Hopkins finds chemical that slims mice


Scientists have discovered a compound that can quickly turn off the appetite of mice, enabling the rodents to drop up to a third of their weight. The finding offers new targets for researchers struggling to stop one of the fastest-growing health problems in the country: obesity.

Published in today's edition of the journal Science, the report provides fresh insight into how the brain controls feeding behavior.

Essentially, investigators interrupted the normal flow of a complex "assembly line" that regulates appetite in the mouse brain. By blocking one step, researchers say, they changed the next few steps in the line, ultimately making the mouse not feel hungry anymore.

"We trick the brain into thinking the mouse is well-fed and full and happy, so the mouse ignores the food," said Dr. Frank Kuhajda, spokesman for the team of scientists from the Johns Hopkins University and School of Medicine.

The report offers hope as the United States and other developed countries combat an epidemic of obesity. More than half of Americans are overweight or obese, putting them at increased risk for heart disease, diabetes and other potentially fatal conditions.

But scientists warned yesterday that they are years away from turning their discovery into a weight-loss drug.

"We don't have a new fat pill. There is a long, long way to go," said Kuhajda, a pathologist and biochemist. "What this paper points out is we've got a new chance at obesity.

"It very clearly works in mice. Will it work in people? That's the question we have to answer."

They have invested roughly 14 years to get to this point. The Hopkins scientists had been working on cancer, not weight loss. The cells in breast, prostate and other cancers make a lot of fat, and scientists theorized that if they could shut down the fat production, they might shut down the tumors.

After four years of work to create the right substance to block one step in the fat assembly line, scientists injected the new molecule, C75, into the brains of mice.

The growth of cancer cells slowed - and the mice lost weight.

"It appeared they had no interest in food. We thought, 'Wow, this is maybe more special than we thought,'" said Kuhajda, who teamed up with scientists from the departments of chemistry, biological chemistry, neuroscience and pathology.

"This is where the magic is. ... We had no notion that it would do this. It was all a surprise."

It appears to be working in a way that no one has seen before, without any help from other appetite-influencing substances such as the hormone leptin. Researchers found that after the C75 treatment, the production of an appetite hormone dropped sharply, wiping out the animals' interest in eating in 20 minutes.

With a moderate dose, food intake was reduced by more than 90 percent in the first 24 hours, and then returned to normal over the next few days as the chemical wore off.

The treatment also reversed an insulin-resistant form of diabetes the mice experienced. And it didn't cause any harmful side effects to the mice.

Also, when the Hopkins scientists compared the C75 treatment with fasting, they found that the mice on C75 lost 45 percent more than those that fasted.

Researchers said this suggests that unlike many diets, when restricting eating sparks the body to automatically lower metabolism to compensate, the metabolic rate in the C75-treated mice didn't slow down.

Kuhajda noted that no one would propose this dramatic level he doubts it would ever be this simple.

Compared with mice, for example, humans have many more cues to consume calories. People are out with friends and wind up drinking a few cold beers, or they're working late and get a hankering for a Snickers bar.

Still, experts said, the discovery is important.

"This is a very intriguing and provocative finding," said Dr. Denis McGarry, an expert in the field and a professor of internal medicine and biochemistry at the University of Texas Southwestern Medical Center in Dallas.

"If it were correct in its various implications, there is no question it would have a profound impact on the field of obesity research."

He and others said it will likely set off a round of intense investigations of these findings.

"It is truly novel as an idea, and their data support their idea," added Dr. Michael Schwartz, head of the section of clinical nutrition, and associate professor of medicine at the University of Washington in Seattle.

"Whether it really turns out to be valid or not is going to have to await further study."

For many, it can't come fast enough.

Over the past several years, the incidence of obesity has increased sharply throughout the country, particularly among young people.

One study found that only smoking exceeds obesity in its contribution to total U.S. mortality rates.

Experts blame a changing society in which snacks and fast foods are readily available, people watch more television and use labor-saving devices, and cars have replaced bikes and walking.

But over the past six years, as scientists have uncovered several genes involved in body weight regulation, as well as the hormone leptin, researchers are realizing that weight gain isn't simply a matter of gluttony.

Even though lifestyle, diet and exercise are key factors, experts say that at least half the determinants of body weight are inherited.

"The world of medicine is finally coming to recognize that it is not all willpower, that there are powerful genes at work that predispose certain individuals to gain weight," McGarry said.

Some predict that one day, obesity will be treated with a pill, just like high cholesterol. For now, though, treatment options are limited.

The few FDA-approved drugs that can be used long term don't work for everyone and, on average, induce only modest weight loss. Those who are extremely obese can try surgical treatment.

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