The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL

Nature Medicine 23, 1215 (2017). doi:10.1038/nm.4393 Authors: Paul J Emmerson, Feng Wang, Yong Du, Qian Liu, Richard T Pickard, Malgorzata D Gonciarz, Tamer Coskun, Matthew J Hamang, Dana K Sindelar, Kimberly K Ballman, Lisa A Foltz, Avinash Muppidi, Jorge Alsina-Fernandez, Gavin C Barnard, Jason X Tang, Xilin Liu, Xudong Mao, Robert Siegel, John H Sloan, Pamela J Mitchell, Bei B Zhang, Ruth E Gimeno, Bei Shan & Xinle Wu Growth/differentiation factor 15 (GDF15), also known as MIC-1, is a distant member of the transforming growth factor-β (TGF-β) superfamily and has been implicated in various biological functions, including cancer cachexia, renal and heart failure, atherosclerosis and metabolism. A connection between GDF15 and body-weight regulation was initially suggested on the basis of an observation that increasing GDF15 levels in serum correlated with weight loss in individuals with advanced prostate cancer. In animal models, overexpression of GDF15 leads to a lean phenotype, hypophagia and other improvements in metabolic parameters, suggesting that recombinant GDF15 protein could potentially be used in the treatment of obesity and type 2 diabetes. However, the signaling and mechanism of action of GDF15 are poorly understood owing to the absence of a clearly identified cognate receptor. Here we report that GDNF-family receptor α-like (GFRAL), an orphan member of the GFR-α family, is a high-affinity receptor for GDF15. GFRAL binds to GDF15 i...
Source: Nature Medicine - Category: General Medicine Authors: Tags: Letter Source Type: research