The role of endocannabinoids in circadian disruption induced metabolic dysregulation

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ABSTRACT: Obesity and its co-morbid pathologies cardiovascular disease and diabetes are significant and growing public health problems. Obesity occurs as a result of interactions between multiple organs (e.g. liver, muscle, adipose), genetic factors, physiological factors (e.g. insulin, cytokines, and glucocorticoids), and environmental factors, particularly those associated with modern life (e.g. diet, lack of exercise, stress). Growing evidence suggests one of the most insidious of these environmental factors is the change in our circadian (daily) rhythms, driven by inappropriately timed exposure to light, shiftwork, and a 24h “always-on” society. Both epidemiologic and experimental data, including work from our own laboratory, support a role for circadian disruption in metabolic dysregulation. As such, manipulating environmental light-dark (LD) cycles could serve as a powerful tool to probe the mechanisms of environmentally driven metabolic dysregulation. Importantly, the mechanisms that link environmental circadian desynchronization (CD) to metabolic dysregulation remain unknown, limiting our mechanistic understanding of the role of circadian rhythms in the development of obesity. This proposal builds upon our published findings in mouse showing CD caused by shortening the LD cycle from 24h to 20h (LD10:10) results in weight gain, hyperinsulinemia, and other aspects of metabolic syndrome. Our focus now is to determine the mechanisms by which this environmental challenge leads to obesity. New data from our lab demonstrates that the endocannabinoid (eCB) system may be an important link between circadian rhythms and metabolic dysregulation. This is strengthened by recent data in humans that show rhythmic profiles of eCBs in the blood, that sleep/circadian disruption can alter these rhythms, and that over-activity in the eCB system is associated with obesity. The objective of this proposal is to mechanistically determine if the eCB system is an essential factor by which environmental and genetic circadian disruption contribute to changes in metabolic function, including increases in adiposity. We will use state-of-the art behavioral and metabolic phenotyping, gene expression and mass spectrometry to assess outcomes, and targeted pharmacology and tissue specific genetic manipulations to probe the mechanistic links between eCB signaling, circadian desynchronization, and metabolic dysregulation.