The role of epigenetic modulators on circadian rhythms and metabolism

Thesis

The earth’s rotation on its axis with a 24-hour period gave rise to circadian rhythms, which originated pervasive biologic fluctuations in gene expression, cellular physiology and whole-organism behaviour. The advancements in technology and culture accentuated behaviours and phenomena that implicated a disruption in the synchronisation between our inner circadian clock and the outer environment. This desynchrony was associated with a deregulated molecular clock and an increased incidence of metabolic disorders. We have identified circadian rhythm enhancers as a potential chronotherapeutic mechanism in tackling the circadian deregulations that could be key in the pathogenesis of these associated metabolic deregulations.

Here, we describe the characteristics and efficacy of bromodomain inhibitors, a novel class of epigenetic modulators, in enhancing the amplitude of mammalian circadian clock, with the aim of improving on the pathophysiologies correlated with dampened circadian rhythms. IBET-762, a selective and potent bromodomain inhibitor, is shown to enhance the expression of several clock genes including Bmal1 and Per2, via BRD4 and Specificity Protein 1 (SP1), a transcription factor with widespread metabolic effects, and impact on metabolic pathophysiology at least partially through SP1.

IBET-762 reduces both glucose uptake and adipogenesis in 3T3-L1 cells, giving rise to the potential of being useful in tackling obesity and diabetes. The drug was further tested in-vivo in a C57BL/6 mouse model of diet-induced obesity, and showed to be efficacious in reducing weight gain and hepatosteatosis. This demonstrates the usefulness of BRD inhibitors in tackling obesity and non-alcoholic fatty liver disease (NAFLD). However, IBET-762 also induced a pre-diabetes like phenotype that was not associated to either insulin insensitivity or to β-cell toxicity, but rather to an acute inhibition of several genes involved in glucose metabolism and transport. It is therefore pivotal to further dissect the mechanism of action behind the metabolic effects of IBET-762 and identify the molecular mechanisms and pathways activated, such that one could be tackled independently from the deleterious effects of the others.

Authors: Mosneagu, DI

• DOI: 10.5287/ora-damo0pa1g
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: obesity; metabolism; T2D; epigenetics; bromodomain inhibitors; circadian rhythms
• Subjects: The impact of epigenetics on metabolic disorders