Metformin affects the circadian clock and metabolic rhythms in a tissue-specific manner

Maayan Barnea, Liyan Haviv, Roee Gutman, Nava Chapnik, Zecharia Madar, Oren Froy*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

60 Scopus citations


Metformin is a commonly-used treatment for type 2 diabetes, whose mechanism of action has been linked, in part, to activation of AMP-activated protein kinase (AMPK). However, little is known regarding its effect on circadian rhythms. Our aim was to evaluate the effect of metformin administration on metabolism, locomotor activity and circadian rhythms. We tested the effect of metformin treatment in the liver and muscle of young lean, healthy mice, as obesity and diabetes disrupt circadian rhythms. Metformin led to increased leptin and decreased glucagon levels. The effect of metformin on liver and muscle metabolism was similar leading to AMPK activation either by liver kinase B1 (LKB1) and/or other kinases in the muscle. AMPK activation resulted in the inhibition of acetyl CoA carboxylase (ACC), the rate limiting enzyme in fatty acid synthesis. Metformin also led to the activation of liver casein kinase I α (CKIα) and muscle CKIε, known modulators of the positive loop of the circadian clock. This effect was mainly of phase advances in the liver and phase delays in the muscle in clock and metabolic genes and/or protein expression. In conclusion, our results demonstrate the differential effects of metformin in the liver and muscle and the critical role the circadian clock has in orchestrating metabolic processes.

Original languageAmerican English
Pages (from-to)1796-1806
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Issue number11
StatePublished - Nov 2012


  • AMPK
  • Circadian rhythm
  • Clock
  • Metabolism
  • Metformin


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