Scientists at the Monell Chemical Senses Center discovered that fructose and glucose communicate with the brain through separate gut-brain pathways. Their findings indicate that these differences may influence food and beverage preferences and could help explain why certain sweetened products are especially appealing.

The study, published June 10 in the journal Neuron, identified a specific signaling route that allows fructose to communicate with the brain. In experiments involving mice, researchers found that this pathway was far less effective than the one used by glucose when it came to reducing activity in neurons associated with hunger.

“This work adds to our growing understanding of how modern diets, especially those high in fructose or high-fructose corn syrup, interact with the neural systems involved in appetite,” said senior author and Monell Member Amber Alhadeff, PhD.

How Fructose and Glucose Affect Hunger Neurons

To investigate how the sugars influence the brain, researchers recorded neural activity in mice after exposure to fructose and glucose.

The team found that fructose increased levels of the gut hormone PYY. That hormone then signaled through the vagus nerve, leading to a modest reduction in the activity of agouti-related protein (AgRP) neurons, which play a major role in driving hunger. When researchers disrupted this pathway, fructose could no longer affect those neurons.

Glucose produced a very different response. According to the researchers, it did not rely on the same PYY-Y2 vagus nerve pathway. Instead, glucose strongly suppressed AgRP neuron activity, resulting in a much larger effect on hunger-related brain signaling.

Sugar Type Influenced Food Preferences

Although fructose and glucose produced similar short-term effects on food intake, the mice eventually developed preferences that corresponded to the degree of AgRP neuron inhibition triggered by each sugar.

The researchers also examined high-fructose corn syrup (HFCS), a widely used sweetener made from a combination of fructose and glucose. The mice showed a preference for HFCS, and the sweetener suppressed AgRP neuron activity more strongly than fructose alone.

According to the researchers, this stronger effect on hunger-related neurons may help explain why foods and beverages containing HFCS can be particularly appealing.

Challenging Assumptions About Calories and Hunger

The results call into question a long-held assumption that AgRP neurons primarily track calorie intake regardless of where those calories come from.

Instead, the findings suggest that these hunger-related neurons can distinguish between different sugars and respond through separate biological pathways. Even though fructose and glucose provide the same amount of energy, the mice’s brains processed them differently.

The study highlights the complexity of nutrient sensing in the body and suggests that even simple sugars can have distinct effects on the gut, the brain, and behavior.

This research was supported by grants R01DK131558, DP2AT011965, R01DK116004, F31DK13558, and S10OD030354 from the National Institutes of Health; the American Heart Association; the New York Stem Cell Foundation; the Klingenstein Fund; the Simons Foundation, the Pew Charitable Trusts, the Penn Institute for Diabetes, Obesity, and Metabolism; the Hearst Fellowship, and the Monell Chemical Senses Center.