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, Helene 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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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/m(2) (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
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number30
Publication statusPublished - 24 Jul 2018


  • circadian misalignment
  • shift work
  • diabetes
  • insulin sensitivity
  • skeletal muscle
  • Heart
  • Fatty Acids/blood
  • Humans
  • Male
  • Gene Expression Profiling
  • Adult
  • Diabetes Mellitus, Type 2/blood
  • Insulin Resistance
  • Muscle, Skeletal/metabolism
  • Obesity/blood


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