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.