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Calorie Overload Sends The Brain Haywire: Study

Posted: Wednesday, October 08, 2008

Overeating makes the brain go haywire, prompting a cascade of damage that may cause diabetes, heart disease and other ills, U.S. researchers reported on Thursday.
Eating too much appears to activate a usually dormant immune system pathway in the brain, sending out immune cells to attack and destroy invaders that are not there, Dongsheng Cai of the University of Wisconsin-Madison and colleagues found.
The finding, reported in the journal Cell, could help explain why obesity causes so many different diseases. It might also offer a way to prevent obesity itself.

"This pathway is usually present but inactive in the brain," Cai said in a statement.

Obesity is a growing global problem, with 1.8 billion people estimated to be overweight or obese in 2007. Drugs marketed so far to fight obesity have only limited success and, often, severe side-effects.

Cai's team worked in mice, seeking to explain studies that have shown that obesity causes chronic inflammation throughout the body. This inflammation is found in a range of diseases related to obesity, including heart disease and diabetes.
They homed in on a compound known as IKKbeta/NK-kappaB.

Immune cells such as macrophages and leukocytes use it but Cai's team found it in the hypothalamus, a part of the brain linked with metabolism in mice and humans alike.

"The hypothalamus is the 'headquarters' for regulating energy," they wrote.

They found high levels of the compound there but it was normally inactive.

When they fed mice a high-fat diet, it became extremely active. And when it was active, the body ignored signals from leptin, a hormone that normally helps regulate appetite, and insulin, which helps convert food into energy.

Stimulating IKKbeta/NK-kappaB made the mice eat more, while suppressing it made them eat less.

Cai believes his team has discovered a master switch for the diseases caused by overeating.

"Hypothalamic IKKb/NF-kB could underlie the entire family of modern diseases induced by overnutrition and obesity," his team wrote.

Cai does not know why this compound would be in the brain and in the immune system but suspects it evolved long ago in primitive animals that do not have the same sophisticated immune system as modern animals, including mice and humans.
"Presumably it played some role to guide the immune defense," Cai said.� "In today's society, this pathway is mobilized by a different enviornmental challenge -- overnutrition."

"Knocking out" the gene using genetic engineering kept mice eating normally and prevented obesity. This cannot be done in people but Cai believes a drug, or even gene therapy, might work.

Suppressing the pathway might be a potent weapon in the war to fight the burgeoning epidemic of overweight and obesity and its attendant problems, including heart disease and even cancer.

Two-thirds of U.S. adults are overweight or obese; one-third are obese.

Current efforts to combat obesity -- namely dieting and exercise -- are rarely effective and certainly are not long-lasting.
"Exercise and diet may correct abnormal brain regulation [but] long-term food control is very difficult," said Cai, an assistant professor of physiology at the University of Wisconsin-Madison.
"We don't understand why. . . The first important thing to understand is how the dysregulation of the brain is processed. The study we just did provides a new pathway. It's the opening of a new direction."

With gene therapy, a virus or other so-called vector is used to carry corrective DNA into the body, but the approach is still highly experimental.

Source: Diabetes In Control: Zhang, X. Cell, Oct. 3, 2008; vol 136: pp 61-73.

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