ARTICLE

A closed-loop synthetic gene circuit for the treatment of diet-induced obesity in mice Katrin Rössger1, Ghislaine Charpin-El-Hamri2 & Martin Fussenegger1,3 Diet-induced obesity is a lifestyle-associated medical condition that increases the risk of developing cardiovascular disease, type 2 diabetes and certain types of cancer. Here we report the design of a closed-loop genetic circuit that constantly monitors blood fatty acid levels in the setting of diet-associated hyperlipidemia and coordinates reversible and adjus-table expression of the clinically licensed appetite-suppressing peptide hormone pramlintide. Grafting of the peroxisome proliferator-activated receptor-a onto the phloretin-responsive repressor TtgR produces a synthetic intracellular lipid-sensing receptor (LSR) that reversibly induces chimeric TtgR-specific promoters in a fatty acid-adjustable manner. Mice with diet-induced obesity in which microencapsulated cells engineered for LSR-driven expression of pramlintide are implanted show significant reduction in food consumption, blood lipid levels and body weight when put on a high-fat diet. Therapeutic designer circuits that monitor levels of pathologic metabolites and link these with the tailored expression of protein pharma-ceuticals may provide new opportunities for the treatment of metabolic disorders