Insights Into Mechanisms of GDF15 and Receptor GFRAL: Therapeutic Targets

Growth and differentiation factor 15 (GDF15) belongs to the TGF-β superfamily proteins. Glial-derived neurotrophic factor-family receptor α-like is an endogenous receptor for GDF15 detected selectively in the brain. GDF15 serum levels rise in response to cell stress. GDF15 is an established predictive biomarker of adverse cardiovascular events.GDF15-induced weight loss and reduction in food intake are centrally mediated. In obesity, GDF15 increases lipolysis, oxidative metabolism, and thermogenesis. These actions are associated with reduction of inflammatory process and insulin resistance.Experimental and clinical studies support the potential use of GDF15 as a novel therapeutic target in relation to: (i) preventing and treating obesity by modulating metabolic activity; (ii) promoting an adaptive angiogenesis; and (iii) promoting regenerative processes. Growth and differentiation factor 15 (GDF15) belongs to the transforming growth factor-β (TGF-β) superfamily proteins. GDF15 acts as an inflammatory marker, and it plays a role in pathogenesis of tumors, ischemic diseases, metabolic disorders, and neurodegenerative processes. GDF15 is not normally expressed in the tissue; it is prominently induced following ‘injury’. GDF15 functions are critical for the regulation of endothelial adaptations after vascular damage. Recently, four research groups simultaneously identified glial-derived neurotrophic factor (GDNF)-family receptor α-like (GFRAL) in the brain, an orphan receptor as the receptor for GDF15, signaling through the coreceptor RET. In this article, new aspects of the biology of GDF15 and receptor GFRAL, and their relationship with various pathologies, are commented on. Growth and differentiation factor 15 (GDF15) belongs to the transforming growth factor-β (TGF-β) superfamily proteins. GDF15 acts as an inflammatory marker, and it plays a role in pathogenesis of tumors, ischemic diseases, metabolic disorders, and neurodegenerative processes. GDF15 is not normally expressed in the tissue; it is prominently induced following ‘injury’. GDF15 functions are critical for the regulation of endothelial adaptations after vascular damage. Recently, four research groups simultaneously identified glial-derived neurotrophic factor (GDNF)-family receptor α-like (GFRAL) in the brain, an orphan receptor as the receptor for GDF15, signaling through the coreceptor RET. In this article, new aspects of the biology of GDF15 and receptor GFRAL, and their relationship with various pathologies, are commented on. GDF15 (see Glossary) also termed macrophage inhibitory cytokine 1 (MIC-1), belongs to the transforming growth factor-β (TGF-β) superfamily proteins. TGF-secreted factor superfamily consists of more than 30 members. They were originally identified as molecules important for regulating development, differentiation, and tissue repair in various organs. The TGF-β superfamily comprises a lot of ligands including TGF-βs, activins, bone morphogenetic proteins (BMP), and GDFs. GDFs belong to the activin/myostatin subclass. Several members of this subfamily have been described, and named GDF1 through to GDF15 [1.Herpin A. et al.Transforming growth factor-beta-related proteins: an ancestral and widespread superfamily of cytokines in metazoans.Dev. Comp. Immunol. 2004; 28: 461-485Crossref PubMed Scopus (153) Google Scholar]. TGF-β family proteins bind to distinct type I and type II serine/threonine kinase receptors. TGF-β signaling is known for its pleiotropic regulatory role in the inflammatory process. GDFs have been involved in many of the pathophysiological processes. Signaling induced by the TGF family ligands are necessary for multiple processes during vertebrate development, tissue homeostasis, and repair [2.Tobin J.F. Celeste A.J. Bone morphogenetic proteins and growth differentiation factors as drug targets in cardiovascular and metabolic disease.Drug Discov. Today. 