Midgut-Derived Activin Regulates Glucagon-like Action in the Fat Body and Glycemic Control

• Published in: Cell metabolism Vol. 25; no. 2; pp. 386 - 399
• Main Authors: Song, Wei, Cheng, Daojun, Hong, Shangyu, Sappe, Benoit, Hu, Yanhui, Wei, Neil, Zhu, Changqi, O’Connor, Michael B., Pissios, Pavlos, Perrimon, Norbert
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.02.2017
• Subjects: Activin Receptors - metabolism; Activins - metabolism; Animals; Carbohydrate Metabolism; Carrier Proteins - metabolism; Dietary Carbohydrates - adverse effects; Disease Models, Animal; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Enteroendocrine Cells - metabolism; Fat Body - metabolism; Gastrointestinal Tract - metabolism; Glucagon - metabolism; Hepatocytes - metabolism; Hyperglycemia - metabolism; Hyperglycemia - pathology; Insect Hormones - metabolism; Larva - metabolism; Mice; Oligopeptides - metabolism; Pyrrolidonecarboxylic Acid - analogs & derivatives; Pyrrolidonecarboxylic Acid - metabolism; Receptors, Glucagon - genetics; Receptors, Glucagon - metabolism; RNA Interference; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2017.01.002

While high-caloric diet impairs insulin response to cause hyperglycemia, whether and how counter-regulatory hormones are modulated by high-caloric diet is largely unknown. We find that enhanced response of Drosophila adipokinetic hormone (AKH, the glucagon homolog) in the fat body is essential for hyperglycemia associated with a chronic high-sugar diet. We show that the activin type I receptor Baboon (Babo) autonomously increases AKH signaling without affecting insulin signaling in the fat body via, at least, increase of Akh receptor (AkhR) expression. Further, we demonstrate that Activin-β (Actβ), an activin ligand predominantly produced in the enteroendocrine cells (EEs) of the midgut, is upregulated by chronic high-sugar diet and signals through Babo to promote AKH action in the fat body, leading to hyperglycemia. Importantly, activin signaling in mouse primary hepatocytes also increases glucagon response and glucagon-induced glucose production, indicating a conserved role for activin in enhancing AKH/glucagon signaling and glycemic control. [Display omitted] •Enhanced fly AKH action is essential for high-sugar diet-induced hyperglycemia•Babo signaling directly promotes AKH response in the fat body•Midgut-derived Actβ signals to the fat body via Babo and modulates AKH action•Chronic high-sugar diet impairs midgut homeostasis and increases Actβ production Song et al. reveal an insulin-independent mechanism driving hyperglycemia on a high-sugar diet and identify Activin-β as a gut hormone boosting AKH/glucagon signaling in the fly fat body, ultimately perturbing carbohydrate homeostasis. Activin signaling in mouse hepatocytes also increases glucagon-stimulated glucose production, indicating a conserved role in enhancing glucagon response.