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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 30; pp. 7789 - 7794
• Main Authors: Wefers, Jakob, van Moorsel, Dirk, Hansen, Jan, Connell, Niels J., Havekes, Bas, Hoeks, Joris, van Marken Lichtenbelt, Wouter D., Duez, Hélène, Phielix, Esther, Kalsbeek, Andries, Boekschoten, Mark V., Hooiveld, Guido J., Hesselink, Matthijs K. C., Kersten, Sander, Staels, Bart, Scheer, Frank A. J. L., Schrauwen, Patrick
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 24-07-2018
• Subjects: Adult; Biological Sciences; Body mass; Body mass index; Body size; Chair Nutrition Metabolism and Genomics; Circadian rhythms; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - pathology; Energy metabolism; Fatty acids; Fatty Acids - blood; Gene expression; Gene Expression Profiling; Glucose; Health risks; Heart; HNE Nutrition, Metabolism and Genomics; HNE Voeding, Metabolisme en Genomics; Human behavior; Humans; Insulin; Insulin Resistance; Life Sciences; Male; Metabolic rate; Metabolism; Misalignment; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscles; Musculoskeletal system; Nutrition, Metabolism and Genomics; Obesity - blood; Obesity - pathology; Peroxisome proliferator-activated receptors; Sensitivity; Sensitivity analysis; Shift work; Skeletal muscle; VLAG; Voeding, Metabolisme en Genomica; Workers; Working conditions; insulin sensitivity; shift work; skeletal muscle; circadian misalignment; diabetes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1722295115

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.