Growth Differentiation Factor 15 Receptor Research Articles

Growth differentiation factor-15 is an IFN-γ regulated mediator of infection-induced weight loss and the hepatic FGF21 response

Infections are often accompanied by weight loss caused by alterations in host behavior and metabolism, also known as sickness behaviors. Recent studies have revealed that sickness behaviors can either promote or impede survival during infections depending on factors such as the type of infectious pathogen. Nevertheless, we have an incomplete understanding of the underlying mechanisms of sickness behaviors. Furthermore, although the host immune responses to infections have long been known to contribute to the induction of sickness behaviors, recent studies have identified emerging cytokines that are also key regulators of host metabolism during infection and inflammation, such as growth differentiation factor 15 (GDF-15). GDF-15 is a distant member of the TGF-β superfamily that causes weight loss by suppressing appetite and food consumption and causing emesis. These effects require activation of neurons that express the only known GDF-15 receptor, the GFRAL receptor. GDF-15 also functions in the periphery including the induction of ketogenesis and immunoregulation. Nevertheless, the functions and regulation of GDF-15 during live infections is not yet known. Murine infection with avirulent Toxoplasma gondii is an established model to understand infection-induced weight loss. Past studies have determined that acute T. gondii infection causes weight loss due to diminished food consumption and increased energy expenditure through unknown mechanisms. Additionally, our lab previously demonstrated that T. gondii causes upregulation in serum GDF-15 in an IFN-γ-dependent manner during the post-acute phase of the infection. In this study, we interrogated the in-vivo functions and immune regulation of GDF-15 during Toxoplasma gondii infection. First, we found that in wild-type mice, acute T. gondii infection caused a significant weight loss that is preceded by elevation of serum levels of IFN-γ and GDF-15. To determine whether IFN-γ regulates GDF-15, we neutralized IFN-γ on days 5 and 6 and measured GDF-15 on day 7 and found that serum but not tissue levels of GDF-15 decreased after IFN-γ neutralization. Additionally, exogenous IFN-γ was sufficient to elevate serum GDF-15 in the absence of infection. Next, we compared the outcomes of T. gondii infection between WT and Gdf15−/− mice. We observed that the weight trajectories were declining in WT mice while they were increasing in Gdf15−/−mice during the acute phase of the infection. This difference in trajectories extended throughout the chronic infection resulting to an overall weight loss relative to initial weights in WT mice but not Gdf15−/−mice. Then, we determined that GDF-15 is not essential for survival and immunoregulation during T. gondii infection. We also demonstrated that GDF-15 is required for the induction of FGF21, stress-induced cytokine with prominent roles in regulating host metabolism. Finally, we discovered a cytokine cascade IFN-γ-GDF-15-FGF21 that is likely involved in the regulation of host metabolism. Overall, our study provides evidence that IFN-γ contributes to the regulation of host metabolism during infection by inducing GDF-15 and FGF21. GDF-15 orchestrates changes in host metabolism that supports the host immune response in clearing the infection. These physiological alterations induce FGF21, which in turn, orchestrates the adaptive responses to the effects of GDF-15, which can be detrimental when protracted.

Dietary medium-chain fatty acids reduce food intake via the GDF15-GFRAL axis in mice

