The researchers say that the normal function of the AdPLA enzyme is to trigger a series of molecular signals that block the breakdown of fat. "When AdPLA is eliminated," says Duncan, "this 'brake' on fat breakdown is removed, and lipolysis [fat metabolism] proceeds at full speed, resulting in leanness, even in animals that eat a fatty diet or overeat." The enzyme-deficient animals had a normal number of fat cells, but no fat molecules were stored in them.

Scientists disagree about whether this enzyme provides a promising target for obesity drugs. Preventing all fat storage in adipose cells is unhealthy. Stored fat can be released as fuel for muscle cells. Moreover, humans who lack fat tissue store fat in other organs, such as the liver, which then become less responsive to insulin. The researchers found this same problem in mice lacking the enzyme. "They had excess fat molecules present in liver and muscle, tissues that are big contributors to insulin resistance," says Rosalind Coleman, a scientist at the University of North Carolina in Chapel Hill, who wasn't involved in the research. "It highlights the fact that lipid storage in nonfat cells is a dangerous thing."

The Berkeley researchers hope that it will be possible to turn down the AdPLA enzyme just enough to increase fat breakdown without triggering insulin resistance. But some experts are skeptical, saying that it's unclear whether tinkering with the enzyme would be beneficial or detrimental. "I would be reluctant to develop a drug that inhibits this enzyme," says Andrew S. Greenberg, director of the Obesity and Metabolism Laboratory at the Jean Mayer USDA nutrition research center at Tufts University.

But Duncan is optimistic, thanks to a relatively little-studied component of fat metabolism: breakdown of fat molecules within fat cells themselves. Researchers saw an increase in this kind of fat metabolism in enzyme-deficient mice. "This is exciting, because it means that to some extent, the fats were prevented from ever getting into the blood, and therefore to the liver and pancreas," Duncan says. "There is a limit to how much the fat cells can use, though. The goal is to decrease AdPLA to this limit, rather than remove it completely and cause extreme effects." The researchers are now studying animals with one copy of the AdPLA gene, to determine whether partially reducing enzyme levels prevents insulin resistance.