The Impact of Circadian Rhythm Disruption in Obesity: a Murine Model

The 2017 Nobel Prize in Medicine or Physiology awarded to JC Hall, M Rosbash and MW Young for their research in revealing the molecular mechanism of circadian rhythm in Dorsophila. This award highlighted the scientific importance of the influence of circadian rhythm on human health. Circadian rhythms are driven by an internal time-keeping system and changes in the external environment, particularly in the light-dark cycle, to entrain this biologic clock. The circadian clock is synchronized to the 24-hour day by the daily light-dark cycle with light acting through both direct and indirect retina-to-SCN (suprachiasmatic nuclei) neural pathway. In mammals, many physiological processes, such as heartbeat, sleep-wake cycles and functions of the immune system and metabolism, are under the control of circadian clocks. To date, at least 11 mammalian core circadian clock genes have been identified (PER1, PER2, PER3, CLOCK, CRY1, CRY2, BMAL1, CK1e, TIM, RORa and REV-ERBa) which constitute the molecular translation-transcriptional feedback loop. Two major concerns of a modern lifestyle is the disruption of circadian rhythms and obesity. Recent studies demonstrated mice lacking Clock or Bmal1 circadian clock genes displayed metabolic defects and obesities. Circadian rhythm disrupted rats also developed obesity and glucose resistance and these symptoms could be improved after treated with melatonin and metformin. Studies also showed that high-fat diet (HFD) induced changes in the composition of the gut microbiota which impairs the intestinal integrity and leads to release of endotoxin lipopolysaccaride into the bloodstream, in turn, leading to metabolic inflammation and development of obesity. Reversion of the altered gut microbiota composition could reduce inflammation and obesity. However, whether circadian rhythm disruption and HFD induce obesity through the same pathway remains unclear. Most studies proposed that HFD or feeding time disturbs circadian rhythm and gut microbiot and in turn induces development of obesity. In this project we propose to investigate the impact of circadian rhythm disruption, as evaluated by the expression levels and oscillations of circadian clock genes, on the changes of gut microbiota composition, chronic inflammation, and obesity. We have established a circadian rhythm disruption-induced obesity mice model by exposing the mice in continuous light or dark for four weeks. We will utilize this model to investigate:1. Whether circadian rhythm disruption-induced obesity is developed through the alteration of gut micrbiota composition and subsequent chronic inflammation? 2. Whether circadian rhythm disruption-induced obesity is developed directly through chronic inflammation?3. Does circadian rhythm disruption and HFD have a synergistic effect on the development of obesity? If circadian rhythm disruption and HFD do have a synergistic effect on the development of obesity and gut microbiota composition, chronic inflammation and obesity can be reversed by reversion of circadian rhythm disruption, we hope to further investigate the molecular mechanism of the involved pathways and target circadian clock genes.

Project ID:PC10707-0068
External Project ID:MOST107-2320-B182-022