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

Nature. 2020 Feb;578(7795):444-448. doi: 10.1038/s41586-019-1911-y.

Anthony P Coll ^# ¹, Michael Chen ², Pranali Taskar ², Debra Rimmington ³, Satish Patel ³, John A Tadross ³, Irene Cimino ³, Ming Yang ³, Paul Welsh ⁴, Samuel Virtue ³, Deborah A Goldspink ³, Emily L Miedzybrodzka ³, Adam R Konopka ⁵, Raul Ruiz Esponda ⁵, Jeffrey T-J Huang ⁶, Y C Loraine Tung ³, Sergio Rodriguez-Cuenca ³, Rute A Tomaz ⁷, Heather P Harding ⁸, Audrey Melvin ³, Giles S H Yeo ³, David Preiss ⁹, Antonio Vidal-Puig ³, Ludovic Vallier ⁷, K Sreekumaran Nair ⁵, Nicholas J Wareham ¹⁰, David Ron ⁸, Fiona M Gribble ³, Frank Reimann ³, Naveed Sattar ^# ⁴, David B Savage ^# ³, Bernard B Allan ^# ², Stephen O'Rahilly ^# ¹¹

Affiliations

1 MRC Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK. [email protected].
2 NGM Biopharmaceuticals, South San Francisco, CA, USA.
3 MRC Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
4 Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
5 Division of Endocrinology, Mayo Clinic, Rochester, MN, USA.
6 Division of Systems Medicine, School of Medicine, University of Dundee, Dundee, UK.
7 Wellcome -Medical Research Council Cambridge Stem Cell Institute, Department of Surgery, University of Cambridge, Cambridge, UK.
8 Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
9 MRC Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
10 MRC Epidemiology Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
11 MRC Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK. [email protected].
# Contributed equally.

PMID: 31875646 DOI: 10.1038/s41586-019-1911-y

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 manner³. 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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