2006; 11: 405-411Crossref PubMed Scopus (39) Google Scholar, 3.Unsicker K. et al.The multiple facets of the TGF-beta family cytokine growth/differentiation factor-15/macrophage inhibitory cytokine-1.Cytokine Growth Factor Rev. 2013; 24: 373-384Crossref PubMed Scopus (160) Google Scholar, 4.Rochette L. et al.Growth and differentiation factor 11 (GDF11): functions in the regulation of erythropoiesis and cardiac regeneration.Pharmacol. Ther. 2015; 156: 26-33Crossref PubMed Scopus (38) Google Scholar]. A receptor of the GDNF-family receptor α-like (GFRAL) has been identified as the receptor for GDF15. The GDNF family is one of the best characterized families of neurotrophic factors, which supports the survival of a variety of target neurons. Four ligands are identified in this family. They require a heterodimeric receptor complex, and the receptor complex is comprised of two molecules: a common transmembrane receptor tyrosine kinase, and a glycosylphosphatidylinositol (GPtdIns)-anchored membrane protein GDNF family receptor α (GFR α). The GDNF family of ligands (GFLs) is comprised of four related factors: GDNF, neurturin, artemin, and persephin [5.Fielder G.C. et al.The GDNF family: a role in cancer?.Neoplasia. 2018; 20: 99-117Crossref PubMed Scopus (28) Google Scholar]. The human GDF15 locus was mapped by fluorescence in situ hybridization (FISH) to chromosome 19p12.1-13.1, and it was shown that the gene contained a single 1820 bp intron [6.Lawton L.N. et al.Identification of a novel member of the TGF-beta superfamily highly expressed in human placenta.Gene. 1997; 203: 17-26Crossref PubMed Scopus (133) Google Scholar]. Studies suggest that genetic factors play an important role in determining GDF15 concentrations. It has been reported that specific variants near the GDF15 gene on chromosome 19p13.11 were strongly associated with GDF15 concentration [7.Ho J.E. et al.Clinical and genetic correlates of growth differentiation factor 15 in the community.Clin. Chem. 2012; 58: 1582-1591Crossref PubMed Scopus (72) Google Scholar]. Several polymorphisms in the GDF15 gene have been identified. GDF15 is synthesized as a precursor protein: proGDF15 that undergoes disulfide-linked dimerization (a 25-kDa disulfide-linked dimer) like TGF-β. The unprocessed translated form of GDF15 (pre-pro-GDF15) is 308 amino acids (aa) long, including the signal sequence (29 aa), the propeptide (167 aa) and a mature protein (112 aa), which contains a cystine knot typical for the TGF-β family. GDF15 is produced as a ≈ 40kDa propeptide form. The mature protein is secreted as a homodimer linked by disulfide bonds and is released from the propeptide following intracellular cleavage at RXXR furine-like cleavage site. Mature GDF15 is soluble and evaluated in blood. The mature peptide is a dimer with a broad normal circulating range of ~0.15–1.15ngml−1 in healthy humans. GDF15 concentrations increase with age, but do not vary by sex in healthy elderly individuals. GDF15 concentrations have been associated with cystatin C and C-reactive protein concentrations [8.Brown D.A. et al.Concentration in plasma of macrophage inhibitory cytokine-1 and risk of cardiovascular events in women: a nested case-control study.Lancet. 2002; 359: 2159-2163Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar,9.Kempf T. et al.Circulating concentrations of growth-differentiation factor 15 in apparently healthy elderly individuals and patients with chronic heart failure as assessed by a new immunoradiometric sandwich assay.Clin. Chem. 2007; 53: 284-291Crossref PubMed Scopus (194) Google Scholar]. Circulating GDF15 increases during exercise and during recovery from exercise in humans. GDF15 is expressed in most tissues including skeletal muscle. It is possible that GDF15 is secreted from muscle in response to cellular stress or injury, to act locally in an autocrine or paracrine manner [10.Kleinert M. et al.Exercise increases circulating GDF15 in humans.Mol. Metab. 