ETH-Zurich biotechnologists have constructed a genetic regulatory circuit from human components that monitors blood-fat levels. In response to excessive levels, it produces a messenger substance that signalises satiety to the body. Tests on obese mice reveal that this helps them to lose weight.
Humankind has a weight problem – and not only in industrialised nations, either: the growing prosperity in many Asian or Latin American countries goes hand in hand with a way of life that quite literally has hefty consequences. According to the WHO, over half the population in many industrialised nations is overweight, one in three people extremely so. Overweight people are at an increased risk of developing type-2 diabetes or cardiovascular disease, the latter being the most common cause of death in western industrialised nations. Not only is high-calorie and fatty food a lifetime on the hips, backside and stomach; it also leaves traces in the blood, where various fats ingested via food circulate. Increased blood-fat values are also regarded as a risk factor for heart attacks and strokes.
The implantable genetic circuit mainly composed of human gene components. On the one hand, it constantly monitors the circulating fat levels in the blood. On the other hand, it has a feedback function and forms a messenger substance in response to excessively high blood-fat levels that conveys a sense of satiety to the body.
In order to construct this highly complex regulatory circuit, the biotechnologists skilfully combined different genes that produce particular proteins and reaction steps. They implanted the construct in human cells, which they then inserted into tiny capsules.
The researchers studied obese mice that had been fed fatty food. After the capsules with the gene regulatory circuit had been implanted in the animals and intervened due to the excessive levels, the obese mice stopped eating and their bodyweight dropped noticeably as a result. As the blood-fat levels also returned to normal, the regulatory circuit stopped producing the satiety signal.
“Instead of placing the mice on a diet to achieve weight loss, we kept giving the animals as much high-calorie food as they could eat,” stresses Fussenegger. The animals ate less because the implant signalised a feeling of satiety to them. Mice that received normal animal feed with a five-per-cent fat content did not lose any weight or reduce their intake of food, says the biotechnologist.
Sensor for different dietary fats
One major advantage of the new synthetic regulatory circuit is the fact that it is not only able to measure one sort of fat, but rather several saturated and unsaturated animal and vegetable fats that are ingested with food at once. However, this development cannot simply be transferred to humans. It will take many years to develop a suitable product. Nonetheless, Fussenegger can certainly envisage that one day obese people with a body mass index of way over thirty could have such a gene network implanted to help them lose weight. Fussenegger sees the development as a possible alternative to surgical interventions such as liposuction or gastric bands. “The advantage of our implant would be that it can be used without such invasive interventions.” Another merit: instead of intervening in the progression of a disease that is difficult to regulate, it has a preventive effect and exploits the natural human satiety mechanism.
This gene network is one of the most complex that Fussenegger and his team have constructed to date and was made possible thanks to the biotechnologist’s years of experience in the field. It is not the first time he and his team have succeeded in constructing such a complex feedback regulatory circuit: a number of years ago, they produced an implant that can also be used to combat gout via a feedback regulatory circuit.
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 adjustable expression of the clinically licensed appetite-suppressing peptide hormone pramlintide. Grafting of the peroxisome proliferator-activated receptor-α 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 pharmaceuticals may provide new opportunities for the treatment of metabolic disorders.
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