ObjectiveMedium chain fatty acids (MCFAs), which are fatty acids with chain lengths of 8–12 carbon atoms, have been shown to reduce food intake in rodents and humans, but the underlying mechanisms are unknown. Unlike most other fatty acids, MCFAs are absorbed from the intestine into the portal vein and enter first the liver. We thus hypothesized that MCFAs trigger the release of hepatic factors that reduce appetite. MethodsThe liver transcriptome in mice that were orally administered MCFAs as C8:0 triacylglycerol (TG) was analyzed. Circulating growth/differentiation factor 15 (GDF15), tissue Gdf15 mRNA and food intake were investigated after acute oral gavage of MCFAs as C8:0 or C10:0 TG in mice. Effects of acute and subchronic administration of MCFAs as C8:0 TG on food intake and body weight were determined in mice lacking either the receptor for GDF15, GDNF Family Receptor Alpha Like (GFRAL), or GDF15. ResultsHepatic and small intestinal expression of Gdf15 and circulating GDF15 increased after ingestion of MCFAs, while intake of typical dietary long-chain fatty acids (LCFAs) had no effect. Plasma GDF15 levels also increased in the portal vein with MCFA intake, indicating that in addition to the liver, the small intestine contributes to the rise in circulating GDF15. Acute oral provision of MCFAs decreased food intake over 24 h compared with a LCFA-containing bolus, and this anorectic effect required the GDF15 receptor, GFRAL. Moreover, subchronic oral administration of MCFAs reduced body weight over 7 days, an effect that was blunted in mice lacking either GDF15 or GFRAL. ConclusionsWe have identified ingestion of MCFAs as a novel nutritional approach that increases circulating GDF15 in mice and have revealed that the GDF15-GFRAL axis is required for the full anorectic effect of MCFAs.

Integrated stress response regulates GDF15 secretion from adipocytes, preferentially suppresses appetite for a high-fat diet and improves obesity

SummaryThe eIF2α phosphorylation-dependent integrated stress response (ISR) is a signaling pathway that maintains homeostasis in mammalian cells exposed to various stresses. Here, ISR activation in adipocytes improves obesity and diabetes by regulating appetite in a non-cell-autonomous manner. Adipocyte-specific ISR activation using transgenic mice decreases body weight and improves glucose tolerance and obesity induced by a high-fat diet (HFD) via preferential inhibition of HFD intake. The transcriptome analysis of ISR-activated adipose tissue reveals that growth differentiation factor 15 (GDF15) expression is induced by the ISR through the direct regulation of the transcription factors ATF4 and DDIT3. Deficiency in the GDF15 receptor GFRAL abolishes the adipocyte ISR-dependent preferential inhibition of HFD intake and the anti-obesity effects. Pharmacologically, 10(E), 12(Z)-octadecadienoic acid induces ISR-dependent GDF15 expression in adipocytes and decreases the intake of the HFD. Based on our findings the specific activation of the ISR in adipocytes controls the non-cell-autonomous regulation of appetite.

The Role of GDF15 as a Myomitokine.

Growth differentiation factor 15 (GDF15) is a cytokine best known for affecting systemic energy metabolism through its anorectic action. GDF15 expression and secretion from various organs and tissues is induced in different physiological and pathophysiological states, often linked to mitochondrial stress, leading to highly variable circulating GDF15 levels. In skeletal muscle and the heart, the basal expression of GDF15 is very low compared to other organs, but GDF15 expression and secretion can be induced in various stress conditions, such as intense exercise and acute myocardial infarction, respectively. GDF15 is thus considered as a myokine and cardiokine. GFRAL, the exclusive receptor for GDF15, is expressed in hindbrain neurons and activation of the GDF15–GFRAL pathway is linked to an increased sympathetic outflow and possibly an activation of the hypothalamic-pituitary-adrenal (HPA) stress axis. There is also evidence for peripheral, direct effects of GDF15 on adipose tissue lipolysis and possible autocrine cardiac effects. Metabolic and behavioral outcomes of GDF15 signaling can be beneficial or detrimental, likely depending on the magnitude and duration of the GDF15 signal. This is especially apparent for GDF15 production in muscle, which can be induced both by exercise and by muscle disease states such as sarcopenia and mitochondrial myopathy.

550P Initial results of a phase Ia/Ib study of NGM120, a first-in-class anti-GDNF family receptor alpha like (GFRAL) antibody in patients (pts) with advanced solid tumors

Growth Differentiation Factor 15 (GDF15) has been shown to have both protumorigenic and procachectic effects. NGM120 is a novel, 1st-in class, humanized monoclonal antibody that inhibits GFRAL (the receptor for GDF15) resulting both in antitumor and anticachexia effects in experimental models. In a healthy volunteer study, NGM120 (10-400 mg) was well tolerated with a favorable safety profile. We present the data from Ph1a/1b dose finding study (NCT04068896) of NGM120 and NGM120 + gemcitabine (Gem)/nab-paclitaxel (nab-P) in advanced cancer pts.

