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

Klein, Anders Bue; Nicolaisen, T; Johann, Kornelia; Fritzen, Andreas M.; Mathiesen, Cecilie Vad; Gil, Cláudia; Pilmark, Nanna S.; Karstoft, Kristian; Blond, Martin B.; Quist, Jonas Salling; Seeley, Randy J.; Færch, Kristine; Lund, J. W.; Kleinert, Maximilian; Clemmensen, Christoffer

doi:10.1016/j.celrep.2022.111258

Cited by 25 publications

(24 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This relationship between GDF15 and metformin might provide new clues about the mechanism of action through which metformin produces its beneficial clinical outcomes. Metformin treatment increases the levels of Gdf15 mRNA in the intestine, kidney, skeletal muscle and the liver of mice fed a high-fat diet 14 , 214 , 215 . However, the role of the AMPK signalling pathway in Gdf15 gene regulation by metformin remains disputed 13 , 215 .…”

Section: Introductionmentioning

confidence: 99%

“…Metformin might promote body weight loss in people with or without type 2 diabetes mellitus (T2DM) 219 , 220 . For instance, elevated circulating levels of GDF15 are associated with metformin-induced weight loss in patients with T2DM; this effect could be mediated by a reduction in food intake as a result of taking metformin 13 , 14 , independently of its glucose-lowering effect 14 , 214 , 221 . Supporting the requirement of the GDF15–GFRAL signalling axis, metformin-induced weight loss was abrogated in both GDF15-knockout and GFRAL-knockout mice 13 , 14 .…”

Section: Introductionmentioning

confidence: 99%

“…Supporting the requirement of the GDF15–GFRAL signalling axis, metformin-induced weight loss was abrogated in both GDF15-knockout and GFRAL-knockout mice 13 , 14 . Nevertheless, studies have challenged this concept by showing that metformin can lower body weight and food intake independently of GDF15–GFRAL signalling in obese mice 214 , 222 . In addition, the association between metformin-induced increases in circulating levels of GDF15 and changes in body weight was not confirmed in individuals with prediabetes and overweight following metformin administration for up to 13 weeks 214 .…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, studies have challenged this concept by showing that metformin can lower body weight and food intake independently of GDF15–GFRAL signalling in obese mice 214 , 222 . In addition, the association between metformin-induced increases in circulating levels of GDF15 and changes in body weight was not confirmed in individuals with prediabetes and overweight following metformin administration for up to 13 weeks 214 . These results question the importance of long-term drug exposure and individual responsiveness to the weight-lowering effects of the metformin-induced rise in GDF15 levels and warrant further clarification 223 .…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Metformin: update on mechanisms of action and repurposing potential

2023

View full text Add to dashboard Cite

Currently, metformin is the first-line medication to treat type 2 diabetes mellitus (T2DM) in most guidelines and is used daily by >200 million patients. Surprisingly, the mechanisms underlying its therapeutic action are complex and are still not fully understood. Early evidence highlighted the liver as the major organ involved in the effect of metformin on reducing blood levels of glucose. However, increasing evidence points towards other sites of action that might also have an important role, including the gastrointestinal tract, the gut microbial communities and the tissue-resident immune cells. At the molecular level, it seems that the mechanisms of action vary depending on the dose of metformin used and duration of treatment. Initial studies have shown that metformin targets hepatic mitochondria; however, the identification of a novel target at low concentrations of metformin at the lysosome surface might reveal a new mechanism of action. Based on the efficacy and safety records in T2DM, attention has been given to the repurposing of metformin as part of adjunct therapy for the treatment of cancer, age-related diseases, inflammatory diseases and COVID-19. In this Review, we highlight the latest advances in our understanding of the mechanisms of action of metformin and discuss potential emerging novel therapeutic uses.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Metformin: update on mechanisms of action and repurposing potential

2023

View full text Add to dashboard Cite

show abstract

“…Several papers 9,10,12 also demonstrate that metformin’s effects on body weight are diminished or completely abolished in mouse and rat models with genetically or pharmacologically disrupted GDF15/GFRAL pathways. However, Klein et al 11 dispute these results and claim that the GDF15/GFRAL pathway is not required for metformin’s effects on energy balance. As a result, there is ongoing debate about the precise molecular mechanisms that mediate metformin’s anorexigenic and anti-obesity effects.…”

mentioning

confidence: 99%

Lac-Phe mediates the anti-obesity effect of metformin

Xiao,

Li,

Lyu

et al. 2023

Preprint

View full text Add to dashboard Cite

Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. The mechanisms that mediate metformin’s effects on energy balance remain incompletely defined. Here we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite Lac-Phe in mice as well as in two independent human cohorts. In cell culture, metformin drives Lac-Phe biosynthesis via inhibition of complex I, increased glycolytic flux, and intracellular lactate mass action. Other biguanides and structurally distinct inhibitors of oxidative phosphorylation also increase Lac-Phe levelsin vitro. Genetic ablation of CNDP2, the principal biosynthetic enzyme for Lac-Phe, in mice renders animals resistant to metformin’s anorexigenic and anti-obesity effects. Mediation analyses also support a role for Lac-Phe in metformin’s effect on body mass index in humans. These data establish the CNDP2/Lac-Phe pathway as a critical mediator of the effects of metformin on energy balance.

show abstract

The development and benefits of metformin in various diseases

Dong

Jiang

et al. 2023

Front. Med.

View full text Add to dashboard Cite

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

Cited by 25 publications

References 27 publications

Metformin: update on mechanisms of action and repurposing potential

Metformin: update on mechanisms of action and repurposing potential

Lac-Phe mediates the anti-obesity effect of metformin

The development and benefits of metformin in various diseases

Contact Info

Product

Resources

About