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.
Bibliographical noteFunding Information:
We thank the Transgenic RNAi Project (TRiP) and Bloomington Drosophila Stock Center (BDSC) for providing RNAi stocks; Ronald K?hnlein for AkhR stocks; and Richard Binari, Young Kwon, Stephanie Mohr, Richelle Sopko, Ilia Droujinine, Charles Xu, and Xiaochun Ni for comments. This work was supported in part by the American Diabetes Association (1-16-PDF-108) and the Joslin Pilot and Feasibility Program (P30DK03683629). Work in the M.B.O. lab is supported by NIH grant R01 GM095746. Work in the P.P. lab is supported by NIH grant R01 DK083694. Work in the N.P. lab is supported by NIH and HHMI. N.P. is an Investigator of the Howard Hughes Medical Institute.