Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss
Abstract
Metformin is the most commonly prescribed medication for type 2 diabetes, owing to its glucose-lowering effects, which are mediated through the suppression of hepatic glucose production (reviewed in refs. 1-3). However, in addition to its effects on the liver, metformin reduces appetite and in preclinical models exerts beneficial effects on ageing and a number of diverse diseases (for example, cognitive disorders, cancer, cardiovascular disease) through mechanisms that are not fully understood 1-3. Given the high concentration of metformin in the liver and its many beneficial effects beyond glycemic control, we reasoned that metformin may increase the secretion of a hepatocyte-derived endocrine factor that communicates with the central nervous system 4. Here we show, using unbiased transcriptomics of mouse hepatocytes and analysis of proteins in human serum, that metformin induces expression and secretion of growth differentiating factor 15 (GDF15). In primary mouse hepatocytes, metformin stimulates the secretion of GDF15 by increasing the expression of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP; also known as DDIT3). In wild-type mice fed a high-fat diet, oral administration of metformin increases serum GDF15 and reduces food intake, body mass, fasting insulin and glucose intolerance; these effects are eliminated in GDF15 null mice. An increase in serum GDF15 is also associated with weight loss in patients with type 2 diabetes who take metformin. Although further studies will be required to determine the tissue source(s) of GDF15 produced in response to metformin in vivo, our data indicate that the therapeutic benefits of metformin on appetite, body mass and serum insulin depend on GDF15.
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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 [24]
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- Authors
- Day, E. A., Ford, R. J., Smith, B. K., Mohammadi-Shemirani, P., Morrow, M. R., Gutgesell, R. M., Lu, R., Raphenya, A. R., Kabiri, M., McArthur, A. G., McInnes, N., Hess, S., Paré, G., Gerstein, H. C., & Steinberg, G. R.
- Affiliations
- McMaster University (CA)
- Sanofi (Germany) (DE)
- Population Health Research Institute (CA)
- Corresponding author
- Steinberg, Gregory R.
- ORCID
- Venue
- Nature Metabolism
- Published
- 2019-12-09
- Volume
- 1
- Issue
- 12
- Pages
- 1202-1208
- ISSN
- 2522-5812 (ISSN-L)
- OpenAlex
- W2992288250
- Cited by
- 307
- References
- 48
- Citations by year
- 2026: 31 · 2025: 43 · 2024: 56 · 2023: 49 · 2022: 49 · 2021: 49 · 2020: 27 · 2019: 2
- FWCI
- 24.09
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Gouvernement du Canada | Canadian Institutes of Health Research (201709FDN-CEBA-116200 to GS)
- Diabetes Canada (DI-5-17-5302-GS)
- Topics
- Health Sciences › Medicine › Rheumatology › 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 › Fibroblast Growth Factor Research
- Keywords
- metformin, appetite suppression, weight loss, ATF4, CHOP, DDIT3, type 2 diabetes, insulin resistance, impaired glucose tolerance, high-fat diet
- MeSH terms
- Animals, Appetite Depressants, Body Weight, Diabetes Mellitus, Type 2, Eating, Humans, Hypoglycemic Agents, Insulin, Male, Metformin, Weight Loss, Up-Regulation, Glucose Intolerance, Hepatocytes, Mice, Growth Differentiation Factor 15, Diet, High-Fat, Primary Cell Culture
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