GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates

Abstract

Growth differentiation factor 15 (GDF15), a distant member of the transforming growth factor (TGF)-β family, is a secreted protein that circulates as a 25-kDa dimer. In humans, elevated GDF15 correlates with weight loss, and the administration of GDF15 to mice with obesity reduces body weight, at least in part, by decreasing food intake. The mechanisms through which GDF15 reduces body weight remain poorly understood, because the cognate receptor for GDF15 is unknown. Here we show that recombinant GDF15 induces weight loss in mice fed a high-fat diet and in nonhuman primates with spontaneous obesity. Furthermore, we find that GDF15 binds with high affinity to GDNF family receptor α-like (GFRAL), a distant relative of receptors for a distinct class of the TGF-β superfamily ligands. Gfral is expressed in neurons of the area postrema and nucleus of the solitary tract in mice and humans, and genetic deletion of the receptor abrogates the ability of GDF15 to decrease food intake and body weight in mice. In addition, diet-induced obesity and insulin resistance are exacerbated in GFRAL-deficient mice, suggesting a homeostatic role for this receptor in metabolism. Finally, we demonstrate that GDF15-induced cell signaling requires the interaction of GFRAL with the coreceptor RET. Our data identify GFRAL as a new regulator of body weight and as the bona fide receptor mediating the metabolic effects of GDF15, enabling a more comprehensive assessment of GDF15 as a potential pharmacotherapy for the treatment of obesity.

Selective Liver Estrogen Receptor α Modulation Prevents Steatosis, Diabetes, and Obesity Through the Anorectic Growth Differentiation Factor 15 Hepatokine in Mice

“…Noteworthy, Gdf15 gene expression in the liver perfectly correlates with plasma concentrations measured in WT and LERKO mice. Mainly produced by the liver, Gdf15 is a divergent member of the transforming growth factor‐β superfamily, which exerts anorectic effects and controls body weight through the activation of the glial cell line‐derived neurotrophic factor family receptor α‐like (GFRAL), recently identified as the specific receptor of Gdf15 in hindbrain neurons of the area postrema and nucleus of the solitary tract . In rodent models, even a moderate increase in Gdf15 circulating levels reduces food intake, and a sustained exposition to this hepatokine leads to cachexia, both under normal diet and HFD .…”

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.…”

TAKling GDF-15 and skeletal muscle atrophy in pulmonary hypertension: are we there yet?

“…GDF-15 can also signal through TAK-1 and nuclear factor kappa light-chain-enhancer of activated B cells (NF-κB), as well as via their short-loop feedback system, in infection-associated epithelial stress and early tumour development 18. In this new study, TAK-1–NF-κB was found to mediate a direct muscle atrophic effect of GDF-15 through upregulating atrogin-1, a mechanism independent of appetite suppression, as GFRAL expression was not detected in skeletal muscle 14. The authors also found that targeting TAK-1–NF-κB with TAK-1 inhibitor 5(Z)−7-oxozeanol reduced GDF-15-mediated muscle atrophy in C2C12 myotubes and in rats with MCT-induced PH without significantly affecting circulating GDF-15 levels and pulmonary pressures.…”