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

Nature Medicine

Volumn 23, Issue 10, 2017, Pages 1150-1157

  Mullican, Shannon E ^a   Lin Schmidt, Xiefan ^a   Chin, Chen Ni ^a   Chavez, Jose A ^a   Furman, Jennifer L ^a   Armstrong, Anthony A ^a   Beck, Stephen C ^a   South, Victoria J ^a   Dinh, Thai Q ^a   Cash Mason, Tanesha D ^a   Cavanaugh, Cassandre R ^a   Nelson, Serena ^a   Huang, Chichi ^a   Hunter, Michael J ^a   Rangwala, Shamina M ^a  

^a JANSSEN RESEARCH AND DEVELOPMENT   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

BDNF FAMILY RECEPTOR ALPHA LIKE; GLUCOSE; GROWTH DIFFERENTIATION FACTOR 15; HUMAN SERUM ALBUMIN; INSULIN; PROTEIN; PROTEIN RET; UNCLASSIFIED DRUG; GDF15 PROTEIN, HUMAN; GLIAL CELL LINE DERIVED NEUROTROPHIC FACTOR RECEPTOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; AREA POSTREMA; ARTICLE; BINDING AFFINITY; CELL NUCLEUS; CONTROLLED STUDY; DIET INDUCED OBESITY; DISEASE EXACERBATION; FOOD INTAKE; GENE DELETION; GLUCOSE HOMEOSTASIS; HUMAN; HUMAN CELL; INSULIN RESISTANCE; LIPID DIET; MALE; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN EXPRESSION; SIGNAL TRANSDUCTION; SINGLE DRUG DOSE; WEIGHT REDUCTION; ANIMAL; DRUG EFFECTS; EATING; GENETICS; KNOCKOUT MOUSE; MACACA FASCICULARIS; METABOLISM; OBESITY;

ANIMALS; DIET, HIGH-FAT; EATING; GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR RECEPTORS; GROWTH DIFFERENTIATION FACTOR 15; HUMANS; MACACA FASCICULARIS; MICE; MICE, KNOCKOUT; OBESITY; WEIGHT LOSS;

EID: 85029757839     PISSN: 10788956     EISSN: 1546170X     Source Type: Journal    
DOI: 10.1038/nm.4392     Document Type: Article

References (38)

