Maybe it starts with a low-energy feeling, or maybe you’re getting a little cranky. You might have a headache or difficulty concentrating. Your brain is sending you a message: You’re hungry. Find food.
Studies in mice have pinpointed a cluster of cells called AgRP neurons near the underside of the brain that may create this unpleasant hungry, even “hangry,” feeling. They sit near the brain’s blood supply, giving them access to hormones arriving from the stomach and fat tissue that indicate energy levels. When energy is low, they act on a variety of other brain areas to promote feeding.
By eavesdropping on AgRP neurons in mice, scientists have begun to untangle how these cells switch on and encourage animals to seek food when they’re low on nutrients, and how they sense food landing in the gut to turn back off. Researchers have also found that the activity of AgRP neurons goes awry in mice with symptoms akin to those of anorexia, and that activating these neurons can help to restore normal eating patterns in those animals.
Understanding and manipulating AgRP neurons might lead to new treatments for both anorexia and overeating. “If we could control this hangry feeling, we might be better able to control our diets,” says Amber Alhadeff, a neuroscientist at the Monell Chemical Senses Center in Philadelphia.
To eat or not to eat
AgRP neurons appear to be key players in appetite: Deactivating them in adult mice causes the animals to stop eating — they may even die of starvation. Conversely, if researchers activate the neurons, mice hop into their food dishes and gorge themselves.
Experiments at several labs in 2015 helped to illustrate what AgRP neurons do. Researchers found that when mice hadn’t had enough to eat, AgRP neurons fired more frequently. But just the sight or smell of food — especially something yummy like peanut butter or a Hershey’s Kiss — was enough to dampen this activity, within seconds. From this, the scientists concluded that AgRP neurons cause animals to seek out food. Once food has been found, they stop firing as robustly.
One research team, led by neuroscientist Scott Sternson at the Janelia Research Campus in Ashburn, Virginia, also showed that AgRP neuron activity appears to make mice feel bad. To demonstrate this, the scientists engineered mice so that the AgRP neurons would start firing when light was shone into the brain with an optical fiber (the fiber still allowed the mice to move around freely). They placed these engineered mice in a box with two distinct areas: one colored black with a plastic grid floor, the other white with a soft, tissue paper floor. If the researchers activated AgRP neurons whenever the mice went into one of the two areas, the mice started avoiding that region.
Sternson, now at the University of California San Diego, concluded that AgRP activation felt “mildly unpleasant.” That makes sense in nature, he says: Any time a mouse leaves its nest, it’s at risk from predators, but it must overcome this fear in order to forage and eat. “These AgRP neurons are kind of the push that, in a dangerous environment, you’re going to go out and seek food to stay alive.”
Sternson’s 2015 study had shown that while the sight or smell of food quiets AgRP neurons, it’s only temporary: Activity goes right back up if the mouse can’t follow through and eat the snack. Through additional experiments, Alhadeff and colleagues discovered that what turns the AgRP neurons off more reliably is calories landing in the gut.