Circadian misalignment induces fatty acid metabolism gene profiles and compromises insulin sensitivity in human skeletal muscle

Jakob Wefers, Dirk van Moorsel, Jan Hansen, Niels J. Connell, Bas Havekes, Joris Hoeks, Wouter D. van Marken Lichtenbelt, Hélène Duez, Esther Phielix, Andries Kalsbeek, Mark V. Boekschoten, Guido J. Hooiveld, Matthijs K.C. Hesselink, Sander Kersten, Bart Staels, Frank A.J.L. Scheer, Patrick Schrauwen

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39 Citations (Scopus)

Abstract

Circadian misalignment, such as in shift work, has been associated with obesity and type 2 diabetes. However, direct effects of circadian misalignment on skeletal muscle insulin sensitivity and the muscle molecular circadian clock have never been studied in humans. Here, we investigated insulin sensitivity and muscle metabolism in 14 healthy young lean men [age 22.4 ± 2.8 years; body mass index (BMI) 22.3 ± 2.1 kg/m2 (mean ± SD)] after a 3-d control protocol and a 3.5-d misalignment protocol induced by a 12-h rapid shift of the behavioral cycle. We show that short-term circadian misalignment results in a significant decrease in muscle insulin sensitivity due to a reduced skeletal muscle nonoxidative glucose disposal (rate of disappearance: 23.7 ± 2.4 vs. 18.4 ± 1.4 mg/kg per minute; control vs. misalignment; P = 0.024). Fasting glucose and free fatty acid levels as well as sleeping metabolic rate were higher during circadian misalignment. Molecular analysis of skeletal muscle biopsies revealed that the molecular circadian clock was not aligned to the inverted behavioral cycle, and transcriptome analysis revealed the human PPAR pathway as a key player in the disturbed energy metabolism upon circadian misalignment. Our findings may provide a mechanism underlying the increased risk of type 2 diabetes among shift workers.
Original languageEnglish
Pages (from-to)7789-7794
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number30
Early online date9 Jul 2018
DOIs
Publication statusPublished - 24 Jul 2018

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    Circadian misalignment induces fatty acid metabolism gene profiles and induces insulin resistance in human skeletal muscle

    Wefers, J. (Creator), van Moorsel, D. (Creator), Hansen, J. (Creator), Hooiveld, G. (Creator), Kersten, S. (Creator) & Schrauwen, P. (Creator), Wageningen University, 10 Aug 2018

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    Wefers, J., van Moorsel, D., Hansen, J., Connell, N. J., Havekes, B., Hoeks, J., van Marken Lichtenbelt, W. D., Duez, H., Phielix, E., Kalsbeek, A., Boekschoten, M. V., Hooiveld, G. J., Hesselink, M. K. C., Kersten, S., Staels, B., Scheer, F. A. J. L., & Schrauwen, P. (2018). Circadian misalignment induces fatty acid metabolism gene profiles and compromises insulin sensitivity in human skeletal muscle. Proceedings of the National Academy of Sciences of the United States of America, 115(30), 7789-7794. https://doi.org/10.1073/pnas.1722295115