GDF15 mediates the effects of metformin on body weight and energy balance

Coll, A. P. et al. (2020) GDF15 mediates the effects of metformin on body weight and energy balance. Nature, 578, pp. 444-448. (doi: 10.1038/s41586-019-1911-y) (PMID:31875646) (PMCID:PMC7234839)

207415.pdf - Accepted Version



Metformin, the world's most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk . Over 60% of this effect is attributable to the ability of metformin to lower body weight in a sustained manner . The molecular mechanisms by which metformin lowers body weight are unknown. In two, independent randomised controlled clinical trials, circulating levels of GDF15, recently described to reduce food intake and lower body weight through a brain stem-restricted receptor, were increased by metformin. 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 GFRAL. In obese, high-fat-fed mice, 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 required GDF15. Metformin retained its ability to lower circulating glucose levels in the absence of GDF15 action. In summary, metformin elevates circulating levels of GDF15, which are necessary for its beneficial effects on energy balance and body weight, major contributors to its action as a chemopreventive agent.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Preiss, Dr David and Sattar, Professor Naveed and Welsh, Dr Paul
Authors: Coll, A. P., Chen, M., Taskar, P., Rimmington, D., Patel, S., Tadross, J., 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., and O'Rahilly, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Nature
Publisher:Nature Research
ISSN (Online):1476-4687
Published Online:25 December 2019
Copyright Holders:Copyright © 2019 Springer Nature
First Published:First published in Nature 578:444-448
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190022Effect of metformin on progression of carotid atherosclerosis in non-diabetic patients with CHD optimally treated with conventional risk reducing agentsNaveed SattarChief Scientist Office (CSO)CZB/4/613Institute of Cardiovascular & Medical Sciences
303944BHF Centre of ExcellenceRhian TouyzBritish Heart Foundation (BHF)RE/18/6/34217CAMS - Cardiovascular Science