Overexpression of Growth Differentiation Factor 15 Reduces Blood Pressure and Produces Anti‐neuroinflammatory Effects in Mice with Diet‐induced Obesity

The growth differentiation factor 15 (GDF15) is a stress-responsive cytokine, which belongs to the super family of transforming growth factor beta (TGFb). In the past decade, GDF15 has been implicated in multiple biological processes and diseases, including anti-inflammation, anti-obesity and anti-diabetes effects. However, the role of GDF15 in sympathetic regulation of blood pressure has not been reported in the cardiovascular disease state. The purpose of the study was to investigate the effects of GDF15 on the blood pressure and central nervous system neuroinflammatory responses in diet-induced obese mice. NAG-Tg+ transgenic mice (TG) with overexpression of GDF15 and wild-type (WT) littermates were fed on normal chow or high-fat diet (HFD) for 16 weeks. During the experimental period, arterial pressure was recorded by radiotelemetry in conscious mice. WT mice with HFD had higher mean arterial pressure (MAP) compared with the normal diet fed WT mice (WT HFD 110±4 mmHg verse WT 93±4 mmHg). Compared with WT mice with HFD, GDF15 overexpression significantly reduced MAP (TG HFD: 99±3 mmHg verse WT HFD: 110±4 mmHg) accompanied by the decreased urinary norepinephrine excretion and baseline renal sympathetic nerve activity (TG HFD: 38.9±4.1% max verse WT HFD: 61.2±5.6% max). GDF15 TG mice with HFD had lower expressions of pro-inflammatory cytokines interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-a), interleukin 1β (IL-1β), C1q/TNF-related protein-1 (CTRP1) and reduced immune cell infiltration in the hypothalamus and brain stem tissue. A downregulation in GDF15 receptor (GFRAL) expression was detected in brain stem medullary nuclei in WT HFD mice, which was significantly upregulated in GDF15 TG mice with HFD. These data suggest that GDF15 overexpression exerts a potential protective effect on hypertension in obese mice through attenuating sympathetic outflow. The mechanism for this effect involves anti-inflammatory and neuronal protective properties of GDF15 in the central nervous system.

Role of Growth Differentiation Factor 15 in Lung Disease and Senescence: Potential Role Across the Lifespan.

Growth Differentiation Factor 15 (GDF15) is a divergent member of transforming growth factor-beta (TGF-β) superfamily and is ubiquitously expressed, under normal physiological conditions. GDF15 expression increases during many pathological states and serves a marker of cellular stress. GDF15 has multiple and even paradoxical roles within a pathological condition, as its effects can be dose- and time-dependent and vary based on the targeted tissues and downstream pathways. GDF15 has emerged as one of the most recognized proteins as part of the senescence associated secretory phenotype. Cellular senescence plays a major role in many lung diseases across the life-span from bronchopulmonary dysplasia in the premature neonate to COPD and idiopathic pulmonary fibrosis in aged adults. GDF15 levels have been reported to be as a useful biomarker in chronic obstructive pulmonary disease, lung fibrosis and pulmonary arterial hypertension and predict disease severity, decline in lung function and mortality. Glial-cell-line-derived neurotrophic factor family receptor alpha-like (GFRAL) in the brain stem has been identified as the only validated GDF15 receptor and mediates GDF15-mediated anorexia and wasting. The mechanisms and pathways by which GDF15 exerts its pulmonary effects are being elucidated. GDF15 may also have an impact on the lung based on the changes in circulating levels or through the central action of GDF15 activating peripheral metabolic changes. This review focuses on the role of GDF15 in different lung diseases across the lifespan and its role in cellular senescence.

