When you’re hungry, the impulse to eat can be hard to ignore. There’s even a Snickers commercial about it—people just don’t feel like themselves when their stomachs are empty.

It makes sense evolutionarily that our bodies want to avoid starvation. But in today’s society of plentiful calories, wouldn’t it be nice to occasionally quiet those seemingly incessant messages from the brain to eat, eat, eat?

With a new study published in Cell Reports, researchers at Penn have begun to unravel the signals that travel from stomach to brain upon eating, with an eye toward targeting them as a treatment for obesity. While the mere sight or smell of food can temporarily turn off neurons responsible for the drive to eat, the biologists showed that the neurons only stay off if the brain receives a signal from the stomach that calories have been ingested.    

“When these neurons are firing, they’re basically telling you, ‘You’d better go get food; you’re starving,’” says J. Nicholas Betley, an assistant professor in the Department of Biology in the School of Arts and Sciences and senior author on the study. “They’re a sensitive alarm system. And what this study conclusively demonstrated is that nutrients are the primary regulators of this alarm system.”

Betley and colleagues used mice to explore how these neurons, known as agouti-related protein-expressing (AgRP) neurons, responded to food, distinguishing between seeing or smelling food and actually consuming it.

By presenting the animals with one of two versions of a strawberry-flavored gel that they had never had before—one caloric and one calorie-free—the researchers showed that they could “train” the AgRP neurons to anticipate the presence or absence of nutrients.

“In a single trial, the circuits in the brain’s sensory system learn to associate the visual or olfactory stimulus of the [gel] with calories,” Betley says. “If they get the caloric kind first and then see the calorie-free kind, they predict the nutrients because the flavor is the same, the taste is similar. It takes 200 seconds for the animal to realize that whatever has hit its gut isn’t doing what it should be doing and the activity of those neurons comes back.”

The researchers confirmed this effect of caloric food by directly infusing Ensure into the animals’ stomachs, and saw a sustained and dose-dependent reduction in AgRP neuron activity.

Confident that they understood what regulated the neurons’ activity, Betley and colleagues wanted to see if they could turn it off without using food. They found that by combining three hormones that are typically released during digestion, they could dramatically and synergistically reduce AgRP neuron activity, pointing to a pharmaceutical strategy for treating obesity in humans.

The work might also lend insight into behavioral strategies that could reduce total food intake.

“Maybe we can develop better combinations of foods or better ways of eating so we can avoid that 9 p.m. binge on Oreo cookies when you’ve had a really great diet all day,” Betley says.