From: Reuters
Published May 6, 2008 01:13 PM

Blocking brain enzyme helped mice stay slim

By Julie Steenhuysen

CHICAGO (Reuters) - Blocking a single brain enzyme helped short-circuit a key hunger signal in mice and made them eat less, lose weight and have better blood sugar control, U.S. researchers said on Tuesday.

While much more research lies ahead, they said the finding may lead to new treatments for obesity and diabetes in humans.

"We believe we have identified an important drug development target that could potentially turn into a metabolic triple play: appetite control, weight loss and blood sugar management," said Tony Means of Duke University Medical Center in Durham, North Carolina, whose study appears in the journal Cell Metabolism.

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Means' team focused on the enzyme CaMKK2, which plays a role in appetite stimulation in mice and in humans. Found in a region of the brain known as the hypothalamus, it takes its orders from a hormone released in the gut known as ghrelin, which is released when the stomach is empty.

Ghrelin is already linked to appetite control.

In a separate brain imaging study in the same journal, researchers at the Neurological Institute at McGill University in Montreal showed that ghrelin not only makes people feel hungry, but it makes food look more appealing by activating pleasure signals in the brain.

Means' idea is to find a way to interrupt ghrelin's activity by toning down the CaMKK2 enzyme's response to the hunger signal.

His team found that mice genetically engineered to lack the enzyme CaMKK2 stayed slim regardless of whether they were on a low-fat or high-fat diet.

"They don't gain as much weight as wild type mice," Means said in a telephone interview.

They also found that mice ate less and lost weight when the researchers gave them a direct brain infusion of a drug known to block the CaMKK2 enzyme.

Means said blocking CaMKK2 in the brain protected mice on a high-fat diet from insulin resistance and glucose intolerance, a type of pre-diabetes in which the body does not manage insulin well.

The tricky part will be finding drugs that can be given orally and still reach the right target in the brain.

Many chemicals are not able to cross the blood brain barrier, a special characteristic of blood vessels feeding the brain that filters out toxins.

Means said his team is now looking for new drug compounds. "The job will be to identify one that will pass the blood brain barrier," he said.

That is just one of the barriers the researchers will have to cross. Many treatments that can prevent obesity in rodents have failed to work in humans, whose eating and appetite behavior is far more complex.

(Editing by Maggie Fox and Doina Chiacu)

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