Brainstem recordings show that our taste buds are the first line of defense against eating too quickly. Understanding how it happens can lead to new avenues for losing weight.
Sequential appetite suppression via oral and visceral feedback to the brainstem. Summary The completion of a meal is controlled by specific neural circuits in the caudal brainstem. A key challenge is to understand how these circuits transform sensory signals generated during feeding into dynamic control of behavior. The caudal nucleus tractus solitarius (cNTS) is the first site in the brain where many meal-related signals are detected and integrated, but how the cNTS processes ingestive feedback during behavior is unknown. Here we describe how prolactin-releasing hormone (PRLH) and GCG neurons , two major types of cNTS cells that promote non-aversive satiety , are regulated during ingestion. PRLH neurons showed sustained activation by visceral feedback when nutrients were infused into the stomach, but these sustained responses were substantially reduced during oral consumption. Instead, PRLH neurons switched to a phasic pattern of activity that was time-limited to ingestion and linked to the taste of the food. Optogenetic manipulations revealed that PRLH neurons control the duration of feeding bursts on time scales of seconds, revealing a mechanism by which orosensory signals feed back to slow the rate of ingestion . In contrast, GCG neurons were activated by mechanical feedback from the gut, tracking the amount of food consumed and promoting satiety that lasted tens of minutes. These findings reveal that sequential negative feedback signals from the mouth and gut activate distinct circuits in the caudal brainstem, which in turn control elements of feeding behavior that operate on short and long time scales. |
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When you eagerly crave a long-awaited dinner, signals from your stomach to your brain prevent you from eating so much that you’ll later regret it, or so it is thought. That theory had never been directly tested until a team of scientists at the University of California, San Francisco recently addressed the question.
It turns out that the picture is a little different.
The team, led by Zachary Knight, PhD, a UCSF professor of physiology at the Kavli Institute for Fundamental Neuroscience, found that it’s our sense of taste that pulls us back from the brink of inhaling food on a hungry day. Stimulated by the perception of taste, a set of neurons (a type of brain cell) spring to attention almost immediately to reduce our food intake.
"We have discovered a logic that uses the brain stem to control how fast and how much we eat, using two different types of signals , one that comes from the mouth and one that comes much later from the intestine ," said Knight, who is also a Howard Hughes Medical Institute investigator and member of the UCSF Weill Institute for Neurosciences. "This discovery gives us a new framework for understanding how we control our diet."
The Nature study could help reveal exactly how weight-loss drugs work and how to make them more effective.
New views of the brainstem
Pavlov proposed more than a century ago that the sight, smell, and taste of food are important for regulating digestion. More recent studies from the 1970s and 1980s have also suggested that the taste of food may limit how quickly we eat, but it has been impossible to study the relevant brain activity during eating because the brain cells that control this process are located deep in the brainstem making them difficult to access or record in an awake animal. Over the years, the idea had been forgotten, Knight said.
New techniques developed by lead author Truong Ly, PhD, a graduate student in Knight’s lab, allowed for the first time to image and record a brainstem structure critical for feeling full, called the nucleus tractus solitarius , or NTS, in an awake mouse. He used those techniques to look at two types of neurons that have been known for decades to play a role in food intake.
The team found that when they put food directly into the mouse’s stomach, brain cells called PRLH ( prolactin-releasing hormone ) were activated by nutrient signals sent from the gastrointestinal tract, in line with traditional thinking and results from previous studies.
However, when they allowed the mice to eat the food as they normally would, those gut signals did not appear . Instead, the PRLH brain cells switched to a new pattern of activity that was completely controlled by signals from the mouth .
"It was a total surprise that these cells were activated by taste perception ," Ly said. "This shows that there are other components of the appetite control system that we should think about."
While it may seem counterintuitive that our brain slows down eating when we’re hungry, the brain actually uses the taste of food in two different ways at the same time. One part is saying, "This tastes good, eat more," and another part is watching how fast you eat and saying, "Slow down or you’ll get sick . " "The balance between the two is how quickly you eat it," Knight said.
The activity of PRLH neurons appears to affect the taste of food for mice, Ly said. That fits with our human experience that food is less appetizing once you’ve had your fill .
Brain cells that inspire weight loss drugs
The slowing induced by the PRLH neuron also makes sense in terms of timing. The taste of food causes these neurons to change their activity in seconds, from controlling the intestine to responding to signals from the mouth.
Meanwhile, it takes many minutes for a different group of brain cells, called CGC neurons, to begin responding to signals from the stomach and intestines. These cells act on much slower time scales (tens of minutes) and can hold off hunger for a much longer period of time.
"Together, these two sets of neurons create a feedback loop," Knight said. "One uses taste to slow things down and anticipate what’s coming. The other uses a visceral signal to say, ’This is what I really ate. Ok, I’m full now!’"
The response of CGC brain cells to stretch signals from the gut is to release GLP-1, the hormone mimicked by some weight loss drugs (semaglutide).
These drugs act in the same region of the brainstem that Ly’s technology has finally allowed researchers to study. "We now have a way to unravel what happens in the brain that makes these drugs work," she said.
A deeper understanding of how signals from different parts of the body control appetite would open the door to designing weight loss regimens tailored to the individual ways people eat, optimizing how signals from the two sets of brain cells interact. , the researchers said.
The team plans to investigate those interactions, seeking to better understand how food taste cues interact with feedback from the gut to suppress our appetite during a meal.
