Central metabolic-sensing remotely controls nutrient –sensitive endocrine response in <i>Drosophila</i> via <i>Sir2/Sirt1-upd2-IIS axis</i>

Abstract

Endocrine signaling is central in coupling organismal nutrient status with maintenance of systemic metabolic homeostasis. While local nutrient sensing within the insulinogenic tissue is well-studied, distant mechanisms that relay organismal nutrient status in controlling metabolic-endocrine signaling are less understood. Here, we report a novel mechanism underlying the distant regulation of metabolic endocrine response in Drosophila melanogaster. We show that the communication between fat-body and insulin producing cells (IPCs), important for the secretion of dILPs, is regulated by the master metabolic sensor Sir2/Sirt1. This communication involves a fat body-specific direct regulation of the JAK/STAT cytokine upd2, by Sir2/Sirt1. We have also uncovered the importance of this regulation in coupling nutrient-inputs with dILP-secretion, and distantly controlling intestinal insulin signaling. Our results provide fundamental mechanistic insights into the top-down control involving tissues that play key roles in metabolic sensing, endocrine signaling and nutrient uptake.