How Your Brain Prepares Your Body for Food

Pockets of glycogen in pro-opiomelanocortin (POMC) neurons fuel the brain’s ability to prepare the body for food before eating, according to a study published in Nature Metabolism. Researchers found that these neurons in the hypothalamus trigger insulin release in response to the smell of food, a process that, when impaired, can lead to obesity and prediabetes.

The study, co-led by Yale University and the Institut d’Investigacions Biomèdiques August Pi i Sunyer, identifies glycogen synthase as the molecular machinery responsible for this sensory response. This discovery challenges the long-held scientific belief that glycogen in the brain is primarily stored in astrocytes, which are support cells, rather than within the neurons themselves.

How does the brain prepare the body for a meal?

The brain uses the hypothalamus to regulate appetite and satiety. When a person smells or sees food, the brain sends signals to the pancreas to release insulin into the bloodstream. This prepares the body to manage the change in glucose levels that occurs once eating begins.

According to the researchers, this anticipatory activation is powered by glycogen, the body’s primary way of storing energy. In POMC neurons, glycogen is broken down into glucose to provide the fuel necessary for these neurons to fire in response to food cues.

To test this, researchers used mice and presented food through a wire mesh. This allowed the animals to see and smell the food without consuming it. The team observed that food exposure activated glycogen synthase, the mechanism that synthesizes glycogen.

What happens when glycogen synthase is missing?

The research team engineered mouse models that lacked glycogen synthase specifically in their POMC neurons. These mice showed a marked decrease in their response to food cues compared to normal mice.

• The mutant mice were less likely to approach food over non-edible objects.
• They spent less time eating.
• They failed to produce insulin before feeding.

To confirm these results weren’t due to developmental issues, the team injected adult mice with a virus that removed glycogen synthase. These adult mice also became non-responsive to the sight and smell of food.

How does this relate to obesity and diabetes?

The study found that a failure in this anticipatory system has long-term metabolic consequences. When researchers compared mutant mice to typical mice as they aged, the mice lacking glycogen synthase developed indicators of prediabetes and became obese.

“Obesity is a dysregulation of the feeding circuitry at the level of the brain—it’s more of a disease of a brain than a disease of the body,” said Marc Schneeberger Pane, assistant professor in cellular and molecular physiology at Yale and the study’s co-principal investigator.

Schneeberger Pane stated that understanding how these neurons function is an essential first step to targeting obesity properly. The researchers noted that while current anti-obesity drugs, such as glucagon-like peptide-1 (GLP-1) receptor agonists, target satiety circuitry, understanding the anticipation phase offers new therapeutic possibilities.

Which senses trigger the hunger response?

The research team explored whether vision or smell was the primary driver of POMC neuron activation. They discovered that these neurons connect with the parts of the brain that process smell, but they do not connect with the areas that process vision.

“Our study identifies a previously unknown molecular mechanism driving food perception, revealing that neuronal glycogen fuels the brain’s anticipatory responses to food,” said Marc Claret, who leads the Neuronal Control of Metabolism Laboratory at the Institut d’Investigacions Biomèdiques August Pi i Sunyer and the study’s co-principal investigator.

The study was supported by the National Institutes of Health and Yale University, with additional funding from the McCluskey family, the E. Matilda Ziegler Foundation and Interstellar Initiative, and the Foundation for Prader-Willi Research.