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

Shift workers are affected by circadian misalignment and have an increased risk to develop metabolic diseases such as type 2 diabetes. Here, we show that during simulated short-term night shift work insulin sensitivity at the level of skeletal muscle is decreased in male volunteers, which could contribute to the development of type 2 diabetes in the long term. We also find that the muscle molecular clock does not align rapidly to the new behavioral cycle. Importantly, on the level of the transcriptome, circadian misalignment induced upregulation of fatty acid metabolism pathways, potentially resulting in substrate competition on the cellular level. These findings help to better understand the negative consequences during night shift work. 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.

轮班工作者会受到昼夜节律失调的影响，患2型糖尿病等代谢性疾病的风险增加。在此，我们发现，在模拟短期夜班工作期间，男性志愿者的骨骼肌胰岛素敏感性降低，这可能会长期导致2型糖尿病的发生。我们还发现，肌肉分子钟不能迅速与新的行为周期同步。重要的是，在转录组水平上，昼夜节律失调会诱导脂肪酸代谢途径上调，可能导致细胞水平上的底物竞争。这些发现有助于更好地理解夜班工作期间的不良后果。 昼夜节律失调，例如在轮班工作中出现的情况，与肥胖和2型糖尿病有关。然而，昼夜节律失调对骨骼肌胰岛素敏感性和肌肉分子昼夜节律钟的直接影响从未在人体中进行过研究。在此，我们对14名健康的年轻瘦男性[年龄22.4 ± 2.8岁；体重指数（BMI）22.3 ± 2.1 kg/m²（平均值±标准差）]在3天的对照方案和因行为周期快速改变12小时而诱导的3.5天的失调方案之后的胰岛素敏感性和肌肉代谢进行了研究。我们发现，短期昼夜节律失调会导致肌肉胰岛素敏感性显著降低，原因是骨骼肌非氧化葡萄糖处置减少（消失率：23.7 ± 2.4对比18.4 ± 1.4 mg/kg每分钟；对照对比失调；P = 0.024）。在昼夜节律失调期间，空腹血糖和游离脂肪酸水平以及睡眠代谢率更高。对骨骼肌活检的分子分析显示，分子昼夜节律钟与颠倒的行为周期不同步，转录组分析显示人类过氧化物酶体增殖物激活受体（PPAR）途径是昼夜节律失调时能量代谢紊乱的关键因素。我们的研究结果可能为轮班工作者患2型糖尿病风险增加提供了一种潜在机制。