Cholecystokinin/sulfakinin peptide signaling: conserved roles at the intersection between feeding, mating and aggression

Neuropeptides are the most diverse messenger molecules in metazoans and are involved in regulation of daily physiology and a wide array of behaviors. Some neuropeptides and their cognate receptors are structurally and functionally well conserved over evolution in bilaterian animals. Among these are peptides related to gastrin and cholecystokinin (CCK). In mammals, CCK is produced by intestinal endocrine cells and brain neurons, and regulates gall bladder contractions, pancreatic enzyme secretion, gut functions, satiety and food intake. Additionally, CCK plays important roles in neuromodulation in several brain circuits that regulate reward, anxiety, aggression and sexual behavior. In invertebrates, CCK-type peptides (sulfakinins, SKs) are, with a few exceptions, produced by brain neurons only. Common among invertebrates is that SKs mediate satiety and regulate food ingestion by a variety of mechanisms. Also regulation of secretion of digestive enzymes has been reported. Studies of the genetically tractable fly Drosophila have advanced our understanding of SK signaling mechanisms in regulation of satiety and feeding, but also in gustatory sensitivity, locomotor activity, aggression and reproductive behavior. A set of eight SK-expressing brain neurons plays important roles in regulation of these competing behaviors. In males, they integrate internal state and external stimuli to diminish sex drive and increase aggression. The same neurons also diminish sugar gustation, induce satiety and reduce feeding. Although several functional roles of CCK/SK signaling appear conserved between Drosophila and mammals, available data suggest that the underlying mechanisms differ. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-022-04214-4.