people eating

When we say we feel “full” after eating a meal, we probably think that the feeling of satiety results from having a full stomach. The results of studies by researchers at the University of California, San Francisco (UCSF), now suggest that a stretched intestine may play a bigger role in triggering the brain to tell us that we have taken in enough nutrition and can stop eating. By mapping and manipulating the different types of sensory neurons that send signals from the gastrointestinal system back to the brain via the vagus nerve, the team showed that its mechanoreceptors in the intestine, more than those in the stomach, that effectively switch off hunger-promoting neurons in the brain’s hypothalamus.

“This was quite unexpected, because the dogma in the field for decades has been that stomach stretch receptors sense the volume of food being eaten and the intestinal hormone receptors sense its energy content,” said postdoctoral researcher Ling Bai, PhD, who is first author of the team’s published paper in Cell, which is titled, “Genetic identification of vagal sensory neurons that control feeding.”

The body is naturally very good at keeping weight within a narrow range, at least over the long term. It does this by monitoring how much, and what we eat, and balancing intake with how much energy we expend each day. “The size of each meal is tightly regulated by a physiological system that measures the quantity and quality of ingested food,” the authors wrote.

The vagus nerve contains the primary sensory neurons that monitor gastrointestinal signals. The extensive web of nerve endings in the lining of the gut play an important role in controlling food intake by monitoring the contents of the stomach and intestine and then sending signals back to the brain, which then either increases or reduces appetite.

Hormone Sensitive Mucosal
Proximal intestinal hormone-sensitive mucosal [Knight lab/UCSF]
The general reasoning is that this feedback involves hormone-sensitive nerve endings in the gut that monitor the nutrients ingested, but no one has yet tracked down the exact type of neurons that convey these signals to the brain. “This measurement happens primarily in the gastrointestinal (GI) tract, but the identity of the key cells, signals, and pathways remains poorly defined,” the authors wrote.

“Given how central eating is to our lives, it is remarkable that we still don’t understand how our bodies know to stop being hungry when we eat food,” noted senior researcher Zachary Knight, PhD, a Howard Hughes Medical Institute investigator and associate professor in the department of physiology at UCSF.

One of the challenges to answering this question is that the thousands of sensory nerves involved in collecting sensory information from the stomach and intestine come in many different types. All of these nerves, known as vagal afferents, transmit messages from the gut back to the brain via the same vagus nerve bundle, but it hasn’t been possible to identify exactly which are involved in signaling to the brain to stop eating. Scientists have been able to either block or stimulate the activity of the nerve bundle and change animals’ appetites, but not figure out which vagal nerve endings in particular were responsible for the change.

The Knight lab team, led by Bai, has now been able to comprehensively map the molecular and anatomical identities of the vagal sensory cell types and neurons innervating the stomach and intestine. The map allowed the researchers to selectively stimulate different types of vagal neurons in mice, and demonstrate that intestinal stretch sensors are uniquely able to stop even hungry mice from wanting to eat.

Scientists had previously classified gut sensory neurons into three different types based on the anatomy of their nerve endings. Mucosal endings have nerve terminals that line the inner layer of the gut and detect hormones that reflect nutrient absorption. IGLEs (intraganglionic laminar endings) extend into the layers of muscle that surround the stomach and intestine and sense physical stretching of the gut. The function of the third type, IMAs (intramuscular arrays), is still not known, but may also sense stretching.

“The vagus nerve is thought to be critical for satiation, yet the causal role of specific vagal cell types in the control of feeding behavior has not been tested,” the investigators added. “Vagal afferents are anatomically heterogeneous, and their peripheral axons form characteristic sensory endings that are specialized for detection of chemical (mucosal endings) or mechanical (primarily IGLEs) stimuli … Within these broad classes, electrophysiological studies have revealed a diversity of response properties, including cells that respond to hormones, GI luminal nutrients, osmolytes, pH, GI distension, or luminal stroking.”

“The vagus nerve is the major neural pathway that transmits information from gut to brain, but the identities and functions of the specific neurons that are sending these signals were still poorly understood,” Bai said. “We decided to use modern genetic techniques to systematically characterize the cell types that make up this pathway for the first time.”

“We reasoned that if we could identify genetic markers for functionally distinct populations of vagal neurons and then manipulate their activity during behavior, this might provide new insight into the nature of the gastrointestinal signals that regulate food intake,” the investigators noted.

To achieve this, the team carried out target-guided, single-cell sequencing to generate a molecular map of vagal sensory cell types that innervate the GI tract. “…We then used genetic tools to characterize their morphology, innervation pattern, and function.”

DistalIntestinal Stretch Sensitive IGLE
Distal intestinal stretch sensitive IGLE [Knight lab/UCSF]
Using these genetic techniques Bai and colleagues discovered many different types of mucosal endings, four of which they studied in more detail. Some were mainly found in the stomach and others located primarily in different parts of the intestines, but each type was specialized to sense a particular combination of nutrient-related hormones. The results suggested that stretch-sensitive IGLEs also came in at least two different types, one mainly in the stomach and the other primarily in the intestine.

To learn how these different nerve types in the gut might control appetite, Bai and colleagues used a technique called optogenetics to switch individual types of neurons on and off. The technique involves genetically engineering specific groups of neurons so that they can then be selectively stimulated by light. This allowed the team to test the ability of different types of neuron to stop hungry mice from eating.

As expected, the researchers found that stimulating IGLE neurons that sense stomach stretch in the mice effectively halted eating. But they also, and unexpectedly, found that stimulating the different types of hormone-sensing mucosal endings in the intestine—these had been hypothesized to control appetite—had absolutely no impact on the animals’ feeding. Even more surprisingly, the experiments showed that stimulating IGLE stretch receptors in the intestine had an even more profound effect on reducing appetite in hungry animals than stimulating the stomach stretch receptors. ”We found that food intake was most potently inhibited by vagal afferents that innervate the intestine and form IGLEs—the putative mechanoreceptors that sense intestinal stretch,” the scientists wrote. “Stimulation of these intestinal mechanoreceptors was sufficient to activate satiety-promoting pathways in the brain stem and inhibit hunger-promoting AgRP neurons in the hypothalamus.”

The team’s results raise important questions about how these stretch receptors are normally activated during feeding and how they might be manipulated to treat obesity. The findings also suggest a potential explanation for why bariatric surgery, which is used to treat extreme obesity, is so effective at modulating appetite and reducing weight. The surgery effectively reduces the size of the gut, and researchers have suspected that one reason why the procedure is so effective at blocking hunger is that it causes food to pass very rapidly from the stomach into the intestine. “This is thought to promote satiety by over-activating intestinal nutrient sensors, thereby causing exaggerated release of gut peptides, but it has been challenging to confirm this model experimentally,” the scientists commented. The new findings suggest that rather than overloading nutrient receptors, the rapid passage of food stretches the intestine, activating the vagal stretch sensors and so blocking feeding. “Our data suggest an alternative explanation for this phenomenon: that mechanical distension of the intestine may itself be the signal that triggers the profound reduction in hunger caused by bariatric surgery.”

“Identifying the mechanism by which bariatric surgery causes weight loss is one of the biggest unsolved problems in the study of metabolic disease, and so it is exciting that our work could suggest a fundamentally new mechanism for this procedure,” Knight said. “At present, however, this idea is a hypothesis that still needs to be tested.”


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