GDF15, an update of the physiological and pathological roles it plays: a review.

Growth differentiation factor 15 (GDF15) is a peptide hormone, and a divergent member of the transforming growth factor beta (TGFβ) superfamily. In normal physiology, GDF15 is expressed in multiple tissues at a low concentration. GDF15 is overexpressed during and following many pathological conditions such as tissue injury and inflammation in order to play a protective role. However, GDF15 appears to promote tumour growth in the later stages of malignant cancer. The recently identified endogenous receptor for GDF15, GDNF family receptor a-like (GFRAL), has allowed elucidation of a physiological pathway in which GDF15 regulates energy homeostasis and body weight, primarily via appetite suppression. The anorectic effect of GDF15 provides some therapeutic potential in management of cancer-related anorexia/cachexia and obesity. Despite the identification of GFRAL as a GDF15 receptor, there appears to be other signalling mechanisms utilized by GDF15 that further increase the possibility of development of therapeutic treatments, should these pathways be fully characterized. In this review, GDF15 function in both physiological and pathological conditions in various tissues will be discussed.

Mechanism of sensitivity to TPF chemoagents and its potential alternative of erbB2 in oral cancer with GDF15 overexpression.

e18542 Background: To explore the mechanism of sensitivity to docetaxel, cisplatin, and 5-fluorouracil (TPF) chemoagents in patients with oral squamous cell carcinoma (OSCC) and growth differentiation factor 15 (GDF15) overexpression recruited in a TPF induction chemotherapy trial; and to explore potential alternative agents for patients who might not benefit from TPF induction chemotherapy. Methods: GDF15-overexpression and silenced OSCC cells were used to investigate sensitivity to TPF chemoagents in vitro and in vivo. Immunoprecipitation combined with mass spectrometry was used to screen out the possible receptor for GDF15, and associated signaling pathways were detected after intervention with the possible receptor of GDF15. The efficacy of an inhibitor of the phosphorylation of the possible GDF15 receptor was evaluated by treatment of GDF15-overexpression OSCC cells in vitro and in vivo. Results: Overexpression of GDF15 in OSCC cell lines and xenografts lead to an increase of chemotherapeutics sensitivity on apoptosis effects induced by docetaxel, cisplatin and 5-fluorouracil, through a caspase -dependent pathway. Immunoprecipitation combined with mass spectrometry revealed that the erbB2 protein was a potential binding protein of GDF15, as verified by coimmunoprecipitation. When GDF15 was overexpressed, the phosphorylation of erbB2 and downstream PI3K/AKT and MAPK/ERK pathways was significantly upregulated, but was downregulated when GDF15 expression was interfered. The erbB2 phosphorylation inhibitor CI1033 significantly inhibited the proliferation and colony-forming ability of GDF15-overexpression OSCC cells as well as the growth of xenografts. CI1033 might be used as a potential targeted drug or alternative of TPF chemoagents for OSCC patients with GDF15 overexpression. Conclusions: OSCC with GDF15 overexpression exhibit sensitivity to TPF chemoagents through a caspase-dependent pathway. ErbB2 phosphorylation inhibitors might be used as potential targeted drugs or an alternative of TPF chemoagents for OSCC patients with GDF15 overexpression.

Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint.

