A study from the Monell Chemical Senses Center reports that, calorie for calorie, fructose and glucose engage different gut–brain pathways in mice. The researchers found glucose more strongly suppresses activity in hunger-related AgRP neurons, while fructose produces a weaker effect through a pathway involving the gut hormone PYY and signaling via the vagus nerve.
Researchers at the Monell Chemical Senses Center monitored neural activity in mice to compare how the sugars fructose and glucose affect brain circuits involved in appetite.
In the experiments, fructose increased levels of the gut hormone peptide YY (PYY). That rise in PYY then signaled through the vagus nerve and produced a modest decrease in the activity of agouti-related protein (AgRP) neurons—cells in the hypothalamus that help drive hunger. When the researchers disrupted this PYY-related pathway, fructose no longer affected AgRP neuron activity.
Glucose produced a different pattern. The team reported that glucose did not depend on the same PYY–Y2 vagus-nerve route and instead caused a much stronger suppression of AgRP neuron activity.
Although the two sugars produced similar short-term effects on how much the mice ate, the animals later developed preferences that tracked with how strongly each sugar inhibited AgRP neurons.
The researchers also tested high-fructose corn syrup (HFCS), a common sweetener that contains a mixture of fructose and glucose. In these experiments, mice preferred HFCS over fructose alone, and HFCS more strongly suppressed AgRP neuron activity than fructose.
Senior author Amber Alhadeff said the findings add to evidence that modern diets—particularly those high in fructose or HFCS—may interact with neural appetite systems in ways that are not explained by calorie content alone.
The study, titled "Attenuated hypothalamic response to fructose via a dedicated gut-brain pathway," was published June 10, 2026, in the journal Neuron.