2018; 9: 187-191Crossref PubMed Scopus (46) Google Scholar]. GDF15 is not normally expressed in the adult myocardium, although it is prominently induced following ‘injury’ or in failed hearts. Several basic research studies have identified proteins produced by the heart, referred to as cardiokines, which may function analogously to adipokines. They are deregulated during tissular stress and inflammation in signaling either locally or peripherally. In recent years, there has been an increased comprehension of endocrine effects mediated by these factors produced and secreted by the heart. Cardiac fibroblasts and cardiomyocytes were proposed as the principal sources of inflammatory signals in pathological conditions, contributing to the proinflammatory environment in the myocardium by the production of various cardiokines. Within the TGF-β superfamily is the newly identified cardiokine: GDF15 [11.Bootcov M.R. et al.MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily.Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 11514-11519Crossref PubMed Scopus (776) Google Scholar]. During myocardial injury, GDF15 is expressed in cardiomyocytes, adipocytes, macrophages, endothelial cells, and vascular smooth muscle cells. The regulation of GDF15 expression in the cardiovascular system has been extensively reviewed [12.Wollert K.C. et al.Growth differentiation factor 15 as a biomarker in cardiovascular disease.Clin. Chem. 2017; 63: 140-151Crossref PubMed Scopus (200) Google Scholar,13.Planavila A. et al.Cardiokines as modulators of stress-induced cardiac disorders.Adv. Protein Chem. Struct. Biol. 2017; 108: 227-256Crossref PubMed Scopus (17) Google Scholar]. GDF15 is expressed in various tissues, but there are limited data on various organs such as eyes (Box 1).Box 1GDF15 and Ocular PathologiesGDF15 gene is expressed in various tissues, but there are limited data on the ocular expression. Recent studies demonstrated the presence of GDF15 in ocular tissue such as human retinal pigment epithelial cells and murine retina. Alterations in the expression of genes were studied in the rat retina after optic nerve injury. GDF15 mRNA and protein are, respectively, six- and threefold upregulated in the murine retina at 1 day after optic nerve crush. GDF15 protein may be related to the regulation of vitreoretinal inflammatory processes [78.Charalambous P. et al.Regulation and effects of GDF-15 in the retina following optic nerve crush.Cell Tissue Res. 2013; 353: 1-8Crossref PubMed Scopus (18) Google Scholar].Interestingly, it has been recently reported that, in aqueous humor, GDF15 was elevated in patients with primary open-angle glaucoma, compared to control cataract patients without glaucoma. GDF15 expression in the retina is specifically increased after acute injury to retinal ganglion cell axons, and in a murine chronic glaucoma model [79.Ban N. et al.GDF15 is elevated in mice following retinal ganglion cell death and in glaucoma patients.JCI Insight. 2017; 2e91455Crossref PubMed Scopus (22) Google Scholar]. It is suggested that measurement of GDF15 in aqueous humor might give quantitative information about glaucomatous neurodegeneration [80.Ban N. et al.Monitoring neurodegeneration in glaucoma: therapeutic implications.Trends Mol. Med. 2018; 24: 7-17Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar]. HIF is a major transcription factor, in the different ocular tissue; it modulates the expression of many oxygen sensitive genes including vascular endothelial growth factor but also the TGF-β superfamily protein including GDF15. HIF pathway plays vital role in neovascularization in retinal diseases. HIF pathway is intimately associated with the pathobiology of several oxygen-dependent retinal diseases such as diabetic retinopathy, and glaucoma. The expression of proangiogenic genes such as GDF15, is implicated under hypoxic conditions. In retinal pigment epithelial cells, the expression of proangiogenic genes including GDF15, is dependent on histone lysine demethylases (KDMs); KDMs underlining gene regulation. The expression profile of GDF15 gene in the various cell types of retina tissue is not clearly elucidated. The evaluation of molecular mechanisms related to the ocular expression of GDF15 in retinal diseases, may help in understanding the ocular pathologies and has the potential to open a new field for ocular therapeutics. GDF15 gene is expressed in various tissues, but there are limited data on the ocular expression. Recent studies demonstrated the presence of GDF15 in ocular tissue such as human retinal pigment