Resistance to Diet-Induced Obesity in Mice with Synthetic Glyoxylate Shunt
Jason T. Dean, Linh Tran, Simon Beaven, Peter Tontonoz, Karen Reue, Katrina M. Dipple, and James C. Liao
Cell Metabolism (2009) 9, 525–536
Given the success in engineering synthetic phenotypes in microbes and mammalian cells, constructing non-native pathways in mammals has becomeincreasingly attractive for understanding and identifying potential targets for treating metabolic disorders. Here, we introduced the glyoxylate shunt intomouse liver to investigate mammalian fatty acid metabolism. Mice expressing the shunt showed resistance to diet-induced obesity on a high-fat diet despite similar food consumption. This was accompanied by a decrease in total fat mass, circulatingleptin levels, plasma triglyceride concentration, and a signaling metabolite in liver, malonyl-CoA, that inhibits fatty acid degradation. Contrary to plants and bacteria, in which the glyoxylate shunt prevents the complete oxidation of fatty acids, this pathway when introduced in mice increases fatty acid oxidation such that resistance to diet-induced obesity develops. This work suggests that using non-native pathways in higher organisms to explore and modulate metabolism may be a useful approach.