In vivo drug discovery for increasing incretin-expressing cells identifies DYRK inhibitors that reinforce the enteroendocrine system. Issue 9 (15th September 2022)

• Record Type: Journal Article
• Authors: Chu, Lianhe; Terasaki, Michishige; Mattsson, Charlotte L.; Teinturier, Romain; Charbord, Jérémie; Dirice, Ercument; Liu, Ka-Cheuk; Miskelly, Michael G.; Zhou, Qiao; Wierup, Nils; Kulkarni, Rohit N.; Andersson, Olov
• Is Part Of: Cell chemical biology. Volume 29:Issue 9(2022)
• Page Start: 1368
• Page End: 1380.e5
• Publication Date: 2022-09-15
• Subjects: chemical screen -- enteroendocrine cells -- incretin hormones -- diabetes -- zebrafish -- mouse -- DYRK -- GIP -- GLP-1; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2022.08.001
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: Analogs of the incretin hormones Gip and Glp-1 are used to treat type 2 diabetes and obesity. Findings in experimental models suggest that manipulating several hormones simultaneously may be more effective. To identify small molecules that increase the number of incretin-expressing cells, we established a high-throughput in vivo chemical screen by using the gip promoter to drive the expression of luciferase in zebrafish. All hits increased the numbers of neurogenin 3-expressing enteroendocrine progenitors, Gip-expressing K-cells, and Glp-1-expressing L-cells. One of the hits, a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) inhibitor, additionally decreased glucose levels in both larval and juvenile fish. Knock-down experiments indicated that nfatc4, a downstream mediator of DYRKs, regulates incretin + cell number in zebrafish, and that Dyrk1b regulates Glp-1 expression in an enteroendocrine cell line. DYRK inhibition also increased the number of incretin-expressing cells in diabetic mice, suggesting a conserved reinforcement of the enteroendocrine system, with possible implications for diabetes. Graphical abstract: Highlights: In vivo screen identifies small molecules that increase the number of incretin + cells A GnRH agonist and DGAT1 and DYRK inhibitors boost differentiation of incretin + cells DYRK1A/B and downstream NFATC4 regulate the differentiation of incretin + cells DYRK inhibitors improve glucose control in both zebrafish and diabetic mice Abstract : Analogs of the incretin hormones Gip and Glp-1 are typically used to treat diabetes. To identify factors directly increasing the number of incretin-expressing cells, Chu et al. establish a zebrafish screen and identify multiple hits, including DYRK inhibitors that increase incretins and improve glucose control in zebrafish and diabetic mice.