epithelial cells and murine retina. Alterations in the expression of genes were studied in the rat retina after optic nerve injury. GDF15 mRNA and protein are, respectively, six- and threefold upregulated in the murine retina at 1 day after optic nerve crush. GDF15 protein may be related to the regulation of vitreoretinal inflammatory processes [78.Charalambous P. et al.Regulation and effects of GDF-15 in the retina following optic nerve crush.Cell Tissue Res. 2013; 353: 1-8Crossref PubMed Scopus (18) Google Scholar]. Interestingly, it has been recently reported that, in aqueous humor, GDF15 was elevated in patients with primary open-angle glaucoma, compared to control cataract patients without glaucoma. GDF15 expression in the retina is specifically increased after acute injury to retinal ganglion cell axons, and in a murine chronic glaucoma model [79.Ban N. et al.GDF15 is elevated in mice following retinal ganglion cell death and in glaucoma patients.JCI Insight. 2017; 2e91455Crossref PubMed Scopus (22) Google Scholar]. It is suggested that measurement of GDF15 in aqueous humor might give quantitative information about glaucomatous neurodegeneration [80.Ban N. et al.Monitoring neurodegeneration in glaucoma: therapeutic implications.Trends Mol. Med. 2018; 24: 7-17Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar]. HIF is a major transcription factor, in the different ocular tissue; it modulates the expression of many oxygen sensitive genes including vascular endothelial growth factor but also the TGF-β superfamily protein including GDF15. HIF pathway plays vital role in neovascularization in retinal diseases. HIF pathway is intimately associated with the pathobiology of several oxygen-dependent retinal diseases such as diabetic retinopathy, and glaucoma. The expression of proangiogenic genes such as GDF15, is implicated under hypoxic conditions. In retinal pigment epithelial cells, the expression of proangiogenic genes including GDF15, is dependent on histone lysine demethylases (KDMs); KDMs underlining gene regulation. The expression profile of GDF15 gene in the various cell types of retina tissue is not clearly elucidated. The evaluation of molecular mechanisms related to the ocular expression of GDF15 in retinal diseases, may help in understanding the ocular pathologies and has the potential to open a new field for ocular therapeutics. In conclusion, GDF15 is weakly produced in most tissues under physiological conditions, but is strongly induced in response to inflammation and tissue injury. In humans with cardiovascular disease, GDF15 has been detected in atherosclerotic plaque macrophages and in the infarcted myocardium [14.Kempf T. Wollert K.C. Growth-differentiation factor-15 in heart failure.Heart Fail. Clin. 2009; 5: 537-547Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar]. Another important area of the biological actions of GDF15 is the tumor genesis. Several studies showed that higher expression of GDF15 mRNA and protein was found in cancer biopsies. GDF15 is one of the major secreted proteins induced by the tumor suppressor protein p53, which acts as a growth inhibitory molecule in tumor cells. This effect is associated with the prosurvival protein activating transcription factor 3, which is negatively regulated by p53 protein expression [15.Tan M. et al.PTGF-beta, a type beta transforming growth factor (TGF-beta) superfamily member, is a p53 target gene that inhibits tumor cell growth via TGF-beta signaling pathway.Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 109-114Crossref PubMed Scopus (214) Google Scholar]. Some cellular environmental conditions are able to promote tumor angiogenesis via the increased release of GDF15. The interactions between a developing tumor and its microenvironment are known to implicate a complex ‘crosstalk’ among the factors produced by the population of cells. GDF15 could affect tumorigenesis both positively and negatively [16.Rochette L. et al.Functional roles of GDF15 in modulating microenvironment to promote carcinogenesis.Biochim. Biophys. Acta Mol. basis Dis. 1866; 2020: 165798Google Scholar]. Recent findings suggest that GDF15 might modulate mitochondrial functions through induction of mitochondria-related genes. In mice in which the heart, muscle, and brain adenine nucleotide translocator isoform 1 (ANT1) was inactivated, the muscle mitochondria produce excess reactive oxygen species and are partially uncoupled. Muscle transcriptome analysis revealed the induction of mitochondrial biogenesis, and increased expression of the genes encoding the myokines: FGF21 and GDF15 [17.Morrow R.M. et al.Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity.Proc. Natl. Acad. Sci. U. S. A. 2017; 114: 2705-2710Crossref PubMed Scopus (45) Google Scholar]. ANT1 is the most abundant protein in the inner mitochondrial membrane. It forms as a homodimer, a gated channel by which ADP is brought into, and ATP transported out of the mitochondrial matrix. Mice in which the ANT1 gene is deleted promote mitochondrial myopathy in relationship with the hyperproliferation of skeletal muscle mitochondria [18.Wall C.E. et al.High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice.Proc. Natl. Acad. Sci. U. S. A. 2015; 112: 8714-8719Crossref PubMed Scopus (31) Google Scholar]. In this context, muscle mitochondrial stress is correlated with the induction of GDF15 [19.Yatsuga S. et al.Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders.Ann. Neurol. 2015; 78: 814-823Crossref PubMed Scopus (124) Google Scholar]. Various clinical studies in relationship with the mitochondrial metabolism, show a positive correlation between GDF15 and obesity, or type 2 diabetes mellitus (T2DM). Patients with obesity and insulin resistance exhibit impaired mitochondrial function [20.Hesselink M.K. et al.Skeletal muscle mitochondria as a target to prevent or treat type 2 diabetes mellitus.Nat. Rev. Endocrinol. 2016; 12: 633-645Crossref PubMed Scopus (135) Google Scholar]. In these patients, expression and secretion of GDF15 in skeletal myocytes, were associated with altered mitochondrial oxidative phosphorylation function [21.Chung H.K. et al.Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis.J. Cell Biol. 2017; 216: 149-165Crossref PubMed Scopus (137) Google Scholar]. These findings suggest that GDF15 is a regulator of systemic energy homeostasis. Intriguingly, plasma GDF15 was recently reported to be increased in mitochondrial disease (MD) patients, with a lower current velocity of growth than expected values, and organ failures as well as muscular dystrophies. Among the various mitochondrial disorders’ subtypes, GDF15 concentrations were tenfold higher than controls. GDF15 has also been reported to be a useful biomarker for monitoring the state of heart failure and renal failure [19.Yatsuga S. et al.Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders.Ann. Neurol. 2015; 78: 814-823Crossref PubMed Scopus (124) Google Scholar]. The mechanism of elevation of GDF15 is not clear in MDs patients; however, in this context, GDF15 is a useful biomarker for muscle-related diseases. Carbon tetrachloride (CCl4) intoxication and alcohol overdose are examples of hepatic injury resulting from microsomal metabolism and mitochondrial dysfunctions. It has been evoked that the mitochondrial dysfunction induced by alcohol and CCl4 promotes GDF15 production in hepatocytes. In the work, it is reported that recombinant GDF15 decreased the expression of proinflammatory cytokines, and prevented the activation of T cells in the livers of mice with CCl4-induced liver fibrosis [22.Chung H.K. et al.GDF15 deficiency exacerbates chronic alcohol- and carbon tetrachloride-induced liver injury.Sci. Rep. 2017; 7: 17238Crossref PubMed Scopus (43) Google Scholar]. Finally, and interestingly, a new concept is that GDF15 is a marker for diagnosis of MDs. TGF-β family proteins bind to distinct type I and type II serine/threonine kinase receptors [23.Chang H. et al.Genetic analysis of the mammalian transforming growth factor-beta superfamily.Endocr. Rev. 2002; 23: 787-823Crossref PubMed Scopus (625) Google Scholar]. The specificity of the intracellular signaling is mainly determined by type I receptors [activin receptor-like kinase (ALK)-1 to ALK-7]. Intracellular signaling mechanisms induced by the TGF-β superfamily are divided