How the Gut Signals the Brain to Stop Eating

Researchers identify sensory neurons in the gut.

Posted Feb 10, 2020

By the Brain & Behavior Staff

New research has revealed specific types of neurons that control eating behavior. This basic research about how the body and brain work together has important implications for obesity and metabolic disorders, and possibly also for eating disorders such as bulimia and anorexia nervosa.

A team at the University of California, San Francisco led by Zachary A. Knight, Ph.D., used genetic methods to classify and distinguish various types of neurons that are bundled together in the vagus nerve. One of the most important nerve conduits in the body, the vagus nerve connects the brain with the stomach and intestines and has long been known to play a central role in the process by which the body regulates feeding behaviors.

“Given how central eating is in our lives, it’s remarkable that we still don’t understand how our bodies know to stop being hungry when we eat food,” says Dr. Knight, whose 2013 BBRF Young Investigator award supported some of his initial explorations of regulatory systems linking the brain and other parts of the body.

Lining the human gut is an extensive array of nerve endings, which are broadly known to play an important role in controlling how much we eat. The new research extends this knowledge but also challenges long-held assumptions. The prevailing belief has been that hormone-sensitive nerve endings in the gut keep track of nutrients we ingest and initiate signaling when we have eaten enough. But until the new study, no one has been able to discern the specific populations of different neuronal types that convey these “satiety” (fullness) signals from the gut to the brain.

Genetic tools enabled Dr. Knight’s team to map the molecular and anatomical identities of sensory cells in the vagus nerve that have endings in the stomach and intestines. Once different cell types were discernable by markers distinctive to them, it became possible for the researchers to use a technology called optogenetics to manipulate them, individually or in groups. (Optogenetics, which uses beams of colored light to turn neurons on and off, was developed by a team led by BBRF Scientific Council member and 2005 and 2007 BBRF Young Investigator Karl Deisseroth, M.D., Ph.D., of Stanford University).

In freely behaving mice, Dr. Knight’s team experimentally manipulated various subtypes of vagus nerve neurons that have nerve endings in the gut. To their surprise, manipulation of several neuronal subtypes that sense hormones in the intestine—previously hypothesized to control appetite by keeping tabs on nutrient intake—had no impact on the animals’ feeding. Rather, it turned out to be a type of cellular receptor in the intestines, called stretch receptors, which proved a potent target for changing the animals’ appetite. Even more powerfully than similar stretch receptors in the stomach, those in the intestines, when activated via optogenetics, made the mice stop eating.

As their name implies, stretch receptors, when activated during eating, signal to their host cells and then to the brain a “stop eating” signal due to the physical expansion they detect in the gut, once it reaches a certain threshold. These signals work in concert with other signals, including those gauging nutrient intake. But their ability to halt eating independently of other signals makes them an intriguing target for future research on treating metabolic disorders and possibly eating disorders.

For starters, Dr. Knight’s team suggested that the new discovery could help explain why bariatric surgery in people is often effective in long-term appetite and weight reduction. Previously it was thought that this was a consequence of the stomach’s reduction in size, which causes it to pass food very rapidly to the intestine. The new research suggests the key signaling may be taking place in the intestines, however: the rapidly passed food stretches the intestines, with the activation of stretch receptors causing nerve cells to signal to the brain, via the vagus nerve, to stop eating.

Eating disorders are thought to involve, at least in part, problems with signaling between the brain and gut. Bulemia is characterized by binge-eating, followed by purging, while anorexia nervosa involves an inaccurate perception of one’s weight, food restriction, and perhaps also underlying metabolic dysregulation, as suggested in research published last year.

“We don't yet know if our research has any connection to eating disorders like bulimia,” Dr. Knight says. “We think that these intestinal receptors [“stretch receptors”] become activated when people overeat. Given that bulimia is associated with binge eating, dysregulation of these receptors could contribute to these conditions.” Research on the newly discovered regulatory mechanism is just getting underway, he stressed.