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.

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