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

4 years ago

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

Anthony P. Coll, Michael Chen, Pranali Taskar, Debra Rimmington, Satish Patel, John Tadross, Irene Cimino, Ming Yang, Paul Welsh, Samuel Virtue, Deborah A. Goldspink, Emily L. Miedzybrodzka, Adam R. Konopka, Raul Ruiz Esponda, Jeffrey T-J. Huang, Y. C. Loraine Tung, Sergio Rodriguez-Cuenca, Rute A. Tomaz, Heather P. Harding, Audrey Melvin, Giles S. H. Yeo, David Preiss, Antonio Vidal-Puig, Ludovic Vallier, K. Sreekumaran Nair, Nicholas J. Wareham, David Ron, Fiona M. Gribble, Frank Reimann, Naveed Sattar, David B. Savage, Bernard B. Allan, Stephen O'Rahilly

Metformin, the world's most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk^1,2. Over 60% of this effect is attributable to the ability of metformin to lower body weight in a sustained manner³. 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.

Publisher URL: http://feeds.nature.com/~r/nature/rss/current/~3/-zfr8kNDSRE/s41586-019-1911-y

DOI: 10.1038/s41586-019-1911-y