Diabetologie und Stoffwechsel 2016; 11 - P67
DOI: 10.1055/s-0036-1580814

Fndc4, a highly identical ortholog of Irisin binds and activates a novel orphan receptor G-protein coupled receptor

A Georgiadi 1, 2, 3, X Ma 1, M Bosma 1, E Graham 1, O Shilkova 1, F Mattijssen 2, 3, 4, AA Khan 2, 3, 4, JCA Higareda 2, 3, 4, T Wünsch 1, M Johansson 1, S Seaman 5, BS Croix 5, O Ritvos 6, N Nakamura 7, S Hirose 7, 8, M Scheideler 2, 3, 4, S Herzig 2, 3, 4, PA Böstrom 1
  • 1Department for Cell- And Molecular Biology, Karolinska Institutet, Stockholm, Sweden
  • 2Helmholtz Zentrum München – German Research Center for Environmental Health, Institute of Diabetes and Cancer (IDC), München, Germany
  • 3German Center for Diabetes Research (DZD), Munich, Germany
  • 4Heidelberg University Hospital, Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg, Germany
  • 5Tumor Angiogenesis Section, Frederick, United States
  • 6Helsinki University, Helsinki, Finland
  • 7Department of Biological Sciences, Tokyo, Japan
  • 8Faculty of Biomedical Engineering, Toin University of Yokohama, Yokohama, Japan

Aim: Irisin, encoded by the Fndc5 gene, was identified as an exercise-induced, secreted protein promoting beige cell formation. Here we explore Fndc4, a highly identical ortholog of Fndc5. Fndc4 is proteolytically cleaved, to release an extracellular polypeptide, which we named Irisin2.

Methods: In order to investigate the biological effects of Irisin2 we manufactured a stable recombinant Irisin2 and used it in a flow cytometry based assay and immunoprecipatation assays to identify candidate receptors for Irisin2.

Results: Recombinant Irisin2 showed superior stability compared to Irisin and greater cellular binding. In addition, treatment of adipocytes with recombinant Irisin2 increased phosphorylation of ERK1/2 and induced browning/beige markers. We therefore used Irisin2 to screen for cellular receptors utilizing a FACS based cell-binding assay, combined with global gene expression analysis. Using this approach and immunoprecipitation assays, we identified the orphan G-protein coupled receptor 116 (GPR116), as a candidate receptor. Overexpression of GPR116 in adipocytes increased browning/beige cell markers. GPR116 knockout mice showed an adverse metabolic phenotype, where aspects of Irisin2 signaling were blunted. Thus, we propose GPR116 to be a candidate receptor for Irisin2, with potential importance for future therapeutic intervention.