The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.
Long-acting MIC-1/GDF15 molecules to treat obesity: Evidence from mice to monkeys
Abstract
In search of metabolically regulated secreted proteins, we conducted a microarray study comparing gene expression in major metabolic tissues of fed and fasted ob/ob mice and C57BL/6 mice. The array used in this study included probes for ~4000 genes annotated as potential secreted proteins. Circulating macrophage inhibitory cytokine 1 (MIC-1)/growth differentiation factor 15 (GDF15) concentrations were increased in obese mice, rats, and humans in comparison to age-matched lean controls. Adeno-associated virus-mediated overexpression of GDF15 and recombinant GDF15 treatments reduced food intake and body weight and improved metabolic profiles in various metabolic disease models in mice, rats, and obese cynomolgus monkeys. Analysis of the GDF15 crystal structure suggested that the protein is not suitable for conventional Fc fusion at the carboxyl terminus of the protein. Thus, we used a structure-guided approach to design and successfully generate several Fc fusion molecules with extended half-life and potent efficacy. Furthermore, we discovered that GDF15 delayed gastric emptying, changed food preference, and activated area postrema neurons, confirming a role for GDF15 in the gut-brain axis responsible for the regulation of body energy intake. Our work provides evidence that GDF15 Fc fusion proteins could be potential therapeutic agents for the treatment of obesity and related comorbidities.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Altered GDF-15 levels in comparison to matched lean controls have been frequently reported in obese mice, rats, and humans (32, 105).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [32]
In the citing paper
“In line with these studies, exogenous administration of recombinant murine or human GDF-15 induced weight loss in different animal models (26, 32, 40, 41, 107).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [32]
In the citing paper
“Elevated circulating GDF-15 levels have been associated with more severe disease or higher mortality in people with DM2, insulin resistance, hemodialysis, cachexia, cardiovascular diseases, chronic obstructive pulmonary disease (COPD), venous thromboembolism (VTE), cancer, or obesity (28–34).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [32]
Citations
Cites
Coot : model-building tools for molecular graphics
Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571
Phaser crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612
The CCP4 suite: programs for protein crystallography
Number Collaborative Computational Project (1994) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444994003112 · Cited by 17,317
Refinement of Macromolecular Structures by the Maximum-Likelihood Method
Murshudov, G. N., Vagin, A. A., & Dodson, E. J. (1997) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444996012255 · Cited by 14,796
Ng, M., Fleming, T., Robinson, M., Thomson, B., Graetz, N., Margono, C., Mullany, E. C., Biryukov, S., Abbafati, C., Abera, S. F., et al. (2014) · The Lancet · doi:10.1016/s0140-6736(14)60460-8 · Cited by 11,952
MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-β superfamily
Bootcov, M. R., Bauskin, A. R., Valenzuela, S. M., Moore, A. G., Bansal, M., He, X. Y., Zhang, H. P., Donnellan, M., Mahler, S. M., Pryor, K., et al. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.21.11514 · Cited by 1,180
Tumor-induced anorexia and weight loss are mediated by the TGF-β superfamily cytokine MIC-1
Johnen, H., Lin, S., Kuffner, T., Brown, D. A., Tsai, V. W.-W., Bauskin, A. R., Wu, L., Pankhurst, G., Jiang, L., Junankar, S., et al. (2007) · Nature Medicine · doi:10.1038/nm1677 · Cited by 612
Growth Differentiation Factor 15 as a Biomarker in Cardiovascular Disease
Wollert, K. C., Kempf, T., & Wallentin, L. C. (2016) · Clinical Chemistry · doi:10.1373/clinchem.2016.255174 · Cited by 569
Crystal Structure of Transforming Growth Factor-β2: an Unusual Fold for the Superfamily
Daopin, S., Piez, K. A., Ogawa, Y., & Davies, D. R. (1992) · Science · doi:10.1126/science.1631557 · Cited by 440
Anatomy and physiology of the enteric nervous system
