Metformin alters locomotor and cognitive function and brain metabolism in normoglycemic mice

Wenjun Li, Kiran Chaudhari, Ritu Shetty, Ali Winters, Xiaofei Gao, Zeping Hu, Woo Ping Ge, Nathalie Sumien, Michael Forster, Ran Liu, Shao Hua Yang

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Metformin is currently the most effective treatment for type-2 diabetes. The beneficial actions of metformin have been found even beyond diabetes management and it has been considered as one of the most promising drugs that could potentially slow down aging. Surprisingly, the effect of metformin on brain function and metabolism has been less explored given that brain almost exclusively uses glucose as substrate for energy metabolism. We determined the effect of metformin on locomotor and cognitive function in normoglycemic mice. Metformin enhanced locomotor and balance performance, while induced anxiolytic effect and impaired cognitive function upon chronic treatment. We conducted in vitro assays and metabolomics analysis in mice to evaluate metformin's action on the brain metabolism. Metformin decreased ATP level and activated AMPK pathway in mouse hippocampus. Metformin inhibited oxidative phosphorylation and elevated glycolysis by inhibiting mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) in vitro at therapeutic doses. In summary, our study demonstrated that chronic metformin treatment affects brain bioenergetics with compound effects on locomotor and cognitive brain function in non-diabetic mice.

Original languageEnglish
Pages (from-to)949-963
Number of pages15
JournalAging and Disease
Volume10
Issue number5
DOIs
StatePublished - 1 Jan 2019

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Metformin
Cognition
Brain
Energy Metabolism
Glycerolphosphate Dehydrogenase
AMP-Activated Protein Kinases
Metabolomics
Oxidative Phosphorylation
Anti-Anxiety Agents
Glycolysis
Type 2 Diabetes Mellitus
Hippocampus
Adenosine Triphosphate
Glucose

Keywords

  • AMP-activated protein kinase
  • Cognition
  • Diabetes
  • Metabolism
  • Metformin

Cite this

Li, Wenjun ; Chaudhari, Kiran ; Shetty, Ritu ; Winters, Ali ; Gao, Xiaofei ; Hu, Zeping ; Ge, Woo Ping ; Sumien, Nathalie ; Forster, Michael ; Liu, Ran ; Yang, Shao Hua. / Metformin alters locomotor and cognitive function and brain metabolism in normoglycemic mice. In: Aging and Disease. 2019 ; Vol. 10, No. 5. pp. 949-963.
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Metformin alters locomotor and cognitive function and brain metabolism in normoglycemic mice. / Li, Wenjun; Chaudhari, Kiran; Shetty, Ritu; Winters, Ali; Gao, Xiaofei; Hu, Zeping; Ge, Woo Ping; Sumien, Nathalie; Forster, Michael; Liu, Ran; Yang, Shao Hua.

In: Aging and Disease, Vol. 10, No. 5, 01.01.2019, p. 949-963.

Research output: Contribution to journalArticle

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T1 - Metformin alters locomotor and cognitive function and brain metabolism in normoglycemic mice

AU - Li, Wenjun

AU - Chaudhari, Kiran

AU - Shetty, Ritu

AU - Winters, Ali

AU - Gao, Xiaofei

AU - Hu, Zeping

AU - Ge, Woo Ping

AU - Sumien, Nathalie

AU - Forster, Michael

AU - Liu, Ran

AU - Yang, Shao Hua

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Metformin is currently the most effective treatment for type-2 diabetes. The beneficial actions of metformin have been found even beyond diabetes management and it has been considered as one of the most promising drugs that could potentially slow down aging. Surprisingly, the effect of metformin on brain function and metabolism has been less explored given that brain almost exclusively uses glucose as substrate for energy metabolism. We determined the effect of metformin on locomotor and cognitive function in normoglycemic mice. Metformin enhanced locomotor and balance performance, while induced anxiolytic effect and impaired cognitive function upon chronic treatment. We conducted in vitro assays and metabolomics analysis in mice to evaluate metformin's action on the brain metabolism. Metformin decreased ATP level and activated AMPK pathway in mouse hippocampus. Metformin inhibited oxidative phosphorylation and elevated glycolysis by inhibiting mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) in vitro at therapeutic doses. In summary, our study demonstrated that chronic metformin treatment affects brain bioenergetics with compound effects on locomotor and cognitive brain function in non-diabetic mice.

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