Cholecystokinin-like peptide mediates satiety by inhibiting sugar attraction

Author summary Food intake is critical for animal survival and reproduction and is regulated both by internal states that signal appetite or satiety, and by external sensory stimuli. It is well known that the internal nutritional state influences the strength of the chemosensory perception of food signals. Thus, both gustatory and olfactory signals of preferred food are strengthened in hungry animals. However, the molecular mechanisms behind satiety-mediated modulation of taste are still not known. We show here that cholecystokinin-like (SK) peptide in brown planthopper and Drosophila signals satiety and inhibits sugar attraction by lowering the activity of sweet-sensing gustatory neurons and transcription of a sugar receptor gene, Gr64f. We show that SK peptide signaling reflects the nutritional state and inhibits feeding behavior. Re-feeding after starvation increases SK peptide expression and spontaneous activity of SK producing neurons. Interestingly, we found that SK peptide negatively regulates the expression of the sweet gustatory receptor and that activation of SK producing neurons inhibits the activity of sweet-sensing gustatory neurons (GRNs). Furthermore, we found that one of the two known SK peptide receptors is expressed in some sweet-sensing GRNs in the proboscis and proleg tarsi. In summary, our findings provide a mechanism that is conserved in distantly related insects and which explains how feeding state modulates sweet perception to regulate feeding behavior. Thus, we have identified a neuropeptide signal and its neuronal circuitry that respond to satiety, and that regulate feeding behavior by inhibiting gustatory receptor gene expression and activity of sweet sensing GRNs. Feeding is essential for animal survival and reproduction and is regulated by both internal states and external stimuli. However, little is known about how internal states influence the perception of external sensory cues that regulate feeding behavior. Here, we investigated the neuronal and molecular mechanisms behind nutritional state-mediated regulation of gustatory perception in control of feeding behavior in the brown planthopper and Drosophila. We found that feeding increases the expression of the cholecystokinin-like peptide, sulfakinin (SK), and the activity of a set of SK-expressing neurons. Starvation elevates the transcription of the sugar receptor Gr64f and SK negatively regulates the expression of Gr64f in both insects. Interestingly, we found that one of the two known SK receptors, CCKLR-17D3, is expressed by some of Gr64f-expressing neurons in the proboscis and proleg tarsi. Thus, we have identified SK as a neuropeptide signal in a neuronal circuitry that responds to food intake, and regulates feeding behavior by diminishing gustatory receptor gene expression and activity of sweet sensing GRNs. Our findings demonstrate one nutritional state-dependent pathway that modulates sweet perception and thereby feeding behavior, but our experiments cannot exclude further parallel pathways. Importantly, we show that the underlying mechanisms are conserved in the two distantly related insect species.

Automated summary

The study reveals that cholecystokinin-like (SK) peptide functions as a satiety signal, inhibiting sugar attraction by reducing sweet-sensing gustatory neurons' activity and sugar receptor gene transcription. SK peptide's modulation of sweet perception and feeding behavior is influenced by the internal nutritional state, and its signaling pathway is conserved in distantly related insects.