Growth/differentiation factor-15 (GDF-15), also named macrophage inhibitory cytokine-1, is a divergent member of the transforming growth factor β superfamily. While physiological expression is barely detectable in most somatic tissues in humans, GDF-15 is abundant in placenta. Elsewhere, GDF-15 is often induced under stress conditions, seemingly to maintain cell and tissue homeostasis; however, a moderate increase in GDF-15 blood levels is observed with age. Highly elevated GDF-15 levels are mostly linked to pathological conditions including inflammation, myocardial ischemia, and notably cancer. GDF-15 has thus been widely explored as a biomarker for disease prognosis. Mechanistically, induction of anorexia via the brainstem-restricted GDF-15 receptor GFRAL (glial cell-derived neurotrophic factor [GDNF] family receptor α-like) is well-documented. GDF-15 and GFRAL have thus become attractive targets for metabolic intervention. Still, several GDF-15 mediated effects (including its physiological role in pregnancy) are difficult to explain via the described pathway. Hence, there is a clear need to better understand non-metabolic effects of GDF-15. With particular emphasis on its immunomodulatory potential this review discusses the roles of GDF-15 in pregnancy and in pathological conditions including myocardial infarction, autoimmune disease, and specifically cancer. Importantly, the strong predictive value of GDF-15 as biomarker may plausibly be linked to its immune-regulatory function. The described associations and mechanistic data support the hypothesis that GDF-15 acts as immune checkpoint and is thus an emerging target for cancer immunotherapy.

Leukemia cells remodel marrow adipocytes via TRPV4-dependent lipolysis.

Remodeling of adipocyte morphology and function plays a critical role in prostate cancer development. We previously reported that leukemia cells secrete growth differentiation factor 15 (GDF15), which remodels the residual bone marrow (BM) adipocytes into small adipocytes and is associated with a poor prognosis in patients with acute myeloid leukemia. However, little is known about how GDF15 drives BM adipocyte remodeling. In this study, we examined the role of the transient receptor potential vanilloid (TRPV) channels in the remodeling of BM adipocytes exposed to GDF15. We found that TRPV4 negatively regulated GDF15-induced remodeling of BM adipocytes. Furthermore, transforming growth factor-β type II receptor was identified as the main receptor for GDF15 on BM adipocytes. PI3K inhibitor treatment reduced GDF15- induced pAKT, identifying PI3K/AKT as the downstream stress response pathway. Subsequently, GDF15 reduced the expression of the transcription factor Forkhead box C1 (FOXC1) in BM adipocytes subjected to RNAsequencing screening and western blot analysis. Moreover, it was also confirmed that FOXC1 combined with the TRPV4 promoter by chromatin immunoprecipitation with quantitative polymerase chain reaction experiments, which suggests that FOXC1 mediates GDF15 regulation of TRPV4. In addition, an acute myeloid leukemia mouse model exhibited smaller BM adipocytes, whereas the TRPV4 activator 4a-phorbol 12,13-didecanoate partly rescued this process and increased survival. In conclusion, TRPV4 plays a critical role in BM adipocyte remodeling induced by leukemia cells, suggesting that targeting TRPV4 may constitute a novel strategy for acute myeloid leukemia therapy.

Growth differentiation factor 15 (GDF15): A survival protein with therapeutic potential in metabolic diseases.

Growth Differentiation Factor 15 (GDF15), also known as NSAID activated gene-1 (NAG-1), is associated with a large number of biological processes and diseases, including cancer and obesity. GDF15 is synthesized as pro-GDF15, is dimerized, and is cleaved and secreted into the circulation as a mature dimer GDF15. Both the intracellular GDF15 and the circulating mature GDF15 are implicated in biological processes, such as energy homeostasis and body weight regulation. Although there have been many studies on GDF15, GFRAL, a member of the glial-derived neurotropic factor receptor α family, has only been recently identified as a receptor for mature GDF15. In this review, we focused on cancer and energy homeostasis along with obesity and body weight, and the effect of the identification of the GDF15 receptor in these investigations. In addition, the therapeutic potential of GDF15 as a pharmacological agent in obesity and other metabolic diseases was discussed.

GDF-15 in Pulmonary and Critical Care Medicine.

