Plus-sized fly could boost research aimed at treating hereditary obesity

Overeating is a clear cause of obesity, but what causes some people to wolf down too many high-calorie treats while others are naturally predisposed to healthy dietary habits? A growing collection of research suggests it’s all in their genes.

Now scientists at Cold Spring Harbor Laboratory in New York have created the first model of genetic obesity in fruit flies. They believe the plus-sized insects will provide a window into neurological signals that cause overeating and that may be able to be blocked, according to a press release from the lab. Their research was published in the journal Cell Metabolism.

In flies, those brain signals are controlled by a hormone called unpaired 1, which is similar to the human hormone leptin—the master controller of that feeling of fullness that causes people to stop eating. To create the model, Cold Spring scientists genetically manipulated the flies to remove unpaired 1 from their brains, says lead investigator Jen Beshel. This approach differs from most leptin research, which has focused on hormone released from fat cells.

“What we got was overweight flies—flies that couldn’t stop eating,” said Beshel in the release. “They were missing the satiety signal, and this signal was originating from the neurons themselves, not from fat tissue.”

The researchers went on to take the genetic sequence that codes for human leptin and insert it into the fat flies’ brains. This reversed the effect of not having unpaired 1, in essence curing the flies of their tendency to overeat.

Beshel also used genetic engineering to remove certain receptors from fly neurons that are targeted by unpaired 1 and that are similar to human receptors that interact with leptin and regulate eating behavior. They discovered that those brain circuits, and their interplay with obesity-related hormones, work the same way in flies as they do in people.

Obesity researchers, particularly those who are studying leptin’s impact on fat, will no doubt embrace this new fly model. Leptin resistance, for example, is one major area of research.

In September, scientists at Baylor University published research showing that when they deleted a gene called Rap1 from mice and fed them a high-fat diet, they barely gained weight and didn’t become resistant to leptin. Other scientists are pursuing a range of anti-obesity strategies, including manipulating gut bacteria and figuring out how to turn unhealthy white fat cells into energy-burning brown cells.

Beshel plans to perform “thousands of genetic manipulations” on her newly created fly model in an effort to determine what processes in the brain regulate the release of the leptin analog unpaired 1, according to the release from Cold Spring Harbor Laboratory. That could lead to drug candidates for fighting obesity, she said. “Our goal with the fly system is to quickly screen through thousands of different candidates for things that might, for example, confer resiliency in the presence of high-fat food.”