The gut hormone Allatostatin C/Somatostatin regulates food intake and metabolic homeostasis under nutrient stress

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 specific gut hormones that communicate energy availability to target organs to induce appropriate metabolic and behavioral responses are poorly defined. Here we show that the enteroendocrine cells (EECs) of the Drosophila gut sense nutrient stress via the intracellular TOR pathway, and in response secrete the peptide hormone allatostatin C (AstC), a Drosophila Somatostatin homolog. Gut-derived AstC induces secretion of glucagon-like adipokinetic hormone (AKH) via its receptor AstC-R2, a homolog of mammalian somatostatin receptors, to coordinate food intake and energy mobilization. Loss of gut AstC or its receptor in the AKH-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.

Enteric bacterial infection inDrosophilainduces whole-body alterations in metabolic gene expression independently of the Immune Deficiency (Imd) signalling pathway

“…2014; K amareddine et al . 2018a), AstC (K ubrak et al . 2022), and Crz (K ubrak et al 2016), have been shown to alter whole-body metabolism (Z hou et al .…”

“…Indeed, a direct gut-to-brain signaling role has been shown for NPF, AstC and Dh31 in the context of nutrient regulation of feeding and metabolism (Y oshinari et al . 2021; K ubrak et al . 2022; L in et al .…”

“…For example, several of the gut-enriched signaling molecules, such as AstC, CCHa1, NPF and Tk have receptors in the brain, suggesting they may signal from the gut-to-brain to mediate changes in gene expression. Indeed, a direct gut-to-brain signaling role has been shown for NPF, AstC and Dh31 in the context of nutrient regulation of feeding and metabolism (YOSHINARI et al 2021;KUBRAK et al 2022;LIN et al 2022). In addition, several of the changes in both transcription factor levels and intestinal/neuronal signaling could explain the increases in metabolic gene expression that we observed.…”

Interorgan communication through peripherally derived peptide hormones inDrosophila

“…Dietary sugars positively regulate production and secretion of NPF from the gut EECs, whereas AstC secretion is induced by nutrient restriction ( Figure 3c ). Although both the NPF receptor (NPFR) and AstC receptor 2 (AstC-R2) are expressed in the CC, NPF and AstC have an inhibitory and facilitatory effect on secretion of Akh, respectively [ 186 , 187 ] ( Figure 3c ). NPFR is also expressed in the brain IPCs, where it facilitates secretion of Dilps [ 186 ] ( Figure 3c ).…”

“…EEC-derived NPF and AstC also directly act on the CC to regulate secretion of Akh [ 186 , 187 ] ( Figure 3c ). Dietary sugars positively regulate production and secretion of NPF from the gut EECs, whereas AstC secretion is induced by nutrient restriction ( Figure 3c ).…”