While we eat, food-derived signals travel from different parts of our gut to our brains through sensory neurons, to help balance how much we eat to our blood glucose levels. The vagus nerve plays an important role in this complex balancing act. However, the exact routes these different signals take from the gut to the brain, the roles different vagal and spinal neurons play in transmitting information from the gut to the brain, and how their activity contributes to adaptations of feeding behavior and blood sugar levels have remained unclear.

A new study led by scientists at the Max Planck Institute for Metabolism Research in Cologne, the Cluster of Excellence for Ageing Research CECAD at the University of Cologne and the University Hospital Cologne, probes the contributions of distinct sensory neurons in gut-brain communication.

In an article in the journal Cell Metabolism, titled “Gut-brain communication by distinct sensory neurons differently controls feeding and glucose metabolism,” the scientists identify distinct gut-innervating vagal sensory neurons that  control food intake and glucose metabolism in the body, and engage different downstream circuits in the brain. These findings provide specific targets for metabolic control and could play an important role in developing therapeutic strategies against obesity and diabetes.

The authors reconstruct innervation patterns in the gut of vagal and spinal sensory neurons to show GLP1R (glucagon-like peptide 1 receptor)-expressing vagal sensory neurons relay signals from the stomach to brainstem neurons that cause a loss of appetite (anorexigenic signals). These are required to regulate blood glucose levels while eating.

For instance, they show activation of GLP1R vagal sensory neurons increases glucose tolerance (the ability of the body to dispose of a glucose load) and their inhibition increases glucose levels independent of food intake.

In contrast, the scientists show intestinal GPR65 (G protein-coupled receptor 65)-expressing vagal neuron stimulation increases glucose production in liver cells and activates neurons in the brainstem that control glucose levels in the blood. But these, they show are dispensable for feeding regulation.

“The reaction of our brain during food consumption is probably an interplay of these two nerve cell types,” says Henning Fenselau, PhD, senior author on the study. “Food with a lot of volume stretches our stomach and activates the nerve cell types innervating this organ. At a certain point, their activation promotes satiety and hence halts further food intake, and at the same time coordinates the adaptations of blood sugar levels. Food with a high nutrient density tends to activate the nerve cells in the intestine. Their activation increases blood glucose levels by coordinating the release of the body’s own glucose, but they do not halt further food intake.”

In the control center of the vagus nerve, called the nodose ganglion, the cell bodies of various neurons cluster, some innervate the stomach while others innervate the intestine. Some of these neurons detect mechanical stimuli, such as the degree to which the stomach stretches during feeding, while others detect chemical signals, such as nutrients in the food.

“To investigate the function of the nerve cells in the nodose ganglion, we developed a genetic approach that enables us to visualize the different nerve cells and manipulate their activity in mice. This allowed us to analyze which nerve cells innervate which organ, pointing to what kind of signals they detect in the gut,” says Fenselau. “It also allowed us to specifically switch on and off the different types of nerve cells to analyze their precise function.”

The study suggests that the response of our brains to the food we eat is likely mediated by an interplay of the GLP1R and GPR65 expressing neurons.