Abstract
Background and Objectives: The antidiabetic agent metformin is known to activate AMP-activated protein kinase (AMPK) in various tissues. Because AMPK can modulate intracellular circadian clocks through regulating the stability of clock components, a single dose of metformin has been reported to affect circadian clocks in the peripheral tissues. In this study, therefore, we investigated whether chronic treatment with metformin causes the impairment of circadian clocks, especially if given at an inappropriate time. Materials and Methods: Non-diabetic C57BL/6J mice were allowed access to food only during 4 h at the beginning of the dark period, and repeatedly i.p. injected with a nearly maximum non-toxic dose of metformin, once daily either at 4 h after the beginning of the dark period or at the beginning of the light period. Diabetic ob/ob mice were given free access to food and treated with metformin in drinking water. Results: Under the controlled feeding regimen, 8-day treatment with metformin did not alter the mRNA expression rhythms of clock genes in both liver and adipose tissue of C57BL/6J mice, regardless of dosing time. In addition, chronic treatment with metformin for 2 weeks affected hepatic AMPK activation rhythm but did not disrupt the circadian clocks in the liver and adipose tissues of the ob/ob mice. Conclusions: These results mitigate concerns that treatment with metformin impairs peripheral circadian clocks, although confirmation is needed in humans.
Highlights
Various behavioral, physiological, and metabolic processes exhibit 24 h rhythmicity regulated by the intracellular circadian clocks [1]
Accumulating evidence suggests that circadian regulation is closely linked to metabolic homeostasis [3,4], and that impairment of circadian clocks contributes to the development of metabolic diseases, including obesity and type 2 diabetes
We found that circadian clocks are impaired in the peripheral tissues of both obese, diabetic mice [13,14] and patients with type 2 diabetes [15]
Summary
Physiological, and metabolic processes exhibit 24 h rhythmicity regulated by the intracellular circadian clocks [1]. Um et al reported that AMPK promoted degradation of PER2 through the activation of casein kinase Iε, and that a single dose of metformin led to a phase advance of circadian clocks in the peripheral tissues of mice [21]. These findings raise the possibility that treatment with metformin might cause impairment of circadian clocks, especially if given at an inappropriate time. We investigated the effect of chronic treatment with metformin on peripheral circadian clocks in mice
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