According to the Centers for Disease Control and Prevention, approximately 25 percent of American adults and more than 15 percent of children and teenagers are obese. Many major medical problems, premature deaths and skyrocketing healthcare costs can be attributed, in part, to the growing obesity epidemic. Now researchers from the UCLA Henry Samueli School of Engineering and Applied Science, working together with colleagues at the David Geffen School of Medicine at UCLA, have discovered a unique approach to understanding metabolism, which could lead to understanding how to control and prevent obesity. Specifically, the researcher team, led by chemical and biomolecular engineering professor James Liao and associate professor of human genetics and pediatrics Katrina Dipple, constructed a “non-native pathway in mice that increased fatty acid metabolism and resulted in resistance to diet-induced obesity.”
The idea for the novel approach was taken from plants and bacteria, explains Jason Dean, a graduate student on the research team and an author of the study. “We came up with an unconventional idea which we borrowed from plants and bacteria,” says Dean. “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,” he explains.
According to the details about the study, which was published in Cell Metabolism, the researchers 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, where fatty acids are burned in cells. The researchers discovered that the shunt cut the energy-generating pathway of the cell in half. This allowed cells to digest the fatty acid much more quickly. In addition, they created another pathway for converting fatty acid into carbon dioxide. Ultimately, the scientists 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.
“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,” emphasizes Dipple. And adds Karen Reue, a UCLA professor of human genetics and another author of the study, “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. This could have relevance in understanding, and potentially treating, human obesity and associated diseases, such as diabetes and heart disease.”
News Release: Researchers engineer metabolic pathway in mice to prevent diet-induced obesity www.newsroom.ucla.edu June 2, 2009
