The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance

  • Cell Rep. 2022 Aug 23;40(8):111258. doi: 10.1016/j.celrep.2022.111258.
Anders B Klein  1 ,  Trine S Nicolaisen  2 ,  Kornelia Johann  3 ,  Andreas M Fritzen  4 ,  Cecilie V Mathiesen  1 ,  Cláudia Gil  1 ,  Nanna S Pilmark  5 ,  Kristian Karstoft  6 ,  Martin B Blond  7 ,  Jonas S Quist  7 ,  Randy J Seeley  8 ,  Kristine Færch  9 ,  Jens Lund  1 ,  Maximilian Kleinert  10 ,  Christoffer Clemmensen  11
Affiliations
  • 1. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 2. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The August Krogh Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
  • 3. German Center for Diabetes Research (DZD), DIfE, Potsdam-Rehbrücke, Nuthetal, Germany; Muscle Physiology and Metabolism Group, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Nuthetal, Germany.
  • 4. The August Krogh Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
  • 5. Centre for Physical Activity Research, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
  • 6. Centre for Physical Activity Research, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.
  • 7. Clinical Research, Copenhagen University Hospital - Steno Diabetes Center Copenhagen, Gentofte, Denmark.
  • 8. Department of Surgery, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • 9. Clinical Research, Copenhagen University Hospital - Steno Diabetes Center Copenhagen, Gentofte, Denmark; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 10. The August Krogh Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark; German Center for Diabetes Research (DZD), DIfE, Potsdam-Rehbrücke, Nuthetal, Germany; Muscle Physiology and Metabolism Group, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Nuthetal, Germany. Electronic address: [email protected].
  • 11. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: [email protected].
PMID: 36001956 DOI: 10.1016/j.celrep.2022.111258
Abstract

Metformin is a blood-glucose-lowering medication with physiological effects that extend beyond its anti-diabetic indication. Recently, it was reported that metformin lowers body weight via induction of Growth Differentiation Factor 15 (GDF15), which suppresses food intake by binding to the GDNF family receptor α-like (GFRAL) in the hindbrain. Here, we corroborate that metformin increases circulating GDF15 in mice and humans, but we fail to confirm previous reports that the GDF15-GFRAL pathway is necessary for the weight-lowering effects of metformin. Instead, our studies in wild-type, GDF15 knockout, and GFRAL knockout mice suggest that the GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. The data presented here question whether metformin is a sufficiently strong stimulator of GDF15 to drive anorexia and weight loss and emphasize that additional work is needed to untangle the relationship among metformin, GDF15, and energy balance.

Keywords
CP: Metabolism; GDF15; GFRAL; body weight; diabetes; energy balance; food intake; metformin; obesity.