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

7 Scopus citations

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 - 2019

Keywords

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

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