This study investigates the neural basis of melanocortin-4 receptor (MC4R)-regulated appetite, focusing on the role of MC4R-expressing neurons in the paraventricular nucleus of the hypothalamus (PVH). The authors used Cre-recombinase-driven labeling and optogenetic techniques to manipulate MC4R neurons in mice. They found that PVH MC4R neurons are downstream targets of agouti-related peptide (AgRP) neurons, which promote hunger, and that these neurons are essential for satiety. The study also identified a key pathway from PVH MC4R neurons to the lateral parabrachial nucleus (LPBN), which is involved in the regulation of feeding behavior. Optogenetic activation of this pathway reduced food intake in calorie-depleted mice, suggesting its role in satiety. The authors conclude that the PVH MC4R→LPBN pathway is a promising target for anti-obesity drug development, as it encodes positive valence and is responsive to nutritional state.This study investigates the neural basis of melanocortin-4 receptor (MC4R)-regulated appetite, focusing on the role of MC4R-expressing neurons in the paraventricular nucleus of the hypothalamus (PVH). The authors used Cre-recombinase-driven labeling and optogenetic techniques to manipulate MC4R neurons in mice. They found that PVH MC4R neurons are downstream targets of agouti-related peptide (AgRP) neurons, which promote hunger, and that these neurons are essential for satiety. The study also identified a key pathway from PVH MC4R neurons to the lateral parabrachial nucleus (LPBN), which is involved in the regulation of feeding behavior. Optogenetic activation of this pathway reduced food intake in calorie-depleted mice, suggesting its role in satiety. The authors conclude that the PVH MC4R→LPBN pathway is a promising target for anti-obesity drug development, as it encodes positive valence and is responsive to nutritional state.