Functional analyses of the Drosophila insulin- and neuropeptide Y-like signaling systems
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Neuropeptides form the most diverse group of neuronal and hormonal messengers that regulate a wide spectrum of physiological processes and behaviors. The conserved Drosophila neuropeptide F (NPF) signaling system is demonstrated to developmentally regulate two opposing behaviors related to food in larvae: foraging and food aversion. The expression of npf is strong in young larvae attracted to food, and loss of NPF signaling results in the onset of behaviors associated with older larvae, including food aversion, hypermobility, and cooperative burrowing. Conversely, the brain expression of NPF of older nonfeeding larvae is developmentally downregulated, and ectopic expression of npf leads to prolonged feeding, and the suppression of social burrowing behaviors. Furthermore, through a broad array of behavioral characterization of genetically altered animals, a neuronal circuit that includes the NPF and the Drosophila insulin-like peptides (DILP) signaling systems has been identified to adaptively mediate diverse hunger-motivated foraging behaviors under different nutritional states. In fasted animals, hunger stimuli downregulate dS6K activity in DILP2/4 neurons, which in turn leads to attenuated DILP signaling and subsequently disinhibits two downstream signaling systems: an NPF/NPF receptor (NPFR1)-dependent and an NPF/NPFR1-independent pathway. The former selectively mediates hunger-motivated feeding of nonpreferred foods (food preference) by lowering the threshold set by a default pathway. The latter promotes a general increase in ingestion rate, thereby enabling more effective food consumption. For example, upregulation of the DILP signaling through either overexpression of DILP2 in a pan-neural pattern or targeted expression of a constitutively active form of the Drosophila insulin-like receptor (dInR) in the NPFR1 neurons leads to significant attenuation of hunger-motivated response to less-accessible solid media or a bitter-tasting food containing quinine. In contrast, nondeprived animals deficient in NPFR1 or dInR signaling display hyperactive feeding of solid media and the quinine-adulterated noxious food both of which are normally rejected by the controls fed ad libitum. Taken together, the Drosophila NPF/DILP neural network provides an important entry point into understanding how genes, molecular pathways, and neural circuits are integrated in the dynamic regulation of feeding behaviors and energy homeostasis.