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GDF15 mediates the effects of metformin on body weight and energy balance
Open accessPublished version of a preprint
Abstract
Metformin, the world's most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk 1,2. More than 60% of this effect is attributable to the ability of metformin to lower body weight in a sustained manner 3. The molecular mechanisms by which metformin lowers body weight are unknown. Here we show-in two independent randomized controlled clinical trials-that metformin increases circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15), which has been shown to reduce food intake and lower body weight through a brain-stem-restricted receptor. In wild-type mice, oral metformin increased circulating GDF15, with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to a high-fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GDNF family receptor α-like (GFRAL). In obese mice on a high-fat diet, the effects of metformin to reduce body weight were reversed by a GFRAL-antagonist antibody. Metformin had effects on both energy intake and energy expenditure that were dependent on GDF15, but retained its ability to lower circulating glucose levels in the absence of GDF15 activity. In summary, metformin elevates circulating levels of GDF15, which is necessary to obtain its beneficial effects on energy balance and body weight, major contributors to its action as a chemopreventive agent.
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Metformin's beneficial effects on energy balance and body weight are regulated via GDF15.
“More recently, metformin’s beneficial effects on maintaining energy balance and body weight were shown to be regulated via growth/differentiation factor 15 (GDF15)”
From Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) · cites this paper as Coll et al. 2020
GDF-15 is a key mediator of metformin-induced weight loss.
“Recently, the growth differentiation factor 15 (GDF-15), a member of the transforming growth factor beta superfamily, has been identified as a key mediator of metformin-induced weight loss.”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [23]
Metformin-induced GDF-15 expression is detected in gut and kidney epithelial cells.
“Metformin-induced expression was notably detected in gut and kidney epithelial cells (23).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [23]
Coll et al. reported in two independent RCTs that metformin reduced food intake and lowered body weight in association with increasing GDF-15 levels.
“Moreover, Coll et al. (23) reported in two independent RCT that metformin reduced food intake and lowered body weight in association with increasing levels of GDF-15.”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [23]
Metformin and phenformin induce GDF-15 expression in murine and human hepatocytes.
“Metformin and other biguanides such as phenformin were shown to induce GDF-15 expression in murine and human hepatocytes (23), while the direct effect of other anti-diabetes drugs has not been studied yet.”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [23]
Metformin does not induce weight loss when administered to gdf-15 knockout mice.
“These results were further confirmed by Coll et al. as metformin did not induce weight loss when administered to gdf-15 knock out mice (23).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [23]
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Metadata
- Authors
- Coll, A. P., Chen, M., Taskar, P., Rimmington, D., Patel, S., Tadross, J. A., Cimino, I., Yang, M., Welsh, P., Virtue, S., Goldspink, D. A., Miedzybrodzka, E. L., Konopka, A. R., Esponda, R. R., Huang, J. T.-J., Tung, Y. C. L., Rodriguez-Cuenca, S., Tomaz, R. A., Harding, H. P., Melvin, A., Yeo, G. S. H., Preiss, D., Vidal-Puig, A., Vallier, L., Nair, K. S., Wareham, N. J., Ron, D., Gribble, F. M., Reimann, F., Sattar, N., Savage, D. B., Allan, B. B., & O’Rahilly, S.
- Affiliations
- University of Cambridge (GB)
- NGM Biopharmaceuticals (United States) (US)
- University of Glasgow (GB)
- Mayo Clinic (US)
- University of Dundee (GB)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Oxford (GB)
- Corresponding author
- Coll, Anthony P.
- O’Rahilly, Stephen
- ORCID
- Coll, Anthony P.
- Chen, Michael
- Taskar, Pranali
- Rimmington, Debra
- Patel, Satish
- Tadross, John A.
- Yang, Ming
- Welsh, Paul
- Goldspink, Deborah A.
- Miedzybrodzka, Emily L.
- Konopka, Adam R.
- Huang, Jeffrey T.-J.
- Tomaz, Rute A.
- Harding, Heather P.
- Melvin, Audrey
- Yeo, Giles S. H.
- Preiss, David
- Vallier, Ludovic
- Nair, K. Sreekumaran
- Wareham, Nicholas J.
- Ron, David
- Gribble, Fiona M.
- Reimann, Frank
- Sattar, Naveed
- Savage, David B.
- Allan, Bernard B.
- O’Rahilly, Stephen
- Venue
- Nature
- Published
- 2019-12-25
- Volume
- 578
- Issue
- 7795
- Pages
- 444-448
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7234839
- OpenAlex
- W2997621205
- Cited by
- 584
- References
- 42
- Citations by year
- 2026: 64 · 2025: 86 · 2024: 95 · 2023: 98 · 2022: 82 · 2021: 89 · 2020: 66 · 2019: 2
- FWCI
- 45.17
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-02-13)
- Open access
- green
- doi.org
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion, other-oa)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- AstraZeneca (RE/18/6/34217)
- Wellcome Trust (095515, 106262, 107064/Z/15/Z, WT107064, 107064, 051420, 100574, 200848, 100574/Z/12/Z, 100140, WT 095515/Z/11/Z, 095515/Z/11/Z, MC_UU_00014/5, 106263, Wellcome 100140, Wellcome 200848/Z/16/Z, 100140/Z/12/Z, 106263/Z/14/Z, 106262/Z/14/Z, 200848/Z/16/Z)
- Cancer Research UK (RE/13/1/30181)
- National Institute for Health and Care Research (200848/Z/16/Z, 100574/Z/12/Z, NF-SI-0513-10109, CL-2019-14-504, MC_UU_00014/5, ACF-2016-14-004, NF-SI-0507-10380, NF-SI-0512-10135, NF-SI-0617-10149)
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- Department of Health and Social Care
- University of Oxford (RE/13/1/30181)
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/T2T0419)
- Cambridge University Hospitals (146281)
- National Institutes of Health (UL1TR000135)
- Medical Research Council (MC_UU_12015/1, MC_UU_00014/1, 13/1/30181, MC_PC_12009, MC_UU_00014/3, MC_UU_00014/5, MC_UU_00014/2)
- Biotechnology and Biological Sciences Research Council (1645477, BB/S017593/1)
- Cambridge Institute for Medical Research, University of Cambridge (100140)
- NIHR Cambridge Biomedical Research Centre (100574/Z/12/Z)
- Cancer Research UK Cambridge Institute, University of Cambridge
- National Institute on Aging (R21AG060139)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007352)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › GDF15 and Related Biomarkers
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- metformin, GDF15, growth differentiation factor 15, GFRAL, energy balance, body weight, weight gain, high-fat diet, obesity, dietary intake, energy expenditure, blood glucose, type 2 diabetes prevention, chemoprevention
- MeSH terms
- Administration, Oral, Adult, Aged, Animals, Blood Glucose, Body Weight, Energy Intake, Double-Blind Method, Energy Metabolism, Female, Homeostasis, Humans, Intestines, Male, Metformin, Mice, Obese, Middle Aged, Weight Loss, Enterocytes, Glial Cell Line-Derived Neurotrophic Factor Receptors, Mice, Growth Differentiation Factor 15, Diet, High-Fat
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 ›
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