Yale scientists have discovered how a specific group of neurons fits into the larger puzzle of regulating food intake, providing novel ideas for weight loss therapies.

Working on fruit flies, researchers at the Yale School of Medicine switched on and off neurons that connect to the posterior region of the intestine. When the neurons were activated, the fruit flies ate six times less than when the neurons were deactivated. The researchers were also able to pin down the exact molecular mechanism by which this change occurs, providing a target in the gut for weight loss drugs.

“We discovered how fullness is sensed, and it has implications for combating obesity,” said Tian Xu, vice chair of genetics at the Yale School of Medicine and the paper’s senior author. Xu added that because 1 billion people worldwide are obese or overweight, this finding could dramatically impact global health.

Scientists have long known that the stretching of the stomach as it fills with food induces feelings of satiety, yet the mechanism has remained elusive, said Monica Dus, an assistant professor at the University of Michigan.

Lead author William Olds explained that the team set about answering this question first by selectively turning on and off particular groups of neurons and observing the resultant feeding behavior in flies. Having pinpointed the neurons responsible, the researchers found that these neurons did not actually enter the gut. Instead, they embedded themselves in the outer muscular layer of the gut, showing that feelings of satiety may come not just from the presence of sugars and fats inside the gut, but from external mechanical forces.

In other words, the feeling of fullness may very well result from the expansion of the gut — not just the nutrients inside.

To test this idea, the team silenced the expression of a channel protein known to detect mechanical forces. That, in turn, led to a dramatic increase in the amount of food the flies consumed, providing the first genetic evidence that mechanosensors — and not just nutrient sensors — in the gut regulate food intake.

In focusing on the roles of metabolism and the brain, scientists studying feeding behavior have often overlooked the contribution of the gut, said Greg Suh, an associate professor at New York University who was not involved in the study. Suh added that he was very impressed by the team’s finding.

While the authors cautioned that their results might not be directly translatable to humans, they said that fruit flies serve as important research subjects because scientists have a large number of tools to turn genes and neurons on and off. Flies also share many genes in common with humans and have similar feeding behavior, the researchers interviewed said.

“Most of the time, nature tinkers. It doesn’t create something new if it doesn’t have to,” said Olds, explaining that understanding these relatively simple organisms will eventually help us make sense of the incredibly complex processes happening in the human body.

Richard Lifton, chair of genetics at the Yale School of Medicine, said it will be interesting to watch how well the research translates from fruit flies to humans.

If these findings do translate, doctors may have an ideal target for drug delivery, Olds said. The location of these mechanosensors along the walls of the gut makes them easily accessible to drugs that people take for weight loss. This would also allow lower dosages to be used, reducing toxicity and the chances of side effects.

In the past two years, the FDA has approved three new weight-loss drugs after a 13-year drought in new prescriptive weight loss medicines.