Diet-induced Obesity Prevented In Mice With Engineered Metabolic Pathway

While recent research advances and treatment methods have had little effect in reducing obesity levels, researchers at the UCLA Henry Samueli School of Engineering and Applied Science, in collaboration with the David Geffen School of Medicine at UCLA, may have discovered a completely new way to approach the problem.

In a study to be published in the June 3 issue of the journal Cell Metabolism, chemical and biomolecular engineering professor James Liao, associate professor of human genetics and pediatrics Katrina Dipple and their research team demonstrate how they successfully constructed a non-native pathway in mice that increased fatty acid metabolism and resulted in resistance to diet-induced obesity.

"When we looked at the fatty-acid metabolism issue, we noted there are two aspects of the problem that needed to be addressed," Liao said. "One is the regulation; fatty acid metabolism is highly regulated. The other is digestion of the fatty acid; there needs to be a channel to burn this fat."

"We came up with an unconventional idea which we borrowed from plants and bacteria," said Jason Dean, a graduate student on Liao's team and an author of the study. "We know plants and bacteria digest fats differently from humans, from mammals. Plant seeds usually store a lot of fat. When they germinate, they convert the fat to sugar to grow. The reason they can digest fat this way is because they have a set of enzymes that's uniquely present in plants and bacteria. These enzymes are called the 'glyoxylate shunt' and are missing in mammals."

To investigate the effects of the glyoxylate shunt on fatty acid metabolism in mammals, Liao's team cloned bacteria genes from Escherichia coli that would enable the shunt, then introduced the cloned E. coli genes into the mitochondria of liver cells in mice; mitochondria are where fatty acids are burned in cells.

The researchers found that the glyoxylate shunt cut the energy-generating pathway of the cell in half, allowing the cell to digest the fatty acid much faster than normal. They also found that by cutting through this pathway, they created an additional pathway for converting fatty acid into carbon dioxide. This new cycle allowed the cell to digest fatty acid more effectively.

"The significance of this is great. It is a unique approach to understanding metabolism. Perturbing metabolic pathways, such as introducing the glyoxylate shunt and seeing how it affects overall metabolism, is a novel way to understand the control of metabolism," Dipple said.

The team also found that the new pathway decreased the regulatory signal malonyl-CoA. When malonyl-CoA levels are high, a signal is released that tells the body it is too full and that it needs to stop using fat and begin making it. Malonyl-CoA is high after eating a meal, blocking fatty acid metabolism. The new pathway, however, allowed for fat degradation even when the body was full.

Ultimately, the research team found that mice with the glyoxylate shunt that were fed the same high-fat diet — 60 percent of calories from fat — for six weeks remained skinny, compared with mice without the shunt.

"One exciting aspect of this study is that it provides a proof-of-principle for how engineering a specific metabolic pathway in the liver can affect the whole body adiposity and response to a high-fat diet," said Karen Reue, a UCLA professor of human genetics and an author of the study. "This could have relevance in understanding, and potentially treating, human obesity and associated diseases, such as diabetes and heart disease."

"We are very hopeful," said Liao. "This is the first example of how people can build new genes into mammals to achieve a desired function. It's very exciting that we've been able to achieve this new pathway in mammals that could potentially be used to fight a very serious problem."