Abstract
The intestine is a central regulator of metabolic homeostasis. Dietary inputs are absorbed through the gut, which senses their nutritional value and relays hormonal information to other organs to coordinate systemic energy balance. However, the gut-derived hormones affecting metabolic and behavioral responses are poorly defined. Here we show that the endocrine cells of the Drosophila gut sense nutrient stress through a mechanism that involves the TOR pathway and in response secrete the peptide hormone allatostatin C, a Drosophila somatostatin homolog. Gut-derived allatostatin C induces secretion of glucagon-like adipokinetic hormone to coordinate food intake and energy mobilization. Loss of gut Allatostatin C or its receptor in the adipokinetic-hormone-producing cells impairs lipid and sugar mobilization during fasting, leading to hypoglycemia. Our findings illustrate a nutrient-responsive endocrine mechanism that maintains energy homeostasis under nutrient-stress conditions, a function that is essential to health and whose failure can lead to metabolic disorders.
Highlights
The intestine is a central regulator of metabolic homeostasis
To identify intestinal hormones involved in nutrient sensing and in maintaining energy homeostasis during nutrient stress, we used RNAi to knock down secreted factors in the enteroendocrine cells (EECs) of the adult Drosophila midgut and tested for changes in organismal starvation resistance (Fig. 1a)
We focused our attention on AstC, since UAS-AstC-RNAi (AstC-RNAi)-mediated knockdown of this factor in the adult EECs caused a striking prolongation of starvation survival in females, but not in males, compared to voilà> controls (Fig. 1b and Supplementary Fig. 1a)
Summary
The intestine is a central regulator of metabolic homeostasis. Dietary inputs are absorbed through the gut, which senses their nutritional value and relays hormonal information to other organs to coordinate systemic energy balance. Such coordination is achieved through the exchange of metabolic information between organs, mediated by nutrient-responsive hormones These hormones are secreted by specialized tissues that sense changes in internal and external nutritional conditions, and underlie inter-tissue communication that maintains systemic energy homeostasis via the regulation of appetite and metabolism. Ingested nutrients are absorbed through this organ, which senses nutritional value and relays metabolic information to other tissues via the secretion of hormones that are released into circulation from enteroendocrine cells (EECs) and coordinate body-wide processes[3]. GLP-1 is secreted from the intestine in response to ingestion of glucose and acts directly on the pancreatic β-cells to potentiate glucose-dependent insulin secretion This incretin effect is diminished in type-2 diabetes patients, and the use of incretin-hormone therapy is of great medical importance in the treatment of metabolic disorders. To characterize factors secreted by the intestine that are important for energy homeostasis, we performed a genetic screen for gut hormones that affect metabolic stress responses
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