Exploring the Effects of Circadian Disruption on Metabolic Function and Sleep

Derrick J. Phillips

The circadian system plays an important role in regulating nearly every process in the body, keeping them in sync with each other, as well as the outside environment. However, artificial lighting and an “always on” society have led to the breakdown between the circadian system and the solar day. One of the most perceptible outputs of the circadian clock, particularly when it is not working properly, is the timing of the sleep-wake cycle. However, circadian rhythms are found in nearly every physiological system. Thus, it is no surprise that circadian and sleep disruption is associated with negative health outcomes, including metabolic dysregulation and obesity. Therefore, understanding how circadian disruption (CD) alters regulation of the sleep-wake cycle and metabolic function is imperative We induced environmental CD by housing adult male mice in an altered light-dark (LD) cycle with a period of 20h (10hr light, 10hr dark). We used a number of recording techniques to probe metabolic, circadian, and sleep function in normal lighting conditions (LD12:12, 12hr light, 12hr dark) compared to environmental CD (LD10:10). Our model of CD induces a number of changes in both metabolic function and sleep. We find a marked increase in adiposity and decreased glucose tolerance following CD. Diurnal variation in feeding and respiratory quotient are diminished during CD. In addition, there are significant changes in sleep timing and quality. Our work also probed how disrupting the circadian clock alters the ability of an organism to respond to additional stressors. To do this, we applied an immune challenge to circadian disrupted mice, and found that the immune response to lipopolysaccharide challenge was greatly perturbed in CD mice. Conversely, we explored how genetic predisposition to being “stress sensitive” may change the response to CD. To accomplish this, we used a humanized mouse model carrying a val66met polymorphism (Val = normal, and Met = mutant) in the brain derived neurotrophic factor (BDNF) gene, which causes a stress-sensitive phenotype. Val mice show a loss in niche appropriate sleep timing and flattening of delta power in CD (as expected), whereas Met mice maintain both. Contrary to our initial hypothesis of increased vulnerability to CD in mice that are “stress sensitive”, these data suggest the Met mutation may protect against the effects of CD. Together, the following chapters will explore how circadian disruption affects sleep, metabolic, and immune function (Chapters 2 and 3), and further, the role of BDNF in modulating the effects of circadian disruption (Chapter 4).

Exploring the Effects of Circadian Disruption on Metabolic Function and Sleep

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