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DOI: 10.1055/s-0036-1580814
Fndc4, a highly identical ortholog of Irisin binds and activates a novel orphan receptor G-protein coupled receptor
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.