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December 3, 1996

Removing brain chemical helps reduce body fat in genetically obese mice

Mice with a mutation that makes them grossly overweight can be induced to be only pleasingly plump, if they are genetically engineered to lack a certain neurotransmitter. Researchers at the University of Washington hope their findings will provide an important clue for future development of drugs that would suppress the same brain chemical and achieve the same effect in obese humans.

The study, by Drs. Jay C. Erickson, Gunther Hollopeter and Richard D. Palmiter of the UW School of Medicine’s Department of Biochemistry, is published in the Dec. 6 issue of the journal Science.

The researchers used a strain of mice that lack leptin, a hormone normally released by fat cells that acts in the brain to suppress the urge to eat and stimulate metabolism. Without leptin, the mice have nothing to curb their appetites; the brain mistakenly thinks the body is starving. The animals become morbidly obese and suffer the ill effects of overweight. But until now, exactly how the brain triggers these effects has been a mystery.

The UW scientists suspected that excessive production of a neurotransmitter called neuropeptide Y (NPY) caused the leptin-deficient mice to overeat and burn fewer calories than normal mice. To test their premise, they genetically engineered mice that lack not only leptin, but also NPY.

Compared to their morbidly obese cousins, the mice lacking NPY become only half as fat. They eat less (although offered the same amount of food), have a higher metabolic rate, have only half as much fat in their “fat pads,” and, while insulin-resistant, develop a less severe form of diabetes.

“If what goes on in these mice is similar to what happens in humans,” said Erickson, “it suggests that excess NPY may contribute to a slower metabolic rate and an increased drive to eat.”

Erickson, a third-year medical student who has a Ph.D in biochemistry from the UW, noted that the study targeted only one form of genetically induced obesity, caused by the inability to produce leptin. It did not look at dietary-induced obesity or other genetic forms of obesity.

Since the suppression of NPY did not result in normal-weight mice, said Erickson, other neurotransmitters must be responsible for the remaining tendency to obesity. “Another goal is to identify those elements,” he said. “Many labs are working on this.”