GLP-1 weight-loss drugs are remarkably effective, but many people cannot tolerate or afford them, so cheaper and more potent anti-obesity medicines are needed—and better understanding nutrient-specific fullness (e.g. dedicated factors that reduce sugar and fat intake) may lead to rational combination therapies that co-opt natural mechanisms to reduce hunger for all types of food. We propose to test a new idea: after a meal, the liver senses which nutrient was absorbed and releases blood signals that selectively curb desire for that nutrient. In volunteers we will track thousands of proteins and key metabolites over hours after carbohydrate, fat, protein or alcohol challenges, while measuring hunger and cravings. We will then test the strongest liver signals in mice in a multi-choice feeding system and trace the brain pathways involved. Finally, we will give the liver hormone FGF21 to people to see whether it reduces sweet and alcohol reward