Costa, M., Brookes, S., & Hennig, G. (2000) · Gut · doi:10.1136/gut.47.suppl_4.iv15 · Cited by 364
Schlunegger, M. P., & Grütter, M. G. (1992) · Nature · doi:10.1038/358430a0 · Cited by 336
Auricchio, A., Hildinger, M., O'Connor, E., Gao, G., & Wilson, J. M. (2001) · Human Gene Therapy · doi:10.1089/104303401450988 · Cited by 296
Paralkar, V. M., Vail, A. L., GRASSER, W. A., Brown, T. A., Xu, H., Vukičević, S., Ke, H. Z., Qi, H., Owen, T. A., & Thompson, D. D. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.22.13760 · Cited by 289
Enhancing Antibody Fc Heterodimer Formation through Electrostatic Steering Effects
Gunasekaran, K., Pentony, M., Shen, M., Garrett, L., Forte, C. P., Woodward, A., Ng, S. B., Born, T. L., Retter, M. W., Manchulenko, K., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.117382 · Cited by 281
Area Postrema: Chemoreceptor circumventricular organ of the medulla oblongata
Borison, H. L. (1989) · Progress in Neurobiology · doi:10.1016/0301-0082(89)90028-2 · Cited by 261
Structure of the ternary signaling complex of a TGF-β superfamily member
Allendorph, G. P., Vale, W., & Choe, S. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0602558103 · Cited by 251
Integrated Upper Gastrointestinal Response to Food Intake
Camilleri, M. (2006) · Gastroenterology · doi:10.1053/j.gastro.2006.03.023 · Cited by 248
Breit, S. N., Johnen, H., Cook, A. D., Tsai, V. W. W., Mohammad, M. G., Kuffner, T., Zhang, H. P., Marquis, C. P., Jiang, L., Lockwood, G., et al. (2011) · Growth Factors · doi:10.3109/08977194.2011.607137 · Cited by 247
NAG-1/GDF-15 prevents obesity by increasing thermogenesis, lipolysis and oxidative metabolism
Chrysovergis, K., Wang, X., Kosak, J., Lee, S.-H., Kim, J. S., Foley, J. F., Travlos, G., Singh, S., Baek, S. J., & Eling, T. E. (2014) · International Journal of Obesity · doi:10.1038/ijo.2014.27 · Cited by 241
Self-citationLutz, T. A., Senn, M., Althaus, J., Prete, E. D., Ehrensperger, F., & Scharrer, E. (1998) · Peptides · doi:10.1016/s0196-9781(97)00292-1 · Cited by 240
PLAB, a novel placental bone morphogenetic protein
Hromas, R., Hufford, M. B., Sutton, J., Xu, D., Li, Y., & Lu, L. (1997) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/s0167-4781(97)00122-x · Cited by 233
Long, S. D., O’Brien, K. D., MacDonald, K. G., Leggett-Frazier, N., Swanson, M. S., Pories, W. J., & Caro, J. F. (1994) · Diabetes Care · doi:10.2337/diacare.17.5.372 · Cited by 219
Macia, L., Tsai, V. W.-W., Nguyen, A. D., Johnen, H., Kuffner, T., Shi, Y.-C., Lin, S., Herzog, H., Brown, D. A., Breit, S. N., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0034868 · Cited by 211
Identification of a novel member of the TGF-beta superfamily highly expressed in human placenta
Lawton, L. N., Bonaldo, M. F., Jelenc, P. C., Qiu, L., Baumes, S. A., Marcelino, R. A., de Jesus, G. M., Wellington, S., Knowles, J. A., Warburton, D., et al. (1997) · Gene · doi:10.1016/s0378-1119(97)00485-x · Cited by 209
Concise Review: Growth Differentiation Factor 15 in Pathology: A Clinical Role?
Corre, J., Hébraud, B., & Bourin, P. (2013) · Stem Cells Translational Medicine · doi:10.5966/sctm.2013-0055 · Cited by 208
TGF-b superfamily cytokine MIC-1/GDF15 is a physiological appetite and body weight regulator
Tsai, V. W.-W., Macia, L., Johnen, H., Kuffner, T., Manadhar, R., Jørgensen, S. B., Lee-Ng, K. K. M., Zhang, H. P., Wu, L., Marquis, C. P., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0055174 · Cited by 188
Vila, G., Riedl, M., Anderwald, C. H., Resl, M., Handisurya, A., Clodi, M., Prager, G., Ludvik, B. H., Krebs, M., & Luger, A. (2010) · Clinical Chemistry · doi:10.1373/clinchem.2010.153726 · Cited by 184
The diverse roles of nonsteroidal anti-inflammatory drug activated gene (NAG-1/GDF15) in cancer
Wang, X., Baek, S. J., & Eling, T. E. (2012) · Biochemical Pharmacology · doi:10.1016/j.bcp.2012.11.025 · Cited by 154
Self-citationGrowth differentiation factor 15 in erythroid health and disease
Tanno, T., Noel, P., & Miller, J. L. (2010) · Current Opinion in Hematology · doi:10.1097/moh.0b013e328337b52f · Cited by 139
The effect of vertical sleeve gastrectomy on food choice in rats
