‘Shunt’ makes mice super fat burners

By inserting a molecular shunt into the livers of mice, researchers have shown they can make the animals burn more fat. That so-called glycoxylate shunt consists of two metabolic enzymes normally found in bacteria and plants, but not in mammals, according to the report in the June issue of Cell Metabolism, a Cell Press publication.

“It’s an additional channel for burning fat to control obesity,” said James Liao of the University of California, Los Angeles.

“This creates a shortcut through [the normal pathway],” added Katrina Dipple, also of UCLA. “It’s like putting in a toll road.”

In the beginning, the researchers really didn’t know what to expect the enzymes taken from E. coli bacteria would do when placed in mammalian cells. In fact, the glycoxylate shunt actually prevents the complete oxidation of fat in the organisms in which it is normally found.

“There was no guarantee it would work,” Liao said. “But we were brave enough to try.”

Remarkably, they found that human liver cells expressing the enzymes burn more fat. Likewise, mice with the shunt resist becoming obese despite eating a high-fat diet.

Liao and Dipple’s team traced those effects to lower levels of a fat metabolite called malonyl-CoA and an additional fat oxidation pathway.

“By perturbing the system, we were able to find how it’s controlled,” Dipple said.

The findings suggest that malonyl-CoA may be a good target for therapies aimed at ramping up fat breakdown. While the delivery of these genes into humans via gene therapy might some day be an option, Dipple emphasized it is not their intent to suggest such a strategy in the case of obesity.

The study does offers proof-of-principle for a new way to study metabolism.

“Usually, we study metabolism by knocking out a gene or replenishing one that is missing,” Liao said. “In this case, we introduced a new pathway to see the response.”

As an interesting aside, Liao said he has also been tinkering with metabolic pathways in bacteria for biofuel production. In the current study, he wanted to see if he could also do the reverse — design a cell that burns energy faster.

The researchers include Jason T. Dean, University of California, Los Angeles, CA, Linh Tran, University of California, Los Angeles, CA, Simon Beaven, University of California, Los Angeles, CA, Howard Hughes Medical Institute; Peter Tontonoz, Howard Hughes Medical Institute; Karen Reue, University of California, Los Angeles, CA, Katrina M. Dipple, University of California, Los Angeles, CA, and James C. Liao, University of California, Los Angeles, CA.

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