Meet, Zandawala, Maria E, Yurgel, Michael J, Texada, Sifang, Liao, Kim F, Rewitz, Alex C, Keene, and Dick R, Nässel
Behavior and physiology are orchestrated by neuropeptides acting as central neuromodulators and circulating hormones. An outstanding question is how these neuropeptides function to coordinate complex and competing behaviors. In Drosophila, the neuropeptide leucokinin (LK) modulates diverse functions, but mechanisms underlying these complex interactions remain poorly understood. As a first step towards understanding these mechanisms, we delineated LK circuitry that governs various aspects of post-feeding physiology and behavior. We found that impaired LK signaling in Lk and Lk receptor (Lkr) mutants affects diverse but coordinated processes, including regulation of stress, water homeostasis, feeding, locomotor activity, and metabolic rate. Next, we sought to define the populations of LK neurons that contribute to the different aspects of this physiology. We find that the calcium activity in abdominal ganglia LK neurons (ABLKs), but not in the two sets of brain neurons, increases specifically following water consumption, suggesting that ABLKs regulate water homeostasis and its associated physiology. To identify targets of LK peptide, we mapped the distribution of Lkr expression, mined a brain single-cell transcriptome dataset for genes coexpressed with Lkr, and identified synaptic partners of LK neurons. Lkr expression in the brain insulin-producing cells (IPCs), gut, renal tubules and chemosensory cells, correlates well with regulatory roles detected in the Lk and Lkr mutants. Furthermore, these mutants and flies with targeted knockdown of Lkr in IPCs displayed altered expression of insulin-like peptides (DILPs) and transcripts in IPCs and increased starvation resistance. Thus, some effects of LK signaling appear to occur via DILP action. Collectively, our data suggest that the three sets of LK neurons have different targets, but modulate the establishment of post-prandial homeostasis by regulating distinct physiological processes and behaviors such as diuresis, metabolism, organismal activity and insulin signaling. These findings provide a platform for investigating feeding-related neuroendocrine regulation of vital behavior and physiology., Author summary Animals ranging from jellyfish to humans use multiple neuropeptides to orchestrate various aspects of behavior and physiology. A major question in biology is how animals are able to coordinate complex and competing behaviors to ensure maintenance of a stable internal environment. To address this, we delineated the functions of the neuronal pathways using the neuropeptide leucokinin (LK) in the fruit fly Drosophila melanogaster. We discovered that mutant flies lacking LK signaling exhibit defects in diverse but coordinated processes, including regulation of stress, water balance, gut function, activity, and metabolic rate. We also attribute these functions to different subsets of neurons that produce LK. Lastly, we show that this neuropeptide interacts with insulin signaling to affect stress tolerance and metabolism. This is of broad interest since stress, obesity and ensuing metabolic disorders, such as heart disease and diabetes, are immense problems in society. Our work provides a foundation for further investigation of neuroendocrine regulation of vital behavior and physiology associated with feeding.