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

Abstract

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 in vitro and is required for the metabolic actions of GDF15 with respect to body weight and food intake in vivo in mice. Gfral mice were refractory to the effects of recombinant human GDF15 on body-weight, food-intake and glucose parameters. Blocking the interaction between GDF15 and GFRAL with a monoclonal antibody prevented the metabolic effects of GDF15 in rats. Gfral mRNA is highly expressed in the area postrema of mouse, rat and monkey, in accordance with previous reports implicating this region of the brain in the metabolic actions of GDF15 (refs. 4,5,6). Together, our data demonstrate that GFRAL is a receptor for GDF15 that mediates the metabolic effects of GDF15.

Structure and biophysical characterization of the human full-length neurturin–GFRa2 complex: A role for heparan sulfate in signaling

“…GDNF signals through GFRa1, NRTN through GFRa2, ARTN through GFRa3 (7) and persephin through GFRa4 (10), even though a certain cross activity has been described (11,12). In addition, very recently several groups identified GFRa-like (GFRAL), a distant member of the receptor family, as the co-receptor for GDF15 (Growth and differentiation factor 15) and the complex was shown to signal through RET analogously to conventional GFRas (13)(14)(15)(16). Other GFLs, however, do not compete for GFRAL binding, and GDF15 does not bind to GFRa1-4.…”

Ret and Substrate-Derived TGF-β Maverick Regulate Space-Filling Dendrite Growth in Drosophila Sensory Neurons

“…Intriguingly, the GFRAL/ GDF-15 complex signals through Ret in the mammalian brain stem to mediate GDF-15-dependent anti-obesity effects (Emmerson et al, 2017; Hsu et al, 2017; Mullican et al, 2017; Yang et al, 2017). In Drosophila , Ret , mav , and the GFR-like co-receptor form a biochemical complex and function in stomatogastric nervous system development (Myers et al, 2018).…”

Pathogenesis of Nonalcoholic Steatohepatitis and Hormone-Based Therapeutic Approaches

“…Numerous studies suggest that GDF15 is induced by diverse stress stimuli such as fatty acids, ER/mitochondrial stressors, and LPS (132–134), and that serum GDF15 level is increased in human subjects with diseases such as cardiovascular disease, chronic kidney disease, obesity, diabetes, and cancer (135, 136). Intriguingly, recent emerging evidence suggests that GDF15 exerts beneficial effects on obesity-related insulin resistance in mice and monkeys through the suppression of food intake via GDNF family receptor α-like (GFRAL)-dependent anorexic action (137–140). GDF15 also stimulates oxidative metabolism in macrophages or metabolic tissues such as adipose tissue and liver, leading to the improvement of insulin resistance and hepatic steatosis in obese mice (133, 141).…”