Signaling from Glia and Cholinergic Neurons Controls Nutrient-Dependent Production of an Insulin-like Peptide for Drosophila Body Growth

The insulin-like peptide (ILP) family plays key biological roles in the control of body growth. Although the functions of ILPs are well understood, the mechanisms by which organisms sense their nutrient status and thereby control ILP production remain largely unknown. Here, we show that signaling relay and feedback mechanisms control the nutrient-dependent expression of Drosophila ILP5 (Dilp5). The expression of dilp5 in brain insulin-producing cells (IPCs) is negatively regulated by the transcription factor FoxO. Glia-derived Dilp6 remotely regulates the FoxO activity in IPCs, primarily through Jeb secreted by cholinergic neurons. Dilp6 production by surface glia is amplified by cellular response to circulating Dilps derived from IPCs, in concert with amino acid signals. The induction of dilp5 is critical for sustaining body growth under restricted food conditions. These results provide a molecular framework that explains how the production of an endocrine hormone in a specific tissue is coordinated with environmental conditions. [Display omitted] •Nutrient-dependent dilp5 expression is negatively regulated by FoxO in brain IPCs•FoxO activity is regulated by Alk, and its ligand Jeb is secreted by cholinergic neurons•Glia-derived Dilp6 remotely initiates dilp5 expression through cholinergic neurons•The induction of dilp5 is critical to sustain body growth under restricted food Insulin-like peptides (ILPs) play key roles in the control of body growth in response to nutrient status. Okamoto and Nishimura now demonstrate the signaling relay and feedback mechanisms by which insulin-producing cells sense nutritional signals and thereby control the production of an ILP in the fruit fly Drosophila melanogaster.