The creation of a synthetic gene circuit - the combining of genes that don’t normally occur together ? that adjusts production of an appetite suppressing peptide to blood lipid levels is reported in Nature Communications this week. The system could, in principle, be adapted to allow for the tailored production of peptide pharmaceuticals for the treatment of metabolic diseases, such as diabetes and obesity, where blood lipid levels are often elevated.
The nuclear receptor PPARalpha is naturally produced in many cells in the body and activated by fatty acids, which induces the expression of metabolic genes. Pramlintide is an appetite-suppressing peptide drug that is used for the treatment of diabetes. Martin Fussenegger and his team create a genetic circuit in which PPARalpha activation is coupled with the transcription of the gene encoding pramlintide. The resulting synthetic ‘lipid-sensing receptor’ dynamically and reversible adjusts pramlintide expression to fatty acid levels in the environment, creating a system that would increase production of the appetite suppressing peptide if blood lipid levels are elevated, for example due to the consumption of fatty food or as a result of disease. The team then implanted the synthetic receptor ? in the form of genetically modified cells harbouring the construct, and encapsulated in a hydrogel ? in to the belly of mice fed a high-fat diet. They find that mice receiving these implants ate less food, weighed less and had lower levels of blood lipids than mice receiving unmodified cells.