By Merritt McKinney

NEW YORK, Mar 29 (Reuters Health) - It's a dieter's dream--eat more, but weigh less. So far, the idea remains a fantasy, but new research points the way towards diet drugs that could promote weight loss by kicking the body's fat-burning process into overdrive.

Researchers in Texas report that genetically engineered mice lacking an enzyme that helps regulate fat burning consumed 20% to 30% more calories than normal mice, but stayed thin or even lost weight.

"With these mice, the burning of fat is continuous," the study's lead author, Dr. Salih J. Wakil of Baylor College of Medicine in Houston, told Reuters Health.

The mice in the study were missing ACC2, or acetyl-CoA carboxylase 2, one of two enzymes involved in the production of a compound called malonyl-CoA. Malonyl-CoA is essential for both the formation and burning of fat.

Wakil explained that most of the food we consume is converted into the simple sugar glucose. Some glucose is burned for energy, while some is converted to fatty acids, he said. Malonyl-CoA is involved in both the formation and burning of these fatty acids, but the compound depends on a different type of ACC to carry out each task.

Malonyl-CoA works with ACC1 to convert glucose into fatty acids, while it relies on ACC2 to regulate fat burning, Wakil explained.

When Wakil and his colleagues engineered mice to lack ACC1--the enzyme involved in fat production--the embryos died within a week or so.

"The conclusion there is that making fat at the embryonic level is very important to embryonic development," Wakil said.

But mice that lacked ACC2--the enzyme that controls fat burning--developed normally, were able to reproduce and had normal life spans, the authors report in the March 30th issue of the journal Science.

Wakil's team noticed an important difference, however. Compared to normal mice, the ACC2-deficient animals ate considerably more food but weighed about 10% less. And the engineered mice carried around about half as much fat as normal mice, Wakil said. He explained that the mutant mice appear to produce normal levels of fat, but the lack of ACC2 leads to continuous fat burning in the liver and muscles. Normally, the enzyme works with malonyl-CoA to transfer fatty acids into the mitochondria, the cell "powerhouses" that burn fat, Wakil said. Without ACC2 to regulate the process, however, mitochondria do not stop burning fat.

He speculated that a hormone called leptin, which makes its way from fat tissue to the brain to regulate appetite, might help explain why mice lacking ACC2 eat more. As fat is burned, less of the appetite-regulating hormone leptin is released, leading to an increased appetite in the mutant mice, according to Wakil.

Assuming that ACC2 exerts similar control on fat burning in people, a compound that would target ACC2 and reduce its activity--leading to increased fat burning--might help people lose weight without having to cut calories, Wakil said. However, he cautioned that any such drug would have to act only on ACC2, not ACC1, the enzyme needed to produce fats.

More research is needed to get a more complete picture of how removing ACC2 lets mice eat more without gaining weight, according to an editorial that accompanies the study.

"(But) whatever the mechanism, inhibition of ACC2 may be a plausible target for the design of new anti-obesity therapeutics," write Dr. Neil Ruderman of Boston University and Dr. Jeffrey S. Flier of Beth Israel Deaconess Medical Center in Boston, Massachusetts.

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