Two decades ago, the discovery of neuropeptide Y (NPY), a peptide in the mammalian brain involved in food-seeking behavior, sparked a search for a weight-loss remedy that could interfere with its activity. Eventually the promise of other drug targets, along with the possible side effects of targeting NPY, put a damper on the effort—until now. New findings about the action of this appetite-promoting peptide could bring NPY back to the front burner.
A study released this week in Cell reports on fruit fly neural circuitry that is affected by the drosophila equivalent of NPY—dNPF. The latter peptide disrupts a group of neurons that would normally put the brakes on tapping memory to search for food. Instead, dNPF allows neurons to release signals that prompt flies to hunt for a meal. By blocking the effect that dNPF has on neurons that interact with drosophila's memory center, the researchers found they could halt the flies' feeding frenzy, and trick them into thinking they were full, even though they had not eaten. The fact that NPY in mammals has similar appetite-inducing activity as its drosophila analogue suggests that it might also govern an as-yet unknown network in the human brain that regulates our desire to seek sustenance.
"We know quite a lot about the memory system for olfactory memory in the fruit flies. That gave us some hope that we would be able to find a site of integration between [hunger] state and…memory," says Scott Waddell, an associate professor of neurobiology at the University of Massachusetts Medical School in Worcester, and supervisor of the new research.
Waddell's group started by tracing the activity of dNPF. First, they taught the flies to associate a certain scent with hunger. They deprived the flies of food for one night, and exposed the hungry insects to two different odors the next day. The first was associated with no food, the second with sugar. The flies remembered for several days after the training period which scent came with a sweet treat. During those days, the researchers tested the flies' memories by letting them go hungry and then watching which of the two scents the flies would head toward. But, as other researchers had seen, when Waddell's group boosted the levels of dNPF in the insects' brains, the flies beelined for the sugar-associated odor, even if they had been allowed to eat. In essence, dNPF tricked the flies into behaving like they were hungry. Presumably, dNPF triggered the retrieval of the memories that flies had formed during the training period to associate hunger with food-seeking behavior.
To pinpoint where dNPF was acting in the brain, the researchers turned to dNPF receptors, or the proteins on the surface of neurons to which the peptide specifically binds. By interfering with the dNPF receptors on different subsets of neurons, the authors identified one group of neurons that was important for dNPF's effect. These were clustered together in the same area of the brain as olfactory memory neurons. This area of the fly brain is termed the mushroom body, and is associated with motivation and learning.
This cluster of memory neurons is the switch between hungry or satiated behavior, Waddell says. In this food-seeking scenario, dNPF would be the finger that flips the switch. When levels of dNPF get high, either artificially or naturally—as a result of a lack of glucose, for example—flies are driven to a food source. But if these memory neurons do not respond to the increased dNPF levels—perhaps if dNPF receptors are removed—there will be no retrieval of food-seeking memories. When switched "off", this neural circuit can cause the flies to ignore food even if they are hungry.
Although the mushroom body is specific to drosophila brains, researchers have been on the hunt for analogous regions in the human brain. It will likely turn out to be a network of different parts of the cortex, Waddell says. The memory neurons that his group discovered in flies are those that release the neurotransmitter dopamine, which is associated with motivation and reward. It is not clear, however, if dopamine plays a role in the relationship between the neurons and dNPF.
As for treating eating problems in humans, it remains to be seen what clues this connection between dNPF and a memory circuit will offer. "But I think the translational relevance of the drosophila paper is pretty high," says Dianne Figlewicz Lattemann, a senior research career scientist at the U.S. Department of Veterans Affairs and a research professor of psychiatry and behavioral sciences at the University of Washington in Seattle. For one thing, she says, it could shift the current focus from treatments like calorie-counting to looking at motivations for eating. "In terms of the feeding field, we know nothing about memory retrieval," Figlewicz Lattemann adds. "It's fertile for exploration, and so this paper may be a lightbulb, showing a new place for people to look."