Team:Hong Kong HKUST/Project

FAT BUSTER - Artificial Futile Cycle

While a 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 than simply storing fat in a fat cell. This brought our 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 lacking glyoxylate enzymes, while plants and bacteria can. We intend to introduce glyoxylate enzymes into mammalian cells and create an artificial futile cycle.

While the consequences of introducing such a nonnative cycle are not fully known, Dean et al. (2009) at UCLA recently introduced glyoxylate shunt into mammalian liver cells to investigate fatty acid metabolism. 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 an 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 acid uptake will be quantified to compare the activities in wild type cells, cells expressing the shunt constitutively, and cells expressing the shunt in an inducible manner.

So, to sum up, we envision developing an inducible glyoxylate shunt that will serve to generate an artificial futile cycle in human liver cells. We hope our work will point to a future where obesity patients can increase expenditure of calories and thus alleviate health complications, including cardiovascular disease, diabetes, and cancers.