Metformin, the world’s most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk1,2. 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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Source Data for Figs. 1–4 and Extended Data Figs. 1–6, 8–10 are provided with the paper. Other data that support the findings of this study are available from the corresponding authors upon request. The CAMERA trial dataset is held at the University of Glasgow and is available on request from the investigators subject to a signed agreement operating within the confines of the original ethics application.
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The CAMERA trial is funded by a project grant from the Chief Scientist Office, Scotland (CZB/4/613). D.P. is supported by a University of Oxford British Heart Foundation Centre of Research Excellence Senior Transition Fellowship (RE/13/1/30181). N.S. and P.W. acknowledge support from a BHF Centre of Excellence award (COE/RE/18/6/34217). We thank P. Barker, K. Burling and other members of the Cambridge Biochemical Assay Laboratory (CBAL). This project is supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. A.P.C., D. Rimmington, J.A.T., I.C., Y.C.L.T. and G.S.H.Y. are supported by the Medical Research Council (MRC Metabolic Diseases Unit (MC_UU_00014/1)). Mouse studies in Cambridge are supported by S. Grocott and the Disease Model Core, with pathology support from J. Warner and the Histopathology Core (MRC Metabolic Diseases Unit (MC_UU_00014/5) and Wellcome Trust Strategic Award (100574/Z/12/Z). D.B.S. and S.O. are supported by the Wellcome Trust (WT 107064 and WT 095515/Z/11/Z), the MRC Metabolic Disease Unit (MC_UU_00014/1) and The National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre and NIHR Rare Disease Translational Research Collaboration. We thank J. Jones and other members of the Histopathology and ISH Core Facility, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre. D. Ron is supported by a Wellcome Trust Principal Research Fellowship (Wellcome 200848/Z/16/Z) and a Wellcome Trust Strategic Award to the Cambridge Institute for Medical Research (Wellcome 100140). A.V.-P., S.R.-C. and S.V. are supported by the BHF (RG/18/7/33636) and MRC (MC_UU_00014/2). A.M. is supported by a studentship from the Experimental Medicine Training Initiative/AstraZeneca. R.A.T. and L.V. are supported by an ERC advanced grant NewChol and core support from the Wellcome Trust and Medical Research Council to the Wellcome–Medical Research Council Cambridge Stem Cell Institute. M.Y., D.A.G., E.L.M., F.M.G. and F.R. are supported by the MRC (MC_UU_00014/3) and Wellcome Trust (106262/Z/14/Z and 106263/Z/14/Z). M.Y. is supported by a BBSRC-DTP studentship. A.R.K., R.R.E. and K.S.N. are supported by NIH Grants R21 AG60139, UL1 TR000135 and T32DK007352 and acknowledge K. Klaus for technical assistance. N.J.W. is supported by the MRC (MC_UU_12015/1) and is an NIHR Senior Investigator. We acknowledge J. Luan for statistical assistance. CHOP-null mice were a gift from J. Goodall.
P.W. has received grant support from Roche Diagnostics, AstraZeneca and Boehringer Ingelheim. N.S. has consulted for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Napp, Novo Nordisk and Sanofi, and received grant support from Boehringer Ingelheim. M.C., P.T. and B.B.A. are or were employees of NGM Biopharmaceuticals and may hold NGM stock or stock options. F.R. and F.M.G. have received support from AstraZeneca and Eli Lilly. F.M.G. has provided remunerated consultancy services to Kallyope. S.O. has provided remunerated consultancy services to Pfizer, AstraZeneca, Novo-Nordisk and ERX Pharmaceuticals. All other authors declare no competing interests.
Peer review information Nature thanks Samuel Breit, Daniel Drucker, Jerrold M. Olefsky, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Extended data figures and tables
a, Linear association between change in body weight and change in plasma GDF15 between 0 and 18 months among metformin-treated participants (n = 74, Spearman correlation r = –0.26, two-sided P = 0.024). The red line is the linear regression slope, and grey area is 95% CI for the slope. b, Absolute and relative differences in plasma GDF15 concentration between metformin and placebo groups at each time point (total 625 observations in 173 participants). c, d, Individual measures of plasma GDF15 levels in placebo group (c) and metformin group (d) over time. e, Plasma GDF15 concentration (95% CI) in overweight or obese non-diabetic participants with known cardiovascular disease randomized to metformin or placebo in CAMERA; modelled using a mixed linear model as per Fig. 1 and grouped as ‘all participants’ and ‘all participants not reporting diarrhoea and vomiting’. Model includes all participants. Source data
Serum GDF15 levels in male mice measured 2, 4 or 8 h after a single gavage dose of metformin (300 mg kg−1). a, Mice fed ad libitum overnight before gavage. b, Mice fasted for 12 h before gavage. Data are mean ± s.e.m. (a; n = 6 per group, b; n = 4 per group); P values by two-way ANOVA with Tukey’s correction for multiple comparisons. Source data
Extended Data Fig. 3 Body weight changes with metformin treatment in mice with disrupted GDF15–GFRAL signalling.
