Diuretic hormone 44 (DH44) orchestrates metabolic homeostasis in Drosophila melanogaster

PROJECT SUMMARY Metabolic homeostasis is maintained by active modulation of physiology and behavior. Neuropeptides are signaling molecules that directly impact available energy reserves by coordinating responses to stress and changes in internal states. Dysregulation of neuropeptide signaling underlies metabolic diseases including diabetes and obesity. Previous work in Drosophila melanogaster demonstrated the importance of insulin- producing cells (IPCs) and adipokinetic-hormone producing cells (APCs) in maintaining metabolic homeostasis, akin to the action of mammalian insulin and glucagon. IPCs and APCs are known to respond to changes in circulating nutrient levels, however, these cell-types are not capable of directly sensing carbohydrates or lipids. Emerging work suggests that diuretic hormone 44 (DH44) producing neurons in Drosophila are nutrient-sensing, playing a central role in metabolism by integrating nutrient signals, hormonal release, and feeding behavior. Importantly, preliminary data indicates the presence of DH44 receptors in IPCs, APCs, and the metabolically active fat body (liver-adipose equivalent). However, the metabolic physiology and behaviors modulated by DH44 signaling to these targets in normal and disease states is unknown. The objective of the research program outlined in this proposal is to elucidate the role of DH44 neuropeptide in whole-body metabolic homeostasis and feeding behaviors in Drosophila. My central hypothesis is that DH44 orchestrates