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

Abstract

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.

Expression of a constitutively active insulin receptor in Drosulfakinin (Dsk) neurons regulates metabolism and sleep in Drosophila

“…While much is known about the target tissues of the ilps to regulate important biological processes such as growth and energy metabolism [ 17 , 36 ], we have identified an additional cell type in the Drosophila brain (the Dsk neurons) as a site of insulin action. CCK, the Dsk homolog in mammals, is produced in specific endocrine cells in the intestine [ 4 ] and while insulin signaling has been studied in intestinal epithelial cells [ 42 ], the role of insulin signaling in CCK-producing cells has not been studied. This work provides support for our ability to use Drosophila as a model system to further understand the role of insulin signaling in controlling sleep and feeding behaviors as well as metabolism in mammalian systems.…”

“…Animals must balance their nutritional state with their energy expenditure and activity to achieve homeostasis [ 1 ]. Feeding behavior and metabolism are modulated by several pathways that originate in both the brain as well as peripheral tissues such as the muscle, liver, adipose tissue, and the gastrointestinal tract [ 2 ], and endocrine hormones such as insulin, cholecystokinin (CCK) and leptin seem to mediate these effects in mammals [ 3 , 4 ]. Alterations in many of these hormonal signals that originate in the periphery lead to metabolic diseases such as obesity and diabetes [ 5 , 6 ]; therefore, investigating the role of the brain in regulating feeding and metabolism is essential for understanding these metabolic disorders.…”

Endocrine cybernetics: neuropeptides as molecular switches in behavioural decisions

“…The mechanisms by which DSK released from IPCs mediates satiety and reduced feeding [ 199 ] are not yet known. However, it could be speculated that the axon terminations of the IPCs on the crop release DSK that acts to influence crop muscle contractions and thereby inhibit further food intake, similar to mechanisms by which CCK induces satiety in mammals by affecting gastric emptying (see [ 207 ]). Another neuropeptide produced by brain neurons similar to the IPCs, Drosophila myosuppressin (DMS), has in fact been shown to act to modulate crop contractions and thereby increase food intake in female flies after mating [ 208 ].…”

“…Thus, AstA is related to vertebrate galanin and these peptides regulate feeding, sleep and hormone release both in Drosophila and mammals (see [ 91 , 181 ]). Moreover, DSK and vertebrate CCK are ancestrally related and known to regulate satiety, feeding, aggression and reproductive behaviour in flies and mammals (see [ 207 ]).…”

Cholecystokinin Octapeptide Promotes ANP Secretion through Activation of NOX4–PGC-1α–PPARα/PPARγ Signaling in Isolated Beating Rat Atria

“…Cholecystokinin (CCK) is a classical gut hormone and a potent stimulator of gallbladder contraction that was found in extracts of small intestinal mucosa in the 1920s [ 8 , 9 ]. Subsequently, CCK has also been found in neurons [ 10 ], immune cells [ 11 ], kidney cells, and lung cells [ 12 ]. Pro-CCK is processed into several molecular forms such as CCK-58, CCK-33, CCK-22, CCK-8, and CCK-4; however, sulfated carboxyl-terminal CCK octapeptide (CCK-8) is the major biological active fragment of CCK, which retains most of the bioactivities of CCK.…”