabolic syndrome, which is a huge health issue for many Americans," she said.

"Decreasing fat in the abdomen of the mice we studied reduced the fat in their liver and skeletal muscles, and also helped to control insulin resistance, glucose intolerance, blood pressure and inflammation."

Interestingly, reversing the process - adding Neuropeptide Y to certain areas of the mice - increased fat tissue locally, noted co-author Stephen Baker, M.D., D.D.S, of Georgetown University Hospital.

The findings could open to the door to adding fat grafts for cosmetic purposes, such as facial rejuvenation, buttock and lip enhancement, and facial reconstruction, or to removing fat.

"This is the first well-described mechanism found that can effectively eliminate fat without using surgery," he said. "A safe, effective, non-surgical means to eliminate undesirable body fat would be of great benefit to our patients."

While it's hard to duplicate office politics or an ill-starred love life in mice, the researchers did the next best thing. In separate experiments they made the animals stand in cold water for long periods of time or put them in a cage with an aggressive alpha mouse.

In both cases, the animals produced more Neuropeptide Y because of the stress but they didn't gain excessive weight unless they were also fed a high-fat, high-sugar diet.

Then they packed it on. Within two weeks, they had abdominal obesity and within three months had a metabolic syndrome-like condition. In contrast, control mice fed a normal diet - but still subjected to the stress - gained significantly less weight (at P<0.05).

But among the chubby mice either an implanted slow-release pellet of an NPY2R blocker or daily injections caused a 40% reduction in visceral fat within two weeks, the researchers found.

Also, mice genetically modified not to have the receptors in the first place didn't gain weight in response to stress and the high-fat, high-sugar diet.

Lydia Kuo, Ph.D., a co-author, said one key take-home message is that stress has a direct physiological effect on fat tissue, rather then being mediated through the brain.

"This is the first study to show that stress has a direct effect on fat accumulation, body weight and metabolism," Dr. Kuo said. "In humans, this kind of stress-mediated fat gain may have nothing to do with the brain, and is actually just a physiological response of their fat tissue."

Co-author Herbert Herzog, Ph.D., of Sydney, Australia's Garvan Institute of Medical Research said the findings should change how we deal with obesity.

"There are millions of people around the world who have lived with high levels of stress for so long their bodies think it's 'normal'," he said. "If these people also eat a high fat and high sugar diet, which is what many do as a way to reduce their stress, they will become obese."

But pharmaceutical interventions to block the Neuropeptide Y receptor could change all that, he said.