GDF-15 (growth differentiation factor 15) acts both as a stress-induced cytokine with diverse actions at different body sites and as a cell-autonomous regulator linked to cellular senescence and apoptosis. For multiple reasons, this divergent transforming growth factor-β molecular superfamily member should be better known to pulmonary researchers and clinicians. In ambulatory individuals, GDF-15 concentrations in peripheral blood are an established predictive biomarker of all-cause mortality and of adverse cardiovascular events. Concentrations upon admission of critically ill patients (without or with sepsis) correlate with organ dysfunction and independently predict short- and long-term mortality risk. GDF-15 is a major downstream mediator of p53 activation, but it can also be induced independently of p53, notably by nonsteroidal antiinflammatory agents. GDF-15 blood concentrations are markedly elevated in adults and children with pulmonary hypertension. Concentrations are also increased in chronic obstructive pulmonary disease, in which they contribute to mucus hypersecretion, airway epithelial cell senescence, and impaired antiviral defenses, which together with murine data support a role for GDF-15 in chronic obstructive pulmonary disease pathogenesis and progression. This review summarizes biological and clinical data on GDF-15 relevant to pulmonary and critical care medicine. We highlight the recent discovery of a central nervous system receptor for GDF-15, GFRAL (glial cell line-derived neurotrophic factor family receptor-α-like), an important advance with potential for novel treatments for obesity and cachexia. We also describe limitations and controversies in the existing literature, and we delineate research questions that must be addressed to determine whether GDF-15 can be therapeutically manipulated in other clinical settings.

Growth Differentiation Factor-15 (GDF-15) Inhibits Gastric Emptying in Rodents as Part of Its Anorectic Mechanism of Action

GDF-15 is a secreted circulating polypeptide that regulates systemic energy balance. GDF-15 agonists may have therapeutic potential as anorectic agents in obesity and type 2 diabetes. The receptor for GDF-15, Gfral, is expressed on specific neurons in the area postrema (AP) of the hindbrain, and is necessary for the effect of GDF-15 on food intake. Given the role of the AP in vagal control of gastric motility, we sought to investigate the potential effects of GDF-15 on gastric emptying. Food intake reduction by GDF-15 was confirmed in C57Bl/6N mice using BioDAQ continuous food consumption monitoring. Animals were treated sc with recombinant His-tagged human GDF-15 prior to initiation of the dark cycle; GDF-15 treated mice showed significant reduction in food intake relative to vehicle treated controls (12 hour cumulative food intake: 3nmol/kg, -19.9±10.5%; 10nmol/kg, -58.0±10.0%; P<0.0001, n=8). Gastric emptying was assessed using an oral acetaminophen (AAP) absorption test over 90 minute using LC/MS detection. This method was validated using known inhibitor of gastric emptying, Exendin-4 as a positive control; 7.2nmol/kg Exendin-4 significantly reduced integrated AAP absorption by -44.7±5.1% (P<0.01, n=8). In this assay, GDF-15 caused a significant dose-dependent inhibition of gastric emptying, reducing acetaminophen AUC levels by -18.1±10.6% at 1nmol/kg, and by -36.0±9.9% at 10nmol/kg, relative to vehicle treated control mice (P<0.01, n=8). Comparable results were obtained in an independent repetition of the study. We extended the results obtained in mice to SD rats, where we similarly observed a significant reduction in gastric emptying following GDF-15 treatment. Hence, GDF-15 appears to reduce gastric emptying rate in both mouse and rat, potentially contributing to the food intake suppression mechanism of action. Disclosure S.A. Hinke: Employee; Self; Janssen Research & Development. C.R. Cavanaugh: Employee; Self; Janssen Research & Development. T. Kirchner: None. W. Lang: None. R. Meng: None. N.H. Wallace: None. J. Liu: None. K.E. D'Aquino: Employee; Self; Janssen Research & Development. Employee; Spouse/Partner; Janssen Research & Development. G. Ho: None. M.M. Rankin: Employee; Self; Janssen Research & Development. S. Wang: None. J.A. Chavez: None. S.M. Nelson: None. J. Furman: Employee; Self; Janssen Research & Development. S. Mullican: Employee; Self; Janssen Research & Development. S.M. Rangwala: Employee; Self; Janssen Research & Development. A.R. Nawrocki: Employee; Self; Janssen Pharmaceuticals, Inc..

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

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.

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

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.