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

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

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

25 Citations (Scopus)

57 Downloads (Pure)

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
ISSN	2211-1247
DOIs	https://doi.org/10.1016/j.celrep.2022.111258
Publication status	Published - 2022

Bibliographical note

Keywords

Faculty of Science
Metformin
GDF15
Energy balance

Access to Document

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Cite this

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]. https://doi.org/10.1016/j.celrep.2022.111258

The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. / Klein, Anders B; Nicolaisen, Trine Sand; Johann, Kornelia; Fritzen, Andreas Mæchel; Mathiesen, Cecilie V; Gil, Cláudia; Pilmark, Nanna Skytt; Karstoft, Kristian ; Blond, Martin Bæk ; Quist, Jonas Salling; Seeley, Randy J; Færch, Kristine; Lund, Jens ; Kleinert, Maximilian ; Clemmensen, Christoffer.

In: Cell Reports, Vol. 40, No. 8, 111258, 2022.

Research output: Contribution to journal › Journal article › Research › peer-review

Klein, Anders B ; Nicolaisen, Trine Sand ; Johann, Kornelia ; Fritzen, Andreas Mæchel ; Mathiesen, Cecilie V ; Gil, Cláudia ; Pilmark, Nanna Skytt ; Karstoft, Kristian ; Blond, Martin Bæk ; Quist, Jonas Salling ; Seeley, Randy J ; Færch, Kristine ; Lund, Jens ; Kleinert, Maximilian ; Clemmensen, Christoffer. / The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. In: Cell Reports. 2022 ; Vol. 40, No. 8.

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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.",

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AU - Klein, Anders B

AU - Nicolaisen, Trine Sand

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AU - Fritzen, Andreas Mæchel

AU - Mathiesen, Cecilie V

AU - Gil, Cláudia

AU - Pilmark, Nanna Skytt

AU - Karstoft, Kristian

AU - Blond, Martin Bæk

AU - Quist, Jonas Salling

AU - Seeley, Randy J

AU - Færch, Kristine

AU - Lund, Jens

AU - Kleinert, Maximilian

AU - Clemmensen, Christoffer

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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 - Faculty of Science

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