Synthetic genetic circuit for treatment of obesity

As treatment against obesity a cel implant that self-monitors the amount of lipids in the blood and that produces a anorectic hormone when there are too many lipids in the circulation? The production of the anorectic hormone can be stopped by applying a lotion to your skin, so that you won’t have to skip the dessert at special occasions. Pure science fiction? No, since a recent publication reports the successful application of this method in obese mice!

Making use of biological fat sensor: PPARα

PPARα is an old acquaintance of mine. During my final thesis I performed research on this transcription factor that regulates uptake, use and breakdown of lipids in tissues such as the liver, kidneys, hart, muscle and adipose. PPARα’s natural ligands are fatty acids. Upon activation by fatty acids PPARα binds to specific DNA promotor sequences, thereby regulating gene expression of whole sets of genes; PPARα is capable of turning on and shutting down certain genes, for example resulting in increased production of proteins that are involved in fat metabolism processes. The fact that PPARα regulates fat metabolism in interaction with a broad range of fatty acids is why PPARα is commonly referred to as the master regulator of fat metabolism; it is a perfect biological fat sensor. This specific feature of PPARα has been utllized in a brilliant manner.

Creation of new transcription factor by coupling PPARα with repressor

For this research a new fat sensor with special properties was developed. The researchers used the fat-sensing part of PPARα and coupled this to a bacterial DNA-binding repressor, forming a new transcription factor. This new transcription factor is activated by fatty acids (because of the fat-sensing PPARα part) and deactivated by phloretin, a metabolite from apples (property of the bacterial repressor). Upon activation the new transcription factor binds to the bacterial repressor-specific promotor which initiates transcription of the gene that is coupled to it. In this case the researchers coupled the promotor to a gene coding for an appetite-suppressing gene.1 See the figure below for an overview of the applied principle.

Application of synthetic genetic circuit in obese mice

The researchers coupled the new transcription factor to the expression of an appetite-suppressing hormone, called pramlintide, and investigated if this synthetic circuit could treat food-induced obesity in mice. Pramlintide suppresses appetite, stimulates satiety and slows down gastric emptying. Microencapsulated cells containing the pramlintide producing synthetic genetic circuit, were placed around the liver of obese mice. In a dose-dependent fashion more or less pramlintide was produced in response to the amount of fat consumed, resulting in decreased blood lipid levels, lower food intake and decreased body weight as compared to control mice. Mice on a normal diet with cell implants remained their body weights, indicating that pramlintide was only produced in the case of overconsumption of food.1

Will we see this kind of advanced therapies for treatment of obesity in the near future? No, I don’t think so. The fact that developments in the field of synthetic biology move quickly and the successful application has now been demonstrated in obese mice, does however indicate that it won’t take light years either. Nonetheless, the creation of a synthetic fat sensor able of sensing a wide range of fatty acids, which is activated by superfluous amounts and shuts down at normal lipid levels, and after coupling it to an anorectic hormone regulates eating behaviour, fat metabolism and body weight in obese mice is simply a stunning display of brilliant research!

Reference

  1. Rössger K, Charpin-El-Hamri G, Fussenegger M. A closed-loop synthetic gene circuit for the treatment of diet-induced obesity in mice. Nat Commun. 2013 Nov 26;4:2825. doi: 10.1038/ncomms3825.