Written by Nitin Sreekumar ‘25
Edited by Lisa Liong '25
Nothing brings people of all classes together like good food! Its always a shame when we can no longer eat more, but what is the cause behind this phenomenon? How does our body know when we have had enough food and are full?
Interestingly, our gut could slow down our mouth by applying the brakes, just like a highway police officer might. The intestines may be more important than we realize because we typically believe that our full stomachs are what signal us to stop eating. By detecting the food in the stomach, the dense network of neurons that lines the intestines may oversee regulating our hunger. Glucagon-like peptide-1 (GLP-1), a signal peptide released from the entero-endocrine cells (L cells) of the lower intestine following meal intake, triggers this mechanism [1]. Direct interaction between the nutrients and L cells stimulates the release of GLP-1, which is known to reduce hunger by causing fullness and discomfort [2,3]. Because of GLP-1's crucial function, synthetic GLP-1 has been developed to reduce appetite in obese persons. The connection between the gut and the jaws in GLP-1's control of appetite, however, has always been a mystery.
Zhang and colleagues conducted a recent study in which they identified a sophisticated gut-to-jaw circuit that regulates appetite [4]. They performed a several experiments using transgenic mice and discovered that GLP-1 was quickly degraded after being recognized by gut (intestino-fugal) neurons in the submucosa. An intricate signaling circuit that connected these gut neurons to the brain's hypothalamus division ran from the stomach. The brain then sent signals to the jaw muscles telling them to stop chewing. By stimulating particular groups of neurons along this circuit, they were able to imitate the effects of GLP-1, which resulted in stomach distention, a fullness sensation, and reduced food intake. To prove this role, they did further experiments by ablating these specific neurons and demonstrated elimination of intestinal GLP-1 effects. The effects of GLP-1 were also duplicated in later tests using these neurons that had been chemically activated.
They continued their work by giving GLP-1 synthetic analogs, which activated GLP-1 receptors and the ileal mesenteric neurons, reducing gastrointestinal motility and decreasing appetite. Ileal neurons play a role in inducing the "ileal brake," a phenomenon by which the presence of nutrients within the distal intestine triggers an intestinal-gastric feedback loop that inhibits upper gut motility and appetite. These synthetic analogs, however, gave people nausea, vomiting, and diarrhea. Hence, to stop the anorexia and abdominal bloating linked to gastroparesis, a disorder involving the inability of the stomach to empty, targeting gut neurons and the newly discovered enteric circuits may be crucial instead of utilizing synthetic GLP-1. So, it would be extremely therapeutically important to use neuromodulation techniques to target these gut neurons.
Sometimes our mouth is like a kid in a candy store, and we get carried away by eating too much food too fast. If this happens consistently, it increases the risk of developing serious illnesses like diabetes, heart disease, and cancer. Knowing more about how our body regulates are appetite is vital to ensure the good health of the rest of the body, as a healthy diet plays a role in the proper functioning every organ system. After all, the way to a man’s heart (and liver, brain, and everything else) is though the stomach.
References
Müller TD, et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019; 30:72-130.
Drucker DJ. Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metab. 2018; 27:740-756.
Holst JJ, Andersen DB, Grunddal KV. Actions of glucagon-like peptide-1 receptor ligands in the gut. Br J Pharmacol. 2022; 179:727-742
Zhang T, Perkins MH, Chang H, Han W, de Araujo IE. An inter-organ neural circuit for appetite suppression. Cell. 2022; 185:2478-2494.