a, Absolute body weight in Gdf15+/+ and Gdf15−/− mice on a high-fat diet treated with metformin (300 mg kg−1 day−1) for 11 days, mice as in Fig. 2a. Data are mean ± s.e.m., P values by two-way ANOVA with Tukey’s correction for multiple comparisons. b, Absolute body weight in high-fat diet-fed Gfral+/+ and Gfral−/− mice given an oral dose of metformin (300 mg kg−1) once daily for 11 days, mice as in Fig. 2c. Data are mean ± s.e.m. c, Absolute body weight of metformin-treated, obese mice dosed with an anti-GFRAL antagonist antibody or with control IgG weekly for five weeks, starting four weeks after initial metformin exposure; mice as in Fig. 2d. Data are mean ± s.e.m. P values by two-way ANOVA with Tukey’s correction for multiple comparisons. Source data
a, Circulating GDF15 levels in high-fat diet-fed Gdf15+/+ and Gdf15−/− mice given oral dose of metformin (300 mg kg−1) once daily for 11 days. Data are mean ± s.e.m., mice as in Fig. 2a. All Gdf15−/− samples were below lower limit of the assay (<2 pg ml−1); P values by two-way ANOVA with Tukey’s correction for multiple comparisons. b, Circulating GDF15 levels in high-fat diet-fed Gfral+/+ and Gfral−/− mice given oral dose of metformin (300 mg kg−1) once daily for 11 days. Data are mean ± s.e.m., mice as in Fig. 2c; P values by two-way ANOVA with Tukey’s correction for multiple comparisons. c, Cumulative food intake in high-fat diet fed Gfral+/+ and Gfral−/− mice on a high-fat diet given an oral dose of metformin (300 mg kg−1) once daily for 11 days. Data are mean ± s.e.m., mice as in Fig. 2c; no statistically significant difference in vehicle versus metformin by two-way ANOVA. d, Fat mass (left) and lean mass (right) in metformin-treated obese mice dosed with anti-GFRAL antagonist antibody weekly for five weeks, starting four weeks after initial metformin exposure (mice as in Fig. 2d). Body composition was measured using MRI after 4 weeks of metformin exposure, before receiving anti-GFRAL (week 4), after 6 weeks of metformin exposure and 2 weeks after receiving anti-GFRAL (week 6) and after 9 weeks of metformin exposure and 5 weeks after receiving anti-GFRAL (week 9). Data are mean ± s.e.m. (n = 7, vehicle + control IgG and metformin + anti-GFRAL; n = 8, other groups); P values by two-way ANOVA with Tukey’s correction for multiple comparisons. Source data
Extended Data Fig. 5 Response of second, independent cohort of high-fat diet fed Gdf15+/+ and Gdf15−/− mice to metformin.
a–c, Percentage change in body weight (a), absolute body weight (b) and cumulative food intake (c) of Gdf15+/+ and Gdf15−/− mice on a high-fat diet treated with metformin (300 mg kg−1 day−1) for 11 days. Data are mean ± s.e.m. (n = 6 per group, except Gdf15−/− vehicle, n = 7); P values by two-way ANOVA with Tukey’s correction for multiple comparisons. d, Circulating metformin levels in mice 6 h after final dose of metformin on day 11. Data are mean ± s.e.m. (n = 6 per group, except Gdf15+/+ vehicle, n = 4; Gdf15−/− vehicle, n = 7); P values by two-way ANOVA with Tukey’s correction for multiple comparisons. Source data
a, Fasting glucose from oral GTT as in Fig. 3e, f. ANOVA; effect of antibody, P = 0.028; effect of metformin, P = 0.271; interaction of antibody and metformin, P = 0.707. b, Circulating GDF15 in mice undergoing intraperitoneal GTT after a single dose of metformin as in Fig. 3 k, l. P values by two-way ANOVA with Tukey’s correction for multiple comparisons. c, d, Fasting glucose (c) and fasting insulin (d) at time 0 of intraperitoneal GTT as in Fig. 3k, l; not statistically significant by two-way ANOVA. e, AUC analysis of glucose levels as in Fig. 3k, l. P values by two-way ANOVA, effect of genotype, P = 0.392; interaction of genotype and metformin, P = 0.883. a–e, Data all mean ± s.e.m. f, Circulating GDF15 levels in high-fat-diet-fed Gdf15+/+ mice after single oral dose of metformin (600 mg kg−1). Samples were collected 6 h after dosing, data are mean ± s.e.m., n = 7 per group; P values (95% CI) by two-tailed t-test. Source data
a, Representative images from the mouse with circulating GDF15 level closest to the group median shown in Fig. 4b, with images from other regions of the gut and from liver. b, In situ hybridization for Gdf15 mRNA expression (red spots) in colon. Tissue collected from high-fat-diet-fed wild-type mice, 6 h after a single dose of oral metformin (600 mg kg−1) (right, red box, M1–M7) or vehicle gavage (left, blue box, V1–V7); n = 7 mice per group, mice as in Fig. 4.
