CCK in mammals and sulfakinins in insects share conserved roles in regulating satiety, aggression, and sexual behavior, with just eight neurons in the fly brain integrating these competing drives through peptide signaling.
8 neurons coordinate feeding, aggression, and matingIn the Drosophila brain, a remarkably small circuit of sulfakinin-expressing neurons integrates internal state and external stimuli to balance competing survival behaviors — a peptide-driven decision-making hub
What the researchers found
CCK in mammals and sulfakinins (SKs) in invertebrates share deeply conserved functional roles that extend far beyond gut signaling. In mammals, CCK is produced by both gut endocrine cells and brain neurons and regulates gallbladder contraction, pancreatic enzyme secretion, satiety, reward, anxiety, aggression, and sexual behavior.
In Drosophila, a set of just eight SK-expressing brain neurons integrates internal state and external stimuli to coordinate competing behavioral outputs: they diminish sugar gustation, induce satiety, reduce feeding, suppress sex drive in males, and increase aggression. This demonstrates that a single neuropeptide system can arbitrate between multiple survival-critical behaviors depending on context. While the functional roles appear conserved between flies and mammals, the underlying neural mechanisms differ.
Why it matters
Understanding that a single peptide system coordinates multiple critical behaviors — eating, fighting, and mating — has profound implications for drug development. CCK receptor agonists developed for appetite suppression might unexpectedly affect aggression or sexual behavior, and vice versa. The fly model, with its genetically accessible eight-neuron circuit, provides a powerful tool for dissecting how peptide signaling balances competing drives — insights that could inform more targeted therapies for eating disorders, aggression, and behavioral dysregulation.
How the study worked
This is a comprehensive comparative review synthesizing research across invertebrate (primarily Drosophila) and vertebrate (mammalian) systems on CCK/sulfakinin peptide signaling. It draws on genetic manipulation studies in Drosophila, neuroanatomical mapping, behavioral assays, and mammalian pharmacological and neuroimaging studies.
What this study cannot tell us
The review draws heavily on Drosophila genetics, which may not directly translate to mammalian neurobiology despite functional conservation. The eight-neuron SK circuit in flies has no direct mammalian equivalent — CCK signaling in mammalian brains involves numerous distributed circuits. The complexity of human CCK biology (multiple receptor subtypes, gut vs. brain production, interaction with other neurotransmitter systems) is not fully captured by the fly model. Clinical implications for human behavioral disorders remain speculative.
How to read the evidence
This is a comprehensive comparative review integrating genetic, neuroanatomical, and behavioral data across species. The Drosophila genetic evidence is particularly strong due to the precision of available tools, though translation to mammalian systems requires caution.
When this study was published
Published in 2022, this is a recent review that incorporates the latest Drosophila genetic studies and advances in understanding CCK signaling across species.
The bigger picture
Neuropeptides are the oldest and most diverse signaling molecules in the animal kingdom, and CCK/sulfakinins are among the best-conserved. This review positions CCK not just as a gut hormone but as a master behavioral coordinator — a molecule that sits at the intersection of the body's most fundamental survival drives. The evolutionary conservation from flies to humans validates Drosophila as a model for understanding peptide-mediated behavioral integration, while the differences in mechanisms caution against oversimplifying cross-species comparisons.
Questions still open
- Could therapeutic CCK receptor modulation inadvertently affect aggression or sexual behavior in humans, as the fly model predicts?
- How do the eight SK neurons in the fly brain decide whether to prioritize feeding, fighting, or mating — what signals tip the balance?
- Could the ancient conservation of CCK/SK signaling inform the development of more targeted peptide therapies that selectively modulate appetite without affecting other behaviors?
Common questions
What is CCK and why would a gut hormone affect behavior?
What can fruit flies teach us about human appetite and behavior?
Read the original research
Cholecystokinin/sulfakinin peptide signaling: conserved roles at the intersection between feeding, mating and aggression.
Cellular and molecular life sciences : CMLS, 79(3), 188
Citation
Nässel, Dick R; Wu, Shun-Fan. (2022). Cholecystokinin/sulfakinin peptide signaling: conserved roles at the intersection between feeding, mating and aggression.. Cellular and molecular life sciences : CMLS, 79(3), 188. https://doi.org/10.1007/s00018-022-04214-4