Equal calories do not mean equal brain signals, as scientists found that fructose and glucose influence hunger through surprisingly different pathways.
Two common sugars may provide the same number of calories, but the brain does not respond to them in the same way. Researchers at the Monell Chemical Senses Center have found that fructose and glucose communicate with the brain through different gut-brain signaling pathways, a distinction that could influence appetite and help explain why we develop preferences for certain foods and drinks.
In experiments with mice, the scientists identified a specialized pathway that allows fructose to send signals from the gut to the brain. However, compared with glucose, fructose was much less effective at reducing the activity of brain cells involved in driving hunger.
The findings were published in the journal Neuron.
“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 Signals
To investigate how the two sugars influence the brain, the researchers recorded neural activity in mice after each sugar was consumed.
They found that fructose increased levels of the gut hormone PYY, which then sent signals through the vagus nerve to modestly reduce the activity of agouti-related protein (AgRP) neurons. These neurons play a major role in promoting hunger. When the researchers disrupted this signaling pathway, fructose no longer affected the neurons, confirming that this route was responsible for its influence on the brain.
Glucose worked differently. Rather than relying on the same PYY-Y2 vagus nerve pathway, it strongly suppressed AgRP neuron activity through another biological mechanism.
Although mice ate similar amounts of food in the short term after consuming either sugar, their longer-term food preferences reflected the differing levels of AgRP neuron inhibition produced by fructose and glucose.
High-Fructose Corn Syrup Produced a Stronger Response
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 clear preference for HFCS over fructose alone. In addition, HFCS produced stronger inhibition of AgRP neurons than fructose by itself. According to the researchers, this finding may help explain why foods and beverages containing HFCS can be especially appealing to some people.
Rethinking How the Brain Detects Calories
The study challenges the long-standing assumption that hunger-related AgRP neurons respond mainly to calorie intake, regardless of where those calories come from. Instead, the results suggest these neurons can distinguish between different types of sugar and process them through separate biological pathways.
Even though fructose and glucose contain the same number of calories, the mice’s brains responded to them very differently. The findings highlight the complexity of nutrient sensing and suggest that even simple sugars can have distinct effects on communication between the gut and the brain, ultimately shaping eating behavior and food preferences.
Reference: “Attenuated hypothalamic response to fructose via a dedicated gut-brain pathway” by Aaron D. McKnight, Alan de Araujo, Fang-Yu Hsu, Alexandra G. Vargas-Elvira, Alisha A. Acosta, Miliani M. Smith, Wisdom Iwueze, Guillaume de Lartigue and Amber L. Alhadeff, 10 June 2026, Neuron.
DOI: 10.1016/j.neuron.2026.05.013
The 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.
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