1. Ng, M. et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet 384, 766-781 (2014).
2. Heymsfield, S.B. & Wadden, T.A. Mechanisms, pathophysiology, and management of Obesity. N. Engl. J. Med. 376, 254-266 (2017).
3. Khera, R. et al. Association of pharmacological treatments for obesity with weight loss and adverse events: A systematic review and meta-analysis. J. Am. Med. Assoc. 315, 2424-2434 (2016).
4. Johnen, H. et al. Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1. Nat. Med. 13, 1333-1340 (2007).
5. Macia, L. et al. Macrophage inhibitory cytokine 1 (MIC-1/GDF15) decreases food intake, body weight and improves glucose tolerance in mice on normal & obesogenic diets. PLoS One 7, e34868 (2012).
6. Chrysovergis, K. et al. NAG-1/GDF-15 prevents obesity by increasing thermogenesis, lipolysis and oxidative metabolism. Int. J. Obes. 38, 1555-1564 (2014).
7. Wang, X. et al. hNAG-1 increases lifespan by regulating energy metabolism and insulin/IGF-1/mTOR signaling. Aging 6, 690-704 (2014).
8. Morrow, R.M. et al. Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity. Proc. Natl. Acad. Sci. USA 114, 2705-2710 (2017).
9. Chung, H.K. et al. Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis. J. Cell Biol. 216, 149-165 (2017).
10. Tsai, V.W. et al. TGF-b superfamily cytokine MIC-1/GDF15 is a physiological appetite and body weight regulator. PLoS One 8, e55174 (2013).
11. Tsai, V.W. et al. The anorectic actions of the TGFcytokine MIC-1/GDF15 require an intact brainstem area postrema and nucleus of the solitary tract. PLoS One 9, e100370 (2014).
12. 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 359, 2159-2163 (2002).
13. Kempf, T. et al. Growth-differentiation factor-15 improves risk stratification in STsegment elevation myocardial infarction. Eur. Heart J. 28, 2858-2865 (2007).
14. Kempf, T. et al. Growth differentiation factor 15 predicts future insulin resistance and impaired glucose control in obese nondiabetic individuals: results from the XENDOS trial. Eur. J. Endocrinol. 167, 671-678 (2012).
15. Tsai, V.W. et al. Serum levels of human MIC-1/GDF15 vary in a diurnal pattern, do not display a profile suggestive of a satiety factor and are related to BMI. PLoS One 10, e0133362 (2015).
16. Tsai, V.W. et al. Anorexia/cachexia of chronic diseases: A role for the TGF-family cytokine MIC-1/GDF15. J. Cachexia Sarcopenia Muscle 3, 239-243 (2012).
17. Artz, A., Butz, S. & Vestweber, D. GDF-15 inhibits integrin activation and mouse neutrophil recruitment through the ALK-5/TGF-RII heterodimer. Blood 128, 529-541 (2016).
18. Wang, C.Y., Huang, A.Q., Zhou, M.H. & Mei, Y.A. GDF15 regulates Kv2.1-mediated outward K+ current through the Akt/mTOR signalling pathway in rat cerebellar granule cells. Biochem. J. 460, 35-47 (2014).
19. de Jager, S.C. et al. Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis. J. Exp. Med. 208, 217-225 (2011).
20. Li, Z. et al. Identification, expression and functional characterization of the GRAL gene. J. Neurochem. 95, 361-376 (2005).
21. Hätinen, T., Holm, L. & Airaksinen, M.S. Loss of neurturin in frog-comparative genomics study of GDNF family ligand-receptor pairs. Mol. Cell. Neurosci. 34, 155-167 (2007).
22. Vieira, P., Thomas-Crusells, J. & Vieira, A. Internalization of glial cell-derived neurotrophic factor receptor GFR alpha 1 in the absence of the ret tyrosine kinase coreceptor. Cell. Mol. Neurobiol. 23, 43-55 (2003).
23. Hayes, M.R., Skibicka, K.P. & Grill, H.J. Caudal brainstem processing is sufficient for behavioral, sympathetic, and parasympathetic responses driven by peripheral and hindbrain glucagon-like-peptide-1 receptor stimulation. Endocrinology 149, 4059-4068 (2008).
24. Akhurst, R.J. & Hata, A. Targeting the TGFsignalling pathway in disease. Nat. Rev. Drug Discov. 11, 790-811 (2012).
25. Allendorph, G.P., Isaacs, M.J., Kawakami, Y., Izpisua Belmonte, J.C. & Choe, S. BMP-3 and BMP-6 structures illuminate the nature of binding specificity with receptors. Biochemistry 46, 12238-12247 (2007).
26. Allendorph, G.P., Vale, W.W. & Choe, S. Structure of the ternary signaling complex of a TGF-beta superfamily member. Proc. Natl. Acad. Sci. USA 103, 7643-7648 (2006).
27. Greenwald, J. et al. The BMP7/ActRII extracellular domain complex provides new insights into the cooperative nature of receptor assembly. Mol. Cell 11, 605-617 (2003).
28. Parkash, V. & Goldman, A. Comparison of GFL-GFRalpha complexes: further evidence relating GFL bend angle to RET signalling. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 65, 551-558 (2009).
29. Goodman, K.M. et al. RET recognition of GDNF-GFR1 ligand by a composite binding site promotes membrane-proximal self-association. Cell Rep. 8, 1894-1904 (2014).
30. Airaksinen, M.S. & Saarma, M. The GDNF family: signalling, biological functions and therapeutic value. Nat. Rev. Neurosci. 3, 383-394 (2002).
31. Alao, J.P., Michlikova, S., Dinér, P., Grøtli, M. & Sunnerhagen, P. Selective inhibition of RET mediated cell proliferation in vitro by the kinase inhibitor SPP86. BMC Cancer 14, 853 (2014).
32. Ding, Q. et al. Identification of macrophage inhibitory cytokine-1 in adipose tissue and its secretion as an adipokine by human adipocytes. Endocrinology 150, 1688-1696 (2009).
33. Verdeguer, F. et al. Brown adipose YY1 deficiency activates expression of secreted proteins linked to energy expenditure and prevents diet-induced obesity. Mol. Cell. Biol. 36, 184-196 (2015).
34. Hasebe, T. et al. Bone morphogenetic protein-binding endothelial regulator of liver sinusoidal endothelial cells induces iron overload in a fatty liver mouse model. J. Gastroenterol. 52, 341-351 (2017).
35. Quartu, M. et al. Tissue distribution of Ret, GFRalpha-1, GFRalpha-2 and GFRalpha-3 receptors in the human brainstem at fetal, neonatal and adult age. Brain Res. 1173, 36-52 (2007).
36. Bauskin, A.R. et al. The propeptide of macrophage inhibitory cytokine (MIC-1), a TGF-beta superfamily member, acts as a quality control determinant for correctly folded MIC-1. EMBO J. 19, 2212-2220 (2000).
37. Merchant, A.M. et al. An efficient route to human bispecific IgG. Nat. Biotechnol. 16, 677-681 (1998).
38. Turner, L. et al. Severe malaria is associated with parasite binding to endothelial protein C receptor. Nature 498, 502-505 (2013).