Our brain prepares the body for an incoming meal before we even take the first bite. The aroma of food simmering on the stove, for instance, can trigger the brain to send signals to the pancreas, which in turn releases insulin into the bloodstream. A new Nature Metabolism study reveals how a key group of neurons helps mediate this process.

The hypothalamus is the part of the brain that regulates appetite through different groups of neurons, including pro-opiomelanocortin (POMC) neurons that control satiety. Emerging research is finding that these neurons are not only activated while eating, but also by the anticipation of food. However, it has remained unclear what molecular factors are driving this process.

Now, researchers have discovered that this anticipatory activation is powered by pockets of glycogen in POMC neurons. Glycogen is the main way we store energy—the body can break it down into glucose when it’s in need of fuel. Studying the neural circuitry driving hunger and satiety can help scientists better understand how to treat metabolic diseases like obesity, the researchers say.

“Understanding how these neurons function in physiology is an essential first step to be able to target obesity properly,” says Marc Schneeberger Pane, PhD, assistant professor in cellular and molecular physiology and the study’s co-principal investigator

Glycogen powers POMC neurons

To study how the sensory perception of food activates POMC neurons, the researchers presented mice food through a wire mesh so that the animals could see and smell it, but not eat it. Then, the team looked at which molecular signatures were activated in neurons following the presentation of food.

They discovered that food exposure activates glycogen synthase, the molecular machinery that synthesizes glycogen. “That was the first observation that got us thinking that glycogen—how glucose gets stored for energy—is one of these molecular signatures responsible for that sensory response,” says Schneeberger Pane.

The researchers wanted to understand what glycogen was doing in these neurons. So, they engineered mouse models that lacked glycogen synthase in the POMC neurons. When the scientists exposed these mice to food, they found that the mice did not respond as strongly as their normal counterparts. They were less likely to approach food over non-edible objects, spent less time eating, and failed to produce insulin pre-feeding.

To make sure that it was the lack of glycogen causing these effects and not a developmental issue in the mutant mice, the researchers also injected normal adult mice with a virus that removed glycogen synthase. These mice were similarly non-responsive to the sight and smell of food.

“Our study identifies a previously unknown molecular mechanism driving food perception, revealing that neuronal glycogen fuels the brain’s anticipatory responses to food,” says Marc Claret, PhD, 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 team also explored which sensory components of food drive the activation of the neurons. They found that POMC neurons connect with the parts of the brain that process smell, but not those that process vision.

The findings challenge previously-held beliefs about the brain’s physiology. Scientists have believed the glycogen in the brain primarily resides in astrocytes, which act as support cells that provide nutrients to neurons. The study suggests that glycogen may play a more expansive role in the brain than previously thought.

Opening avenues for obesity treatment

The researchers also assessed the consequences of impaired POMC processing. “This sensory aspect of food prepares the organism for what is coming,” says Schneeberger Pane. The secretion of insulin, for instance, prepares the body for the change in glucose levels caused by incoming food. “Dysregulation will compromise the system’s ability to properly respond to food.”

The research team compared the mice lacking glycogen synthase with their typical counterparts as they aged. Mutant mice exhibited significantly reduced metabolic health over time—they became obese and developed indicators of prediabetes.

Obesity has become a massive global health crisis, but the emergence of novel anti-obesity drugs has been a powerful tool in curbing the pandemic. These drugs, including glucagon-like peptide-1 (GLP-1) receptor agonists, work by targeting the circuitry that drives satiety. Better understanding of the neural circuitry underlying appetite can offer further insight into future drug development.

“These findings suggest that defects in how the brain anticipates food may contribute to obesity and diabetes, opening new therapeutic avenues for these diseases,” says Claret.

(Newswise/HG)