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

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

Nature, 2020, vol. 578, issue 7795, 444-448

Abstract: Abstract 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.

Date: 2020
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41586-019-1911-y Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:578:y:2020:i:7795:d:10.1038_s41586-019-1911-y

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-019-1911-y

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().