A genetically engineered weight-loss implant

Enjoy your Thanksgiving dinner --- they're working on it
November 28, 2013
implantable_slimming_aid

Genetically modified cells implanted in the body monitor the blood-fat level. If it is too high, they produce a satiety hormone. The animal stops eating and loses weight. (Credit: Martin Fussenegger / ETH Zurich / Jackson Lab)

ETH-Zurich biotechnologists have constructed an implantable genetic regulatory circuit that monitors blood-fat levels. In response to excessive levels, it produces a messenger substance that signals satiety (fullness) to the body. Tests on obese mice revealed that this helps them lose weight.

According to the WHO, over half the population in many industrialized nations is overweight, one in three people extremely so, with high-calorie and fatty food a lifetime on the hips, backside and stomach. This also leaves traces in the blood, where various fats ingested via food circulate — a risk factor for heart attacks and strokes.

The biotechnologists combined different genes* that produce particular proteins and reaction steps for several different saturated and unsaturated animal and vegetable fats. They implanted this genetic construct in human cells, inserted these cells into tiny capsules, and implanted the capsules in obese mice that had been fed fatty food.

Fix for mouse obesity now; humans will take longer

Result: the mice stopped eating and their body weight dropped noticeably. As the blood-fat levels also returned to normal, the regulatory circuit stopped producing the satiety signal.

“The mice lost weight although we kept giving them as much high-calorie food as they could eat,” said ETH-Zurich professor Martin Fussenegger from the Department of Biosystems Science and Engineering.. “The animals ate less because the implant signalized a feeling of satiety to them. Mice that received normal animal feed with low (five percent) fat content did not lose any weight or reduce their intake of food.”

Fussenegger envisages 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 — an alternative to invasive surgical interventions such as liposuction or gastric bands. “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.”

Unfortunately, this development cannot simply be transferred to humans, he said. “It will take many years to develop a suitable product.”

* 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.


Abstract of Nature Communications paper

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.