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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.
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“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]
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Self-citation
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
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