Attenuated hypothalamic response to fructose via a dedicated gut-brain pathway

Fructose is a simple sugar and a major component of our diet, yet its effects on gut-brain feeding circuits remain poorly understood. Here, we investigated how fructose influences activity in hypothalamic agouti-related protein (AgRP) neurons-key regulators of hunger. Fructose was markedly less effective than equicaloric glucose at suppressing AgRP neuron activity in mice, challenging the prevailing model of AgRP neurons as indiscriminate calorie detectors. This blunted neural response to fructose did not alter short-term food consumption but was instructive for food preference, demonstrating that graded AgRP neuron activity changes are sufficient to guide food choice. Mechanistically, we discovered that fructose activates a distinct gut-brain pathway involving the release of PYY and signaling through Y2 receptor-expressing vagal afferent neurons to inhibit AgRP neurons. These findings unexpectedly reveal that AgRP neurons respond not just to calories, but to specific nutrients, and highlight how fructose engages a unique gut-brain pathway to communicate with AgRP neurons.