Interplay of Dietary Lipid and Circadian Dysregulation in Metabolic Syndrome

描述（由申请人提供）：内脏肥胖和代谢综合征在工业化国家的扩展已导致包括心血管疾病、中风、失明、肾衰竭和血栓形成在内的共病的升级。这些疾病的明显上升与高饱和脂肪饮食和营养过剩有关，表明常量营养素和脂质在疾病的发生和进展中起着重要作用。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。令人兴奋的研究完成后，我们以前提交的这一建议，现在确定，分子钟，一个保守的内部系统，进化到同步生理预期地球的旋转，调节线粒体氧化能力和昼夜节律的破坏phenocopies代谢性肌病综合征在人类中，其特征是肝脏脂质积累，线粒体功能障碍，和禁食诱导癫痫发作。值得注意的是，我们还已经确定，我们可以使用前药NMN逆转昼夜节律破坏中的线粒体缺陷，其提高细胞内NAD+水平并增强代谢适应中至关重要的NAD+依赖性脱乙酰酶的活性。事实上，现在很明显，生物钟存在于身体的所有组织中，大脑生物钟与外周组织生物钟的正常相位对准会因轮班工作、夜间进食甚至高脂肪饮食而发生失调。因此，我们建议的长期目标是测试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的假设。我们工作的一个创新是整合生物钟和线粒体生物学的研究，并剖析生物钟时间对常量营养素代谢的影响。最终，我们现在准备更深入地了解时间对线粒体功能的贡献，这将适用于肥胖，代谢综合征和2型糖尿病治疗。

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.