The latest research from the Monell Chemical Senses Center in the United States shows that although fructose and glucose, two common dietary sugars, are identical in calories, they communicate with the brain through different "gut-brain pathways." Among them, fructose's "I am full" signal to the brain is significantly weaker than that of glucose. This difference may affect our preferences for food and beverages and the amount we eat.
In experiments on mice, the research team found that fructose communicates with the brain through a specialized gut-brain signaling pathway, but is far less effective than glucose in inhibiting hunger-related neurons. The relevant results were published in Neuron magazine on June 10.
Dr. Amber Alhadeff, one of the corresponding authors of the paper and a member of the Monell Center, said that this work further deepens people's understanding of how modern diets-especially high-fructose or high-fructose corn syrup diets-interact with the nervous system involved in appetite regulation. She points out that different types of sugar may affect brain-body communication in different ways, thereby changing our eating behavior.
By recording neural activity in mice, the researchers found that fructose triggers an increase in the levels of the intestinal hormone PYY, which then acts on AgRP neurons in the hypothalamus through the vagus nerve, thus inhibiting these nerve cells that are closely related to hunger to a certain extent. Once this pathway is disrupted, fructose's effects on these neurons disappear. In contrast, glucose does not rely on the same "PYY-Y2-vagus nerve" pathway, but can significantly inhibit the activity of AgRP neurons.
The research team found that in the short term, fructose and glucose had similar effects on the food intake of mice, but over time, the animals formed different food preferences, which were closely related to the degree of inhibition of their corresponding AgRP neurons. In other words, differences in the brain's response to different sugars will in turn shape the animals' tastes and choices.
In further experiments, the researchers also looked at high-fructose corn syrup (HFCS), which is widely found in processed foods and beverages. This sweetener is a mixture of fructose and glucose. Mice prefer high fructose corn syrup to fructose alone. At the same time, high fructose corn syrup has a stronger inhibitory effect on AgRP neurons than fructose alone. Researchers believe this may help explain why foods and drinks containing high fructose corn syrup are particularly appealing to some people.
The research also challenges conventional wisdom. In the past, it was often thought that hunger-related AgRP neurons simply "calculated" overall caloric intake, without distinguishing between nutrient sources. However, new results show that these neurons actually differentiate between different types of sugar and respond differently through separate biological pathways. Even though fructose and glucose contain the same amount of calories, the mouse brains don't treat them the same and respond to them very differently.
The researchers say these findings highlight the complexity of nutrient sensing mechanisms: even sugars with simple structures can affect the gut, brain and behavior in different ways. Understanding these fine differences is expected to provide new ideas for formulating more scientific dietary recommendations and developing targeted intervention strategies in the future.
According to reports, this research has received funding from multiple National Institutes of Health funds (including R01DK131558, DP2AT011965, R01DK116004, etc.), the American Heart Association, the New York Stem Cell Foundation, the Klingenstein Foundation, the Simons Foundation, the Pew Charitable Trust, the Institute of Diabetes, Obesity and Metabolism at the University of Pennsylvania, as well as the Hearst Fellowship and the Monell Chemical Senses Center. The title of the paper is "Attenuated hypothalamic response to fructose via a dedicated gut-brain pathway", and the corresponding Digital Object Unique Identifier (DOI) is 10.1016/j.neuron.2026.05.013.
The Monell Center for Chemical Senses is an independent, non-profit research institution located in Philadelphia, Pennsylvania, USA. Founded in 1968, it is committed to promoting the development and application of chemical perception science such as smell, taste, chemoreception and interoception to address global challenges in the fields of health, society and the environment.
Finally, the research institution stated that information related to potential conflicts of interest in the paper has been disclosed in the paper. Among them, one of the authors, A.L.A., serves as a member of the Scientific Advisory Board of Zealand Pharma, but this work is not directly related to his advisory role.