Hunger is a powerful force essential for survival, driving individuals to seek out food. For early humans, it fueled purposeful movement as they hunted prey and gathered plants over long distances. Today, that drive has mostly shifted to foraging in grocery stores or gardens. But hunger is only one side of the coin—the other is satiation, the feeling of fullness that signals it’s time to stop eating, and it is just as important for maintaining energy balance.
The hypothalamus is traditionally viewed as the primary control center for managing hunger and satiety, processing information about taste, digestive hormones, and nutrient levels. But recent research suggests that other regions, such as the brainstem, also play a role in controlling appetite, although the exact mechanisms are unclear.1 This insight inspired Alexander Nectow, a neuroscientist at Columbia University, to investigate the dorsal raphe nucleus (DRN), a small area in the brainstem.
Alexander Nectow studies brainstem cell types regulating food intake and energy expenditure.
Paul Morejón
Until recently, characterizing the various cell types in the DRN was a challenge due to the region’s molecular and spatial diversity. But using a new single-cell molecular profiling technique, Nectow and his team uncovered previously unknown neurons in the DRN that expressed hormones related to appetite, suggesting a role in regulating satiety. Published in Cell, their findings revealed that unlike other known satiation-related cells, which respond to singular cues, these DRN neurons integrate multiple signals and act as the final decision-making that tell the body when to stop eating.2 This discovery sheds new light on the biology of satiation and could pave the way for innovative treatments for obesity.
“The real challenge is understanding how these [feeding and satiation processes] work together to ultimately control a complex behavior,” said Scott Sternson, a neuroscientist at the University of California, San Diego, who was not involved in the study. “This work provides another part on the list of the [satiation] process.”
For their study, Nectow and his team used single-cell resolution phenotyping to discern the locations and molecular compositions of different cell types within the DRN that might be involved in regulating appetite. To the researchers’ surprise, they found a population of previously unrecognized neurons that expressed high levels of cholecystokinin (CCK).
While CCK is a peptide hormone released in the gut, there are also CCK-expressing neurons elsewhere in the brain that are known to control feeding by suppressing appetite. “So, we were really excited when CCK popped out of this subpopulation of neurons that we hadn't studied before,” said Nectow. “We thought, ‘oh, that's quite interesting.’”
To explore whether these newly identified neurons help regulate appetite, researchers used optogenetics to switch the CCK neurons on and off in mice. Whenever they activated the neurons, the mice ate smaller meals.
To understand how these CCK neurons suppress eating, the team tracked their activity during feeding. Their recordings showed that activity peaked after each bite and then quickly declined. The distinct, repeated firing pattern suggests that these neurons track food intake on a bite-by-bite basis.
Based on this observation, Nectow hypothesized that the neurons act as “a really dumb counter that can count to one and then reset.” He explained, “Even though that's kind of silly, it turns out to be pretty useful for the brain, because [these neurons] can effectively tell the brain what the animal is expecting to receive in terms of caloric content.”
In a separate experiment, the researchers explored whether this effect continued over a longer mealtime. They found that activating CCK neurons before a meal significantly reduced food intake over the duration of an hour. Based on this observation, they reasoned that although the CCK neurons' signals are brief, their effects are sustained, leading to prolonged appetite suppression.
Consistent with this, the mice gradually decreased food intake within the first half of meal, suggesting that CCK neurons produce a delayed satiety signal that gradually curbs appetite and ends the meal. “In order for that delay to exist, these neurons have to hold on to the memory of the fact that they need to have that action,” explained Nectow. However, how CCK neurons store this type of memory remains unclear.
Next, the researchers explored whether these neurons respond to sensory cues associated with food, beyond the act of eating. They found that CCK neurons were activated when mice saw food pellets behind an inaccessible barrier or sniffed chow wrapped in tinfoil, suggesting these neurons can process different sensory cues.
In addition to responding to sensory cues, the researchers also tested the neurons' sensitivity to gut-derived signals. They found that the neurons were silenced by ghrelin, an appetite-stimulating hormone, and activated by a glucagon-like peptide-1 receptor agonist, a drug class commonly used to treat obesity and diabetes.
Because these neurons appeared to integrate various streams of information, the researchers mapped the inputs and signaling pathways of CCK neurons. They found that these neurons are central to several satiety-related feedback loops and project to key brain regions, including the hypothalamus, involved in appetite regulation.
For Nectow, many questions remain. He aims to explore which nutrients activate these neurons, how they interact with other neural networks such as those involved in learning, and whether they contribute to obesity. Sternson added that he's particularly interested in how these CCK neurons might influence hedonic eating, the urge to eat purely for pleasure, even when the body doesn't need the calories.
- Bhave VM, Nectow AR. The dorsal raphe nucleus in the control of energy balance. Trends Neurosci. 2021;44(12):946-960.
- Chowdhury S, et al. Brainstem neuropeptidergic neurons link a neurohumoral axis to satiation. Cell. 2025;188(6):1563-1579.e18.
