Resistance to diet-induced obesity in mice with synthetic glyoxylate shunt.
Given the success in engineering synthetic phenotypes in microbes and mammalian cells, constructing non-native pathways in mammals has become increasingly attractive for understanding and identifying potential targets for treating metabolic disorders. Here, we introduced the glyoxylate shunt into mouse 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, circulating leptin 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.
Dean
Jason T
JT
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, CA 90095, USA.
Tran
Linh
L
Beaven
Simon
S
Tontonoz
Peter
P
Reue
Karen
K
Dipple
Katrina M
KM
Liao
James C
JC
D000818:Animals; D050218:Body Fat Distribution; D045744:Cell Line, Tumor; D004041:Dietary Fats / Q000378:metabolism*; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005943:Gluconeogenesis; D006038:Glyoxylates / Q000378:metabolism*; D006801:Humans; D007522:Isocitrate Lyase / Q000235:genetics / Q000378:metabolism*; D020738:Leptin / Q000097:blood; D008292:Malate Synthase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008316:Malonyl Coenzyme A / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000201:enzymology* / Q000517:prevention & control; D012129:Respiratory Function Tests; D014280:Triglycerides / Q000097:blood
D004041:Dietary Fats; D005227:Fatty Acids; D006038:Glyoxylates; D020738:Leptin; D014280:Triglycerides; D008316:Malonyl Coenzyme A; D008292:Malate Synthase; D007522:Isocitrate Lyase