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Tuesday, January 20, 2009

Blocking Enzyme Prevents Obesity

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Fat begone: Shown here is a mouse lacking an enzyme that controls fat storage. These mice can eat a high-fat diet--the pink pellets are 45 percent fat--and stay lean.
Credit: Robin Duncan

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.

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.