Date of Award

8-1-2015

Degree Name

Doctor of Philosophy

Department

Pharmacology

First Advisor

Tischkau, Shelley

Abstract

Obesity, metabolic syndrome, and diabetes represent a major source of morbidity and mortality in the United States and worldwide. Chronic misalignment of an organism’s internal circadian clock with diurnal, cyclic changes in the external environment, prevalent in professions that require shift work, contributes significantly to Type 2 Diabetes development. Experimentally, only short-term models of circadian disruption have been explored. Therefore, the goal of this study was to establish an animal model of chronic circadian disruption, which would more closely mimic the harmful misalignment associated with metabolic syndrome in clinical studies. Moreover, since high fat diet consumption alters circadian behavior and rhythmic gene expression, contributing to the diet-induced phenotype, I hypothesized that chronic circadian disruption interacts with a high fat diet to worsen metabolic syndrome. To investigate circadian misalignment and diet-induced metabolic syndrome, I examined the contribution of the Aryl Hydrocarbon Receptor (AhR). AhR has similar PAS domain containing motifs as circadian clock proteins allowing for protein/protein interactions and crosstalk between AhR signaling and circadian rhythms. Furthermore, AhR activation is implicated in Type 2 Diabetes risk. To examine chronic circadian disruption, male wild-type (WT; C57Bl/6J) and AhR +/- mice were entrained to 12/12-hour light/dark cycles where lights were on from 10pm-10am and off from 10am-10pm. Misalignment was initiated by delaying the time of lights on by 8 hours on Monday. Mice were exposed to the misalignment schedule Monday-Friday then returned to the entrainment schedule Saturday and Sunday to mimic readjustment to society during the weekend. Circadian misaligned mice were exposed to the altered light schedule for 15 weeks and control animals remained on the12/12-hour light/dark cycle. Mice were fed a normal chow diet (10% fat) or a high fat diet (60% fat). Animals were sacrificed and samples were collected at 4-hour intervals on day 2 of the weekend. Exposure to chronic circadian misalignment by light disruption or high fat diet altered circadian rhythms of behavior, metabolic outputs, and expression of circadian clock, clock-controlled nuclear receptor, and lipid metabolism genes. A combination of light misalignment and high fat diet exacerbated the effects of either treatment alone further disrupting behavior, enhancing % body fat and fasting glucose, and dampening circadian clock gene expression. AhR +/- mice also were protected from the metabolic consequences of chronic misalignment and a high fat diet by resistance to altered behavioral and molecular circadian rhythms and disruption of metabolic outputs. With metabolic syndrome and Type 2 Diabetes occurrence on the rise, it is important to understand all contributing factors, including circadian disruption. Differences between chronic circadian misalignment and high fat diet-induced obesity in WT and AhR +/- mice furthers our understanding of the complex mechanisms that underlie Type 2 Diabetes development and advocates the discovery of potential therapeutic targets for the development of novel treatment options.

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