Interplay of Dietary Lipid and Circadian Dysregulation in Metabolic Syndrome

描述(由申请人提供)：内脏肥胖症和代谢综合征在工业化国家的扩展已导致心血管疾病、中风、失明、肾功能衰竭和血栓形成等共病的增加。这些疾病的明显上升与高饱和脂肪饮食和营养过剩有关，这表明常量营养素和脂肪在疾病的发生和发展中发挥着重要作用。一个令人惊讶的观察是，轮班工作和夜间进食都与代谢综合征的风险增加有关。在我们之前提交这项提议后完成的令人兴奋的研究现在证实，分子钟是一种保守的内部系统，它进化为在预测地球自转时同步生理，调节线粒体的氧化能力，昼夜节律中断会导致人类的代谢性肌病综合征，其特征是肝脏脂肪堆积、线粒体功能障碍和禁食诱导的癫痫发作。值得注意的是，我们还证实了使用前药NMN可以逆转昼夜节律紊乱中的线粒体缺陷，NMN可以提高细胞内NAD+水平，并增强在代谢适应中至关重要的NAD+依赖的脱乙酰酶的活性。事实上，现在很明显，时钟存在于身体的所有组织中，大脑时钟与周围组织时钟的正常相位对齐与轮班工作、夜间进食甚至高脂肪饮食都会发生错位。因此，我们建议的一个长期目标是检验这样一种假设，即昼夜节律紊乱通过改变睡眠/清醒-禁食/进食周期中的线粒体氧化能力而导致代谢紊乱。我们工作的一个创新是将时钟和线粒体生物学的研究结合起来，并剖析时钟时间对大量营养素代谢的影响。最终，我们现在准备更深入地了解时机对线粒体功能的贡献，这将适用于肥胖症、代谢综合征和2型糖尿病的治疗。

DESCRIPTION (provided by applicant): The expansion across industrialized nations of both visceral obesity and metabolic syndrome has caused an escalation of co-morbidities including cardiovascular disease, stroke, blindness, renal failure and thrombosis. The clear rise in these disorders tracks with high-saturated fat diet and overnutrition, suggesting that macronutrient and lipid specifically play a major role in the onset and progression of disease. A surprising observation has been that both shiftwork and night-eating are associated with increased risk of metabolic syndrome. Exciting studies completed subsequent to our previous submission of this proposal now establish that the molecular clock, a conserved internal system that evolved to synchronize physiology in anticipation of the rotation of the Earth, regulates mitochondrial oxidative capacity and that circadian disruption phenocopies the metabolic myopathy syndrome in humans that is characterized by liver lipid accumulation, mitochondrial dysfunction, and fasting-induced seizures. Remarkably, we have also established that we can reverse the mitochondrial defects in circadian disruption using the prodrug NMN, which boosts intracellular NAD+ levels and enhances the activity of NAD+-dependent deacetylases critical in metabolic adaptation. Indeed, it is now apparent that clocks exist throughout all tissues of the body and that the normal phase alignment of the brain clock with peripheral tissue clocks undergoes misalignment with shiftwork, night-eating, and even with high-fat diet. Thus a long-term objective of our proposal is to test the hypothesis that circadian disruption contributes to metabolic disorders by altering mitochondrial oxidative capacity across the sleep/wake-fasting/feeding cycle. An innovation of our work is to integrate studies of clock and mitochondrial biology and to dissect the impact of clock time on macronutrient metabolism. Ultimately, we are now poised to create deeper insight into the contribution of timing to mitochondrial function that will be applicable to obesity, metabolic syndrome, and type 2 diabetes therapeutics.