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Stanford Report, August 7, 2002

Researchers find gene receptors at the source of fat-burning tissue

By AMY ADAMS

Many animals have a specialized type of fat cell that burns through excess food before the body socks it away as added pounds. Now researchers have created mice that lack this tissue and instead grow rotund when they overeat. These mice could help researchers understand the complex web of events that lead to obesity and related health problems such as heart disease and diabetes.

The tissue under investigation, called brown adipose tissue or BAT, lines the upper back between the shoulder blades of many adult animals and newborn humans. BAT serves as the body’s fat-burning stove — it turns excess food into heat, burning through unneeded calories and helping to heat the body in chilly weather.

Researchers knew that molecules called beta-adrenergic receptors dot the outside of BAT and that three forms of these receptors were somehow involved in how the fat-burning tissue forms. Knowing that, the researchers wondered if by removing those receptors the BAT would falter in its development.

Sure enough, when the researchers bred mice that lacked all three types of beta-adrenergic receptors, the mice failed to form normal BAT and grew portly on high-fat food, gaining 50 percent more weight than their BAT-containing counterparts. The receptorless mice also had a 16 percent lower metabolic rate than normal mice and couldn’t heat their bodies when temperatures dropped. The researchers reported their findings in the Aug. 2 issue of the journal Science.

If mice that lack the three beta-adrenergic receptors grow fat, it may seem that activating these receptors could help people drop pounds. The problem, says Brian Kobilka, professor of molecular and cellular physiology who helped create these mice, is that beta-adrenergic receptors serve functions throughout the body including the heart. Activating the receptors might rev up the BAT and help portly people shed weight, but not without consequences. "If you need to activate all three receptors to have an anti-obesity treatment, you’d have too many side-effects," Kobilka said.

The chemicals that stimulate the beta-adrenergic receptors are similar to the ones that induce the "flight or fight" response to danger or excitement. In this response the heart rate increases, blood gets redirected from digesting food to powering muscles, and hair stands on end, among other changes. Although these reactions are useful in preparing people to run from danger, they aren’t a good way to live long-term, which would be the result of constant stimulation.

"I’m not sure how good a model this is for treating human obesity," Kobilka said. Instead, he thinks these mice could help researchers piece together the many pathways leading to obesity. By knocking out the BAT, Kobilka said that researchers may get a better understanding of how appetite, insulin, leptin, or the recently discovered ghrelin work together to regulate weight. "You have to get rid of one system to understand how the other systems work," he said.

The mice may also help researchers learn why in many people obesity goes hand in hand with diabetes and heart disease — a triad that’s so common it has earned it’s own name, Syndrome X. Kobilka, whose main interest lies in the role beta-adrenergic receptors play in heart disease, expects the receptorless mice to have problems in addition to weight gain that could point to how the three diseases interrelate.




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