Inter-organ metabolic feedback via BCAA catabolism regulates glucagon-like hormone secretion in Drosophila

Abstract

Abstract Metabolic homeostasis regulated by nutrient-responsive endocrine hormones is essential for organismal survival. In insects, lipid and carbohydrate mobilization is controlled by adipokinetic hormone (Akh), a glucagon-like peptide secreted from neuroendocrine cells. However, whether Akh secretion is subject to negative feedback via its downstream catabolic effects remains unclear. Here, we develop a quantitative assay for Akh using tandem mass spectrometry and show that inter-organ metabolic communication regulates Akh secretion during starvation in Drosophila . Metabolic profiling reveals that Akh signaling in the fat body promotes branched-chain amino acid (BCAA) catabolism by inducing BCAA transaminase (Bcat). Loss of Akh signaling impairs clearance of BCAAs derived from fat body autophagy, resulting in Akh hypersecretion. BCAA catabolism is coupled to glutathione biosynthesis and redox homeostasis during nutrient stress. Our findings reveal a feedback mechanism in which Akh signaling regulates its own secretion via amino acid catabolism, linking energy mobilization to redox homeostasis during starvation.