title: Metformin affects the circadian clock and metabolic rhythms in a tissue-specific manner.
abstract: 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.
authors.affiliation: Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel.
authors.forename: Maayan
authors.initials: M
authors.lastname: Barnea
authors.forename: Liyan
authors.initials: L
authors.lastname: Haviv
authors.forename: Roee
authors.initials: R
authors.lastname: Gutman
authors.forename: Nava
authors.initials: N
authors.lastname: Chapnik
authors.forename: Zecharia
authors.initials: Z
authors.lastname: Madar
authors.forename: Oren
authors.initials: O
authors.lastname: Froy
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D001481:Basal Metabolism / Q000187:drug effects*; D057906:Circadian Clocks / Q000187:drug effects*; D005934:Glucagon / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008687:Metformin / Q000008:administration & dosage*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018482:Muscle, Skeletal / Q000378:metabolism; D009928:Organ Specificity; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D020738:Leptin; D005934:Glucagon; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase