Gut-brain signaling is activated by incretin peptides released from enteroendocrine cells during a meal (i). By activating neurons in the hindbrain nucleus of the solitary tract and area postrema, these signals induce the perception of satiety and hence reduce food intake (ii). Lying downstream in this pathway are AgRP neurons in the hypothalamic arcuate nucleus, powerful drivers of the adaptive responses to weight loss, and these neurons are inhibited by incretin-induced activation of gut-brain signaling (iii). Thus, the potent weight loss efficacy of incretin mimetics is mediated not only by a sustained reduction of food intake (via increased satiety) but by blunting the normal adaptive responses to weight loss (iv).