a, b,Gdf15 mRNA expression in primary mouse hepatocytes (a) or human iPS-cell-derived hepatocytes (b) treated with vehicle control (Con) or metformin for 6 h. mRNA expression is presented as fold expression relative to control treatment (set at 1), normalized to Hprt and GAPDH in mouse and human cells, respectively. Data are expressed as mean ± s.e.m. from four (a) or two (b) independent experiments. P values (95% CI) by one-way ANOVA with Tukey’s correction for multiple comparisons. c, d, Circulating levels of GDF15 (c) and hepatic Gdf15 mRNA expression (d) (normalized to β2-microglobulin) in chow-fed, wild-type mice 4 h after a single oral dose of phenformin (300 mg kg−1). Data are mean ± s.e.m., n = 6 per group; P values (95% CI) by two tailed t-test. e, Representative image of in situ hybridization for Gdf15 mRNA expression (red spots) of fixed liver tissue derived from animals treated as described in c and d. Source data
a, b, mRNA levels in kidney (a) and colon (b) isolated from obese mice 24 h after a single oral dose of metformin (600 mg kg−1). Data are mean ± s.e.m. (n = 5 per group, except forn = 4 for colon metformin Slc22a1). P values (95% CI) by two-tailed t-test. Gdf15 mRNA fold induction 24 h after metformin (600 mg kg−1) is positively correlated with Chop mRNA induction in both kidney (a, right) and colon (b, right). Black line shows linear regression analysis. c–g, Immunoblot analysis of ISR components (c) and Gdf15 mRNA expression (d) in wild-type mouse embryonic fibroblasts (MEF) treated with vehicle control (Con), metformin (Met, 2 mM) or phenformin (Phen, 5 mM) or tunicamycin (Tn, 5 μg ml−1, used as a positive control) for 6 h. e–g, Gdf15 mRNA expression in ATF4 knockout (KO) MEFs (e), in control siRNA and CHOP siRNA transfected wild-type MEFs treated with Tn or Phen for 6 h (f), or in wild-type MEFs pre-treated for 1 h with either the PERK inhibitor GSK2606414 (GSK, 200 nM) or eIF2α inhibitor ISRIB (ISR, 100 nM) then co-treated with phenformin for a further 6 h (g). mRNA expression is presented as fold expression relative to its respective control treatment (set at 1) or phenformin-treated samples (set as 100) with normalization to Hprt gene expression. Data are mean ± s.e.m. from two (c, d) or at least three (e–g) independent experiments. P values (95% CI) by two tailed t-test relative to phenformin-treated control wild-type and control siRNA-treated samples. h, GDF15 protein in supernatant of mouse derived 2D duodenal organoids treated with metformin in the absence or presence of ISRIB (1 μM). Data are expressed as mean ± s.e.m. from two independent experiments. At least duplicate protein measurements for each sample. P values by two-way ANOVA with Sidak’s correction for multiple comparisons. i, GDF15 protein in supernatants of mouse-derived 2D duodenal organoids from wild-type and Chop-null mice treated with metformin from two independent experiments. At least duplicate protein measurements for each sample. Data are mean ± s.e.m.; P values (95% CI) by two-tailed t-test. Source data
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Coll, A.P., Chen, M., Taskar, P. et al. GDF15 mediates the effects of metformin on body weight and energy balance. Nature 578, 444–448 (2020). https://doi.org/10.1038/s41586-019-1911-y
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