into SMAD-dependent and -independent pathways. SMAD proteins are important in TGF-β signaling [24.Zhang Y.E. Mechanistic insight into contextual TGF-beta signaling.Curr. Opin. Cell Biol. 2018; 51: 1-7Crossref PubMed Scopus (48) Google Scholar]. GDF15 activates type 1 receptor and phosphorylates SMAD2/3 and SMAD1/5/8, which translocate to the nucleus in the form of heteromeric complex with SMAD4. This statement is controversial as use of contaminated GDF15 has been a common problem, which has affected experiments in this field. Purified recombinant proteins for use in biomedical research are invaluable to investigate protein function [25.Olsen O.E. et al.TGF-beta contamination of purified recombinant GDF15.PLoS One. 2017; 12e0187349Crossref PubMed Scopus (29) Google Scholar,26.Tsai V.W.W. et al.The MIC-1/GDF15-GFRAL pathway in energy homeostasis: implications for obesity, cachexia, and other associated diseases.Cell Metab. 2018; 28: 353-368Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar]. In patients, GDF15 levels showed a significant positive correlation with liver stiffness. The GDF15 treatment resulted in enhanced expression of α-smooth muscle actin and collagen I, as well as phosphorylation of SMAD2 and SMAD3. GDF15 elevation might be an adaptation mechanism for liver injury implicating the SMAD signaling system [27.Xu J. et al.GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation.Circ. Res. 2006; 98: 342-350Crossref PubMed Scopus (323) Google Scholar,28.Koo B.K. et al.Growth differentiation factor 15 predicts advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease.Liver Int. 2018; 38: 695-705Crossref PubMed Scopus (36) Google Scholar]. Interestingly, four research groups from different pharmaceutical companies simultaneously identified GFRAL as the receptor for GDF15, signaling through the coreceptor RET. (RET is an abbreviation for ‘rearranged during transfection’.) Alternatively, several laboratories have shown that both GDNF and GFRAL signal independently of RET [29.Yang L. et al.GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand.Nat. Med. 2017; 23: 1158-1166Crossref PubMed Scopus (212) Google Scholar, 30.Mullican S.E. et al.GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates.Nat. Med. 2017; 23: 1150-1157Crossref PubMed Scopus (241) Google Scholar, 31.Emmerson P.J. et al.The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL.Nat. Med. 2017; 23: 1215-1219Crossref PubMed Scopus (205) Google Scholar, 32.Hsu J.Y. et al.Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15.Nature. 2017; 550: 255-259Crossref PubMed Scopus (187) Google Scholar]. GFLs, the GDNF family of ligands, act as biologically active homodimers that signal canonically through the transmembrane receptor RET. RET is present in at least three isoforms, and activation of RET takes a major place within lipid rafts. The stoichiometry of GFL:GDNF receptor α(GFRα):RET binding interaction, is postulated to be one ligand homodimer to two GFRα molecules to two RET receptors, forming a hetero-hexameric complex [5.Fielder G.C. et al.The GDNF family: a role in cancer?.Neoplasia. 2018; 20: 99-117Crossref PubMed Scopus (28) Google Scholar] (Figure 1). Expression of GFRAL gene mRNA was analyzed in various embryonic and adult mouse tissues. Both isoforms of GRAL mRNA were detected in the central nervous system (CNS) of adult mouse. By contrast, there was no detectable GRAL mRNA in peripheral organs examined, such as the heart, liver, spleen, lung, kidney, placenta, skeletal muscle, and small intestine. Among the various regions in the CNS, GFRAL mRNAs were relatively more abundant in some parts of the brain, such as the substantia nigra, the hippocampus, and the area postrema [33.Li Z. et al.Identification, expression and functional characterization of the GRAL gene.J. Neurochem. 2005; 95: 361-376Crossref PubMed Scopus (30) Google Scholar]. GFRAL is an orphan receptor, it is a transmembrane protein with a short cytoplasmic domain (Figure 1). The X-ray crystal structure of GDF15 in complex with the extracellular domain of GFRAL was demonstrated. GDF15 activates GFRAL-expressing neurons localized exclusively in the area postrema, and nucleus tractus solitarius of the mouse brainstem [32.Hsu J.Y. et al.Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15.Nature. 2017; 550: 255-259Crossref PubMed Scopus (187) Google Scholar] (Figure 2). GDF15–GFRAL signaling controls body weight. In normal conditions, the regulation of energy balance by the brain requires precise information regarding the influx of energy. Unlike gut-derived and adipose-tissue-derived hormones that are regulated by changes in nutrient intake and metabolic flux, GDF15 levels increase in response to tissue damage [34.Clemmensen C. et al.Gut-brain cross-talk in metabolic control.Cell. 2017; 168: 758-774Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar]. Recombinant GDF15 induces weight loss, in mice fed a high-fat diet and in nonhuman primates with spontaneous obesity [30.Mullican S.E. et al.GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates.Nat. Med. 2017; 23: 1150-1157Crossref PubMed Scopus (241) Google Scholar]. In this study, germline Gfral gene deleted mice (Gfral−/−) lost the anorexic and metabolic effects caused by recombinant GDF15. In addition, diet-induced obesity and insulin resistance are exacerbated in GFRAL-deficient mice, suggesting a homeostatic role for this receptor in metabolism [30.Mullican S.E. et al.GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates.Nat. Med. 2017; 23: 1150-1157Crossref PubMed Scopus (241) Google Scholar]. Heart disease is connected with GDF15 synthesis and secretion by cardiomyocytes. Recently, GDF15 was identified as a cardiac hormone that regulates body growth. Growth hormone (GH) secreted from the pituitary gland, signals to the liver to stimulate the production of insulin-like growth factor-I (IGF1) and IGFBP acid-labile subunit, via the JAK2-STAT5 pathway [35.Takahashi Y. The role of growth hormone and insulin-like growth factor-I in the Liver.Int. J. Mol. Sci. 2017; 18: 1447Crossref Scopus (68) Google Scholar]. GH achieves its effects by influencing gene expression profiles, IGF1 being a key transcriptional target of GH signaling in the liver. Circulating GDF15 levels act on the liver to inhibit the actions of GH (Figure 2). Recent results demonstrated that plasma GDF15 is increased in children with concomitant heart disease and failure to thrive. These demonstrate that GDF15 mediates the communication between heart and liver during cardiac pathogenesis. It is an important advance in this area, in relation to clinical situations such as pediatric heart disease, however how GDF15 blocks GH signaling remains unresolved [36.Wang T. et al.GDF15 is a heart-derived hormone that regulates body growth.EMBO Mol. Med. 2017; 9: 1150-1164Crossref PubMed Scopus (40) Google Scholar]. GDF15 is upregulated by various cardiovascular events associated with the oxidative stress such as coronary heart diseases, heart failure, and atherosclerosis. GDF15 is also induced during cardiac hypertrophy in a pressure-overload murine model, and its cardiac-specific overexpression protects the heart from hypertrophic responses [27.Xu J. et al.GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation.Circ. Res. 2006; 98: 342-350Crossref PubMed Scopus (323) Google Scholar]. Chronic heart failure patients had increased GDF15 concentrations that were closely related to disease severity. Increased cardiac GDF15 concentrations have been observed in mice with heart failure [27.Xu J. et al.GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation.Circ. Res. 2006; 98: 342-350Crossref PubMed Scopus (323) Google Scholar]. As indicated before, vascular injury implies a degenerative inflammatory process, where different risk factors such as diabetes, hypertension, and dyslipidemia, are implicated; oxidative stress being an aspect in producing the endothelial dysfunction. The decreased synthesis, release and/or activity of endothelium-derived nitric oxide (NO) is the earliest and one of the most important events that characterizes endothelial dysfunction. GDF15 is able to modulate vascular contraction and relaxation responses in an endothelium-dependent fashion that involves the NO pathway, enhancing the basal release of NO [37.Mazagova M.