Wilson, H., Chambers, A. P., Sandoval, D. A., Stefater, M. A., Woods, S. C., Benoit, S. C., & Seeley, R. J. (2012) · International Journal of Obesity · doi:10.1038/ijo.2012.18 · Cited by 134
Tsai, V. W.-W., Manandhar, R., Jørgensen, S. B., Lee-Ng, K. K. M., Zhang, H. P., Marquis, C. P., Jiang, L., Husaini, Y., Lin, S., Sainsbury, A., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0100370 · Cited by 129
A Flexible Activin Explains the Membrane-Dependent Cooperative Assembly of TGF-β Family Receptors
Greenwald, J., Vega, M., Allendorph, G. P., Fischer, W. H., Vale, W., & Choe, S. (2004) · Molecular Cell · doi:10.1016/j.molcel.2004.07.011 · Cited by 125
Noradrenergic neurons of the area postrema mediate amylin's hypophagic action
Potes, C. S., Turek, V. F., Cole, R. L., Vu, C., Roland, B. L., Roth, J. D., Riediger, T., & Lutz, T. A. (2010) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00791.2009 · Cited by 79
Thomas, J. R., & Marcus, E. (2008) · Obesity Surgery · doi:10.1007/s11695-007-9336-3 · Cited by 57
Effect of Roux-en-Y Gastric Bypass on Satiety and Food Likes: The Role of Genetics
Thirlby, R. C., Bahiraei, F., Randall, J., & Drewnoski, A. (2006) · Journal of Gastrointestinal Surgery · doi:10.1016/j.gassur.2005.06.012 · Cited by 57
Zhang, J., Gupte, J., Gong, Y., Weiszmann, J., Zhang, Y., Lee, K. J., Richards, W. G., & Li, Y. (2017) · EBioMedicine · doi:10.1016/j.ebiom.2016.12.016 · Cited by 54
Self-citationThe pharmaceutical market for obesity therapies
Wong, D., Sullivan, K., & Heap, G. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3830 · Cited by 39
Peripheral mechanisms in the control of appetite and related experimental therapies in obesity
Camilleri, M. (2009) · Regulatory Peptides · doi:10.1016/j.regpep.2009.04.011 · Cited by 23
Cited by
Sorted by citations
The endocrine function of adipose tissues in health and cardiometabolic disease
Scheja, L., & Heeren, J. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0230-6 · Cited by 663
Linking cellular stress responses to systemic homeostasis
Galluzzi, L., Yamazaki, T., & Kroemer, G. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0068-0 · Cited by 556
GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease
Wang, D., Day, E. A., Townsend, L. K., Djordjevic, D., Jørgensen, S. B., & Steinberg, G. R. (2021) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00529-7 · Cited by 543
GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans
Patel, S., Alvarez-Guaita, A., Melvin, A., Rimmington, D., Dattilo, A., Miedzybrodzka, E. L., Cimino, I., Maurin, A.-C., Roberts, G. P., Meek, C. L., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2018.12.016 · Cited by 509
Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint
Wischhusen, J., Melero, I., & Fridman, W. H. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00951 · Cited by 506
Metadata
- Authors
- Xiong, Y., Walker, K., Min, X., Hale, C., Tran, T., Komorowski, R., Yang, J., Davda, J., Nuanmanee, N., Kemp, D., Wang, X., Liu, H., Miller, S., Lee, K. J., Wang, Z., & Véniant, M. M.
- Affiliations
- Amgen (United States) (US)
- Department of Cardiometabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
- Corresponding author
- Véniant, Murielle M.
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2017-10-18
- Volume
- 9
- Issue
- 412
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- OpenAlex
- W2765137069
- Cited by
- 236
- References
- 38
- Citations by year
- 2026: 20 · 2025: 28 · 2024: 25 · 2023: 35 · 2022: 32 · 2021: 23 · 2020: 31 · 2019: 24 · 2018: 16 · 2017: 2
- FWCI
- 17.45
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › GDF15 and Related Biomarkers
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- GDF15, MIC-1, obesity, Fc fusion protein, adeno-associated virus gene therapy, dietary intake, body weight, gut-brain axis, gastric emptying, food preferences, secreted proteins, Macaca fascicularis, structure-guided protein engineering
- MeSH terms
- Dependovirus, Animals, Diet, Food Preferences, Gastric Emptying, Humans, Macaca fascicularis, Male, Mice, Inbred C57BL, Mice, Obese, Neurons, Obesity, Receptors, Fc, Recombinant Fusion Proteins, Up-Regulation, Rats, Sprague-Dawley, Crystallography, X-Ray, Growth Differentiation Factor 15
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
