Acute Sleep Loss Can Alter Circadian Genes in Men

Just one night of wakefulness can lead to alterations in epigenetic and transcriptional profile of core circadian clock genes in key metabolic tissues, which could explain why shift workers are at an increased risk of metabolic morbidities, according to a new study published in The Journal of Clinical Endocrinology & Metabolism.

Researchers led by Jonathan Cedernaes, MD, PhD, of Uppsala University in Uppsala, Sweden, pointed out that animal studies have shown the circadian clock gene allows expression to coincide with anticipated metabolic requirements throughout the day and night. “The lack of clock genes, even when ablated only in skeletal muscle or adipose tissue, results in systemic metabolic perturbations in animal models,” they write. “These metabolic responses include hyperglycemia and insulin resistance, and can also result in obesity and type 2 diabetes [T2D] in animals.”

So the investigators set out to determine how these clock genes are affected at the epigenetic and transcriptional level in humans following a sleepless night — or acute total sleep deprivation (TSD). They examined 15 healthy men in a randomized, two-period, two-condition, crossover clinical study. The men underwent two sessions: one of a full night’s sleep and then overnight wakefulness. On the subsequent morning, serum cortisol was measured, followed by skeletal muscle and subcutaneous adipose tissue biopsies for DNA methylation and gene expression analyses of core clock genes (BMAL1, CLOCK, CRY1, PER1). Finally, baseline and two-hour post-oral glucose load plasma glucose concentrations were determined.

The researchers found that in adipose tissue, acute sleep deprivation versus sleep increased methylation in the promoter of CRY1 and in two promoter-interacting enhancer regions of PER1. In skeletal muscle, TSD versus sleep decreased gene expression of BMAL1 and CRY1. Concentrations of serum cortisol, which can reset peripheral tissue clocks, were decreased, whereas postprandial plasma glucose concentrations were elevated after TSD.

The authors conclude that just one night of lost sleep results in hypermethylation of regulatory regions of key clock genes. These effects are tissue specific and occur in adipose tissue but not in skeletal muscle. Gene expression differences were observed for the investigated clock genes in skeletal muscle but not in adipose tissue. They go on to note that shift work is associated with many of the same phenotypes observed in transgenic animal models in which the circadian clock is disrupted, (e.g., glucose intolerance). “This suggests that our findings of altered peripheral clocks at the epigenetic and transcriptional level,” the authors write, “with ensuing glucose intolerance, following acute sleep loss may contribute to metabolic disruptions typically observed in humans with activities regularly scheduled during times that produce chronic desynchrony between tissue-specific clocks.”

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