Team:Hong Kong HKUST/Project

FAT BUSTER
Resistance to Diet-Induced Obesity with Synthetic Glyoxylate Shunt

While low-fat diet and regular exercise are popular approaches to fight obesity, one easy alternative is simply to increase energy metabolism. In terms of fat storage, conversion of carbohydrates or protein into fat uses ten times more calories of energy than simply storing fat in a fat cell. This brought us attention to one method of burning calories - increase energy expenditure by converting fat into glucose. However, mammals cannot convert fatty acids into carbohydrate due to lack of glyoxylate enzymes, while plants and bacteria can. We envision to introduce glyoxylate enzymes into mammalian cells and create an artificial futile cycle. While the consequence of introducing nonnative cycle unknown, Dean et al. at UCLA recently has introduced glyoxylate shunt into mammalian liver cell to investigate fatty acid metabolism (2009). They observed that although fatty acids could not be converted into glucose in normal mammalian cells, human hepatocytes expressing the glyoxylate shunt have increased fatty acid oxidation and mice expressing the shunt were resistance to diet-induced obesity. In addition to introducing a constitutive glyoxylate shunt, our team plans to elaborate the UCLA study by introducing inducible system that allows tunable fatty acid uptake by sensing fatty acid concentrations. This inducible system prevents the risk of fatty acid deficiency, while greater fatty acid uptake at high circulating concentrations can be facilitated. Fatty acids uptake will be quantified to compare the activities in wild type cells and cells expressing constitutive and inducible glyoxylate shunt. We believe the introduction of an inducible glyoxylate shunt will serve as an artificial futile cycle in human liver cell that increases energy expenditure responding to high circulating fatty acid levels. This will help obesity patients increase expenditure of calories and alleviate health complications, including cardiovascular disease, diabetes, and cancers.