Journal
NATURE
Volume 578, Issue 7795, Pages 444-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-019-1911-y
Keywords
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Categories
Funding
- Chief Scientist Office, Scotland [CZB/4/613]
- University of Oxford British Heart Foundation Centre of Research Excellence Senior Transition Fellowship [RE/13/1/30181]
- BHF Centre of Excellence award [COE/RE/18/6/34217]
- National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre
- Medical Research Council (MRC Metabolic Diseases Unit) [MC_UU_00014/1]
- Histopathology Core (MRC Metabolic Diseases Unit) [MC_UU_00014/5]
- Wellcome Trust Strategic Award [100574/Z/12/Z, Wellcome 100140]
- Wellcome Trust [WT 107064, WT 095515/Z/11/Z, 106262/Z/14/Z, 106263/Z/14/Z]
- MRC Metabolic Disease Unit [MC_ UU_00014/1]
- NIHR Rare Disease Translational Research Collaboration
- Wellcome Trust Principal Research Fellowship [Wellcome 200848/Z/16/Z]
- BHF [RG/18/7/33636]
- MRC [MC_UU_00014/2, MC_UU_00014/3, MC_UU_12015/1]
- Experimental Medicine Training Initiative/AstraZeneca
- ERC advanced grant NewChol
- Medical Research Council
- BBSRC-DTP studentship
- NIH [R21 AG60139, UL1 TR000135, T32DK007352]
- NIHR
- BBSRC [BB/S017593/1, 1645477] Funding Source: UKRI
- MRC [G0600717, MC_UU_00014/1, MC_UU_12012/3, MC_UU_12012/2, MC_UU_12012/5, G0400192, MC_UU_12015/1, MC_UU_12012/1, MC_UU_00014/2, G0802051, MC_UU_00014/3, MC_UU_00014/5] Funding Source: UKRI
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In mouse studies, metformin treatment results in increased secretion of growth/differentiation factor 15 (GDF15), which prevents weight gain in response to high-fat diet, and GDF15-independent lowering of circulating blood glucose. 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 alpha-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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