Mice engineered to lack an enzyme found mainly in fat cells can gorge without gaining weight, according to new research. Blocking the enzyme appears to block fat cells' ability to store fat. That sounds like a dream come true for those struggling with excess pounds, but lacking fat has a downside: some mice also developed insulin resistance, a risk factor for diabetes. The researchers who conducted the study hope to find drugs that can turn down the enzyme's activity just slightly, reducing this risk.

"If we can limit activity rather than completely abolish it, we should see positive effects on fat mobilization and fat burning, without seeing the unfavorable effects," says Robin Duncan, a postdoctoral fellow in Hei Sook Sul's lab at the University of California, Berkeley, and a lead author on the paper, published this month in Nature Medicine.

The Berkeley researchers engineered mice to lack an enzyme called adipose-specific phospholipase A2 (AdPLA), which is found mostly in fat cells--technically known as adipose cells. The mice had a normal appetite: they ate about as much as control mice when given unlimited access to high-fat food. But eliminating AdPLA had a huge effect on weight. At 16 months, the engineered mice weighed an average of 39.1 grams, while the normal mice averaged 73.7 grams.

Duncan and her collaborators also found that removing the enzyme could prevent obesity in mice that lack leptin, a hormone that regulates satiety. While a normal mouse eats 2 to 3 grams of food per day, in the Berkeley study, leptin-deficient mice ate about 5 grams, and mice without both leptin and AdPLA ate 7.5 grams. At 17 weeks old, mice lacking both leptin and AdPLA weighed less than half as much as their leptin-deficient counterparts: about 35 grams versus 75 grams. The findings suggest that eliminating the enzyme can prevent obesity even in animals that are genetically prone to it.