Cannabinoid CB1R Receptor Mediates Metabolic Syndrome in Models of Circadian and Glucocorticoid Dysregulation
The most recent projections in the growing obesity rates across the nation show an increase to 60% by the year 2030. These growing rates of obesity are paralleled by an increased rates of depressive conditions, anxiety, and sleep loss, often with environmental factors at the root of the cause. Stress and the stress response is a dynamic system that reflects one's ability to cope with events, behaviorally or physiologically, as stressors occur over a lifetime. While many key players mediate the effects of stress exposure on disease outcomes including the sympathetic nervous system, parasympathetic, inflammatory cytokines and metabolic hormones, this dissertation focuses on glucocorticoids because of the extensive regulatory role they play in mounting the adaptative response to stress. Additionally, glucocorticoids act to regulate feeding and energy balance, and when not properly regulated, they can lead to increased weight gain, particularly the development of abdominal visceral fat. Independent from their role in the stress response, glucocorticoids are also secreted in a diurnal fashion as regulated by the master circadian (daily) clock in the suprachiasmatic nuclei ( SCN). Signaling in this regard is at least partially responsible for entraining circadian clocks outside of the SCN. Just as shifts in glucocorticoid exposure are associated with metabolic disturbances, disruption of circadian rhythms has also been linked to the development of obesity. However, it remains unclear how the two systems independently and/or collectively regulate energy balance. The first aim of this dissertation was to determine how disruptions in the environmental photoperiod impacts clock gene expression and if this environmental exposure affects circulating glucocorticoid levels. The second aim was to determine if increased exposure to a rhythmic corticosterone (CORT) disrupted circadian rhythms. Given that CORT imbalances result in circadian disruption and weight gain in both models, the third aim was to determine a mediator in the two systems that regulates CORT synthesis and affects metabolism. Recent studies have demonstrated that glucocorticoids possess the ability to increase the production and release of endocannabinoid molecules. Additionally, endocannabinoids are potent regulators of appetite, energy balance and metabolic processes through both central and peripheral regulation of feeding and metabolism, making the system an ideal candidate. Mice lacking the cannabinoid CB1 receptor were protected against all of these changes in metabolic function in both mouse models, indicating that endocannabinoid signaling is required for circadian disruption to promote obesity and metabolic syndrome through glucocorticoid regulation. These alterations are prevented by blocking the CB 1 receptor, not only globally, but also through targeted peripheral inhibition, suggesting that the endocannabinoid system mediates glucocorticoid induced metabolic syndrome through a predominantly peripheral mechanism. These data build upon previous findings that indicate the endocannabinoid system is required for diet-induced obesity. They further suggest that this system plays a much broader role in the regulation of metabolic processes, as well as acting as a mediator of changes in metabolic function in response to an array of stimuli, including environmental exposure, and not just diet composition. Research presented also aims to highlight the importance of studying different stress-like exposures in mouse models in order to fully characterize the human condition. Chronic environmental stressors, as in chronic disruption of the-light-dark-cycle, provide one such mean to study the impact of stress on a population. The environmental experience has been identified as a potential pathway linking neighborhood disadvantage and poor health, through the dysregulation of stress-related biological pathways.
obesity, glucocorticoids, circadian rhythm, endocannabinoids, metabolism, stress, Life Sciences
Networked Digital Library of Theses and Dissertations