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

Anders B Klein; Trine S Nicolaisen; Kornelia Johann; Andreas M Fritzen; Cecilie V Mathiesen; Cláudia Gil; Nanna S Pilmark; Kristian Karstoft; Martin B Blond; Jonas S Quist; Randy J Seeley; Kristine Færch; Jens Lund; Maximilian Kleinert; Christoffer Clemmensen

doi:10.1016/j.celrep.2022.111258

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

Anders B Klein, Trine S Nicolaisen, Kornelia Johann, Andreas M Fritzen, Cecilie V Mathiesen, Cláudia Gil, Nanna S Pilmark, Kristian Karstoft, Martin B Blond, Jonas S Quist, Randy J Seeley, Kristine Færch, Jens Lund, Maximilian Kleinert^*, Christoffer Clemmensen^*

^*Corresponding author for this work

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.

Original language	English
Article number	111258
Journal	Cell reports
Volume	40
Issue number	8
Pages (from-to)	111258
DOIs	https://doi.org/10.1016/j.celrep.2022.111258
Publication status	Published - 23 Aug 2022

Keywords

Animals
Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism
Growth Differentiation Factor 15/metabolism
Humans
Metformin/pharmacology
Mice
Obesity/metabolism
Weight Loss

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10.1016/j.celrep.2022.111258

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Klein, A. B., Nicolaisen, T. S., Johann, K., Fritzen, A. M., Mathiesen, C. V., Gil, C., Pilmark, N. S., Karstoft, K., Blond, M. B., Quist, J. S., Seeley, R. J., Færch, K., Lund, J., Kleinert, M., & Clemmensen, C. (2022). The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. Cell reports, 40(8), 111258. Article 111258. https://doi.org/10.1016/j.celrep.2022.111258

Klein, AB, Nicolaisen, TS, Johann, K, Fritzen, AM, Mathiesen, CV, Gil, C, Pilmark, NS, Karstoft, K , Blond, MB , Quist, JS, Seeley, RJ, Færch, K, Lund, J, Kleinert, M & Clemmensen, C 2022, 'The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance', Cell reports, vol. 40, no. 8, 111258, pp. 111258. https://doi.org/10.1016/j.celrep.2022.111258

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title = "The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance",

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 = "Animals, Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism, Growth Differentiation Factor 15/metabolism, Humans, Metformin/pharmacology, Mice, Obesity/metabolism, Weight Loss",

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T1 - The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance

AU - Klein, Anders B

AU - Nicolaisen, Trine S

AU - Johann, Kornelia

AU - Fritzen, Andreas M

AU - Mathiesen, Cecilie V

AU - Gil, Cláudia

AU - Pilmark, Nanna S

AU - Karstoft, Kristian

AU - Blond, Martin B

AU - Quist, Jonas S

AU - Seeley, Randy J

AU - Færch, Kristine

AU - Lund, Jens

AU - Kleinert, Maximilian

AU - Clemmensen, Christoffer

PY - 2022/8/23

Y1 - 2022/8/23

N2 - 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.

AB - 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.

KW - Animals

KW - Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism

KW - Growth Differentiation Factor 15/metabolism

KW - Humans

KW - Metformin/pharmacology

KW - Mice

KW - Obesity/metabolism

KW - Weight Loss

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U2 - 10.1016/j.celrep.2022.111258

DO - 10.1016/j.celrep.2022.111258

M3 - Journal article

C2 - 36001956

SN - 2211-1247

VL - 40

SP - 111258

JO - Cell reports

JF - Cell reports

IS - 8

M1 - 111258

ER -

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

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