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theses

Along with light/dark cycle, food intake is a strong zeitgeber, a cue given by the environment on host to reset the internal body clock. In mammals, metabolic activities are under the regulation of daily feeding rhythms as well as the peripheral clock machinery. In turn, the feeding rhythms influence the circadian rhythms of key clock components via enzymatic reactions and transcriptional regulations. Understanding the mechanism of interplay between the circadian clocks and metabolic activities are important as disruption of one seems to affect the other. Several studies showed evidence that disruption of circadian rhythms can facilitate metabolic syndrome. For example, shift-work and sleep deprivation result in dampened rhythms and obesity. Other studies suggested that obesity, diabetes, and cardiovascular diseases are linked with disruption of daily rhythms in food intake. At a molecular level, clock mutant mice show a decrease in metabolic rate, while liver-specific Bmal1 knockout mice and pancreas-specific Clock or Bmal1 knockout mice exhibit a disruption in glucose homeostasis. On the other hand, time-restricted feeding studies in mice show that metabolic cues influence circadian rhythmicityAlthough proper clock gene functions are linked to a wide variety of energy metabolism functions including lipogenesis and appetite control, glucose homeostasis is of a particular interest since clock gene deficiencies directly lead to diabetes mellitus. Furthermore, possible molecular mechanisms that lead to a breach in glucose homeostasis have been suggested from a number of animal studies. I used semi-mechanistic mathematical models to evaluate the effect of circadian disruption on hepatic gluconeogenesis. The models allow examination of the entrainment dynamics of peripheral clock genes by two convoluted environmental signals, feeding rhythm transmitted through SIRT1 and the light/dark cycle transmitted through the hypothalamic pituitary adrenal axis (HPA) and cortisol. The mechanism behind metabolic implications under circadian disruption is achieved via linking the dynamics of clock genes and cortisol to transcription of gluconeogenic genes and insulin secretion. The model predicts that a few hours of restricted feeding in the early active phase of the host is beneficial for robust oscillation of clock genes, appropriate level of gluconeogenesis, and maximum secretion of insulin. Additionally, an asymmetry between the entrainment strengths of light/dark cycle and feeding/fasting cycle contributes to the convolusion of environmental signals in downstream metabolic activities.

ETD_8871

Ph.D.

Includes bibliographical references

by Seul Bae

doi:10.7282/T30Z76PV

ETD doctoral

The author owns the copyright to this work.