(333a) A Tale of Two Energy Problems: Fuel Shortage and Obesity

Global energy problems have stimulated increased efforts in synthesizing fuels and chemicals from renewable resources. However, through millions of years of evolution, nature only uses a limited set of metabolites to perform all of the biochemical functions. As such, our choice of biochemical fuel production is limited. To increase the metabolic capabilities of biological systems, we have expanded the natural metabolic network using a non-natural approach. We expanded the microbial metabolic system to produce higher alcohols. Compared to the traditional biofuel, higher alcohols offer advantages as gasoline substitutes because of their higher energy density and lower hygroscopicity. In addition, branched-chain alcohols have higher octane numbers compared to their straight-chain counterparts. We successfully engineered various microorganisms to produce higher alcohols containing 3 to 8 carbons.

While fossil energy shortage presents a global economical problem, excess in energy storage in human bodies (obesity) has become a leading health threat in developed countries and is associated with the constellation of clinical problems known as the metabolic syndrome: insulin resistance, diabetes, cardiovascular disease, dyslipidemia, and fatty liver. Given the success in engineering synthetic phenotypes in microbes, 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.

This talk will address the common principles used in engineering metabolic systems to address a series of divergent problems.