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Proc Natl Acad Sci U S A. 2018 Jul 24;115(30):7789-7794. doi: 10.1073/pnas.1722295115. Epub 2018 Jul 9.

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

Author information

1
Department of Nutrition and Movement Sciences, School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands.
2
Division of Endocrinology, Department of Internal Medicine, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands.
3
Université de Lille-European Genomic Institute for Diabetes, Centre Hospitalier Universitaire Lille, Institut Pasteur de Lille, Inserm UMR 1011, 59019 Lille, France.
4
Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, 1105 BA Amsterdam, The Netherlands.
5
Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, 6700 EV Wageningen, The Netherlands.
6
Medical Chronobiology Program, Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA 02115.
7
Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115.
8
Department of Nutrition and Movement Sciences, School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands; p.schrauwen@maastrichtuniversity.nl.

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.

KEYWORDS:

circadian misalignment; diabetes; insulin sensitivity; shift work; skeletal muscle

Comment in

PMID:
29987027
PMCID:
PMC6065021
DOI:
10.1073/pnas.1722295115
[Indexed for MEDLINE]
Free PMC Article

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