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Mice lacking gene for key enzyme stay thin despite hefty appetites
Researchers at Baylor College of Medicine, Houston, have identified a new target for drugs to control obesity. Mice that have been genetically modified so that they lack one form of the enzyme acetyl-coenzyme A carboxylase (ACC2) appear to be just like normal mice in all ways but one: Even when they eat 20 to 30% more food than other mice, they stay thin.
The work was done by Lutfi A. Abu-Elheiga, assistant professor of biochemistry and molecular biology; Salih J. Wakil, a professor in the same department; and their colleagues [Science, 291, 2613 (2001)].
||MORE IS LESS Mice minus one enzyme burn more calories than this normal specimen.
PHOTO BY ED COMPEAN
In both humans and mice, ACC synthesizes malonyl coenzyme A, a molecule long thought to play a key role in the synthesis of fatty acids and in their oxidation to release energy. ACC exists in at least two forms; mice lacking ACC1 die as embryos, in-dicating that this form of the enzyme is critical to normal development. But mice lacking ACC2 "seem very happy, live, and breed well," Wakil says.
They also eat 20 to 30% more, on average, than normal mice but weigh about 10% less and have only half as much fat throughout their bodies. That means they are burning more calories, "a physiological state that humans try to attain through exercise," the researchers write. Because ACC2 is found primarily in the mitochondria of heart, muscle, and liver cells, the researchers propose that the mice oxidize more fatty acids in these organs, which somehow signals to the rest of the body to mobilize stored fat.
But other explanations of how the enzyme's loss could keep the animals lean are also possible, note Neil B. Ruderman of Boston University School of Medicine and Jeffrey S. Flier of Harvard Medical School in a commentary that accompanies the publication. Whatever the mechanism, inhibiting ACC2 is now a promising target for the design of new antiobesity drugs, the commentators note.
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Copyright © 2001 American Chemical Society