Engineering mice with a fat-burning strategy from bacteria keeps the animals thin.
Mice that were engineered with a fat-burning pathway borrowed from bacteria (top) remained thin compared with normal mice (bottom) when both were fed a high-fat diet.
The glyoxylate shunt is composed of just two enzymes. The researchers first introduced genes for these enzymes from E. coli bacteria into cultured human cells and found that they increased the metabolism of fats in the cells. But surprisingly, rather than converting the fat into sugar as bacteria do, the cells burned the fat completely into carbon dioxide. The scientists analyzed gene expression in the cells and found that the new pathway promoted cellular responses that led the cells to metabolize fats rather than sugar.
The researchers then introduced the genes into the livers of mice. While normal mice gain weight when put on a high-fat diet, Liao says that the engineered mice "remained skinny despite the fact that they ate about the same and produced the same waste" and were as active as their normal counterparts. They also had lower fat levels in the liver and lower cholesterol levels. As in the cultured cells, the engineered mice did not convert the fat into sugar, which could have the dangerous side effect of promoting high blood sugar and diabetes. Instead, the scientists found a measured increase in their carbon dioxide output; the excess fat was literally released into thin air. The mice exhibited no visible side effects, although more detailed studies are necessary to verify that.
Liming Pei, a research associate at the Salk Institute for Biological Studies, who coauthored an editorial on the paper in Cell Metabolism, cautions that applying this specific approach to humans is many steps away. But the study is important in terms of finding new strategies to target obesity. Previous approaches, Pei says, "focused on stimulating existing natural pathways" for burning fat. The idea of introducing a strategy from another organism that is not present in the body is a novel one.
"This opens up an opportunity for understanding metabolism and finding new therapeutic applications," Liao says. Someday, it may be possible to actually introduce these bacterial genes or proteins into humans, although Pei points out that such a feat poses many challenges, including a potential immune response to foreign genes. Another possibility would be to search for drugs that could mimic the effects of these enzymes. Furthermore, earlier studies reported glyoxylate shunt activity in chickens and rats, suggesting that higher organisms might retain the genes for this pathway but don't use them; it might be possible to activate dormant genes.
Liao says that the study borrows strategies from synthetic biology, a field that has for the most part focused on engineering new functions into bacteria and other lower organisms. The study suggests that the same concepts could be applied to mammals: just as we create bacteria that produce biofuels, we could introduce new abilities into the bodies of humans and other animals.
"What I found fascinating is that it shows how you could use synthetic biology for human therapies in a highly novel way," says James Collins, a synthetic biologist at Boston University. Current strategies for gene and protein therapy largely focus on single molecules–replacing a missing substance like insulin or inhibiting a harmful protein in cancer. Instead, Collins says, scientists might consider introducing an engineered pathway that allows the body to do something that it couldn't before.