Beneficial reprogramming of lipid metabolism with intermittent fasting

卡路里限制是延长模式生物寿命的最保守的行为干预。 获取卡路里限制的好处，无论是通过饮食处方还是通过确定 可以进行药理操作，有望改善心脏新陈代谢健康。测试是否 延长生命的效果对人类来说是具有挑战性的；然而，多项研究，以不同的方法 对于卡路里限制，已证明对替代终点有好处，如减肥、血脂和血糖 动态平衡。一个重要的问题是，限制卡路里的益处在多大程度上是由于体重 损失-即我们都会从卡路里限制中受益，还是最适用于 超重？此外，长期遵守要求每天坚持的饮食是具有挑战性的。间歇性 禁食已经成为一种不需要每天坚持的选择，早期研究表明新陈代谢 利益。我们的多学科研究小组一直专注于研究禁食，因为这有理论上的好处 不受体重减轻的影响。通过临床表型分析和多组学分析的结合，我们定义了 代谢反应作为禁食时间的函数以及与关键生理事件的关系，例如 体重减轻和骨代谢改变，因为对骨骼的分解代谢影响是一贯的负面结果 减少卡路里摄入，减轻体重。我们发现脂类成分有明显的空腹变化--持续 即使在重新喂养之后-其特征是低碳含量减少，饱和甘油三酯和高密度脂蛋白增加- 碳含量，不饱和甘油三酯；流行病学研究表明甘油三酯的变化可预防 未来的心脏代谢性疾病和虚弱。值得注意的是，甘油三酯质量的有益转变已经很明显。 在禁食第一天，体重减轻或骨转换指标出现负变化。因此，我们的中央 假设禁食可以促进心脏新陈代谢的益处，而与减肥无关，其益处可能是 如果每次禁食剂量限制为一天，则捕获时不会对骨骼产生负面影响。我们提出了一种机械论 临床研究，将糖尿病高危志愿者随机分为3组：1)对照组，2)禁食 每周禁食一天，连续三个月，或3)每周禁食一天，服用卡路里处方以保持身体健康 重量。在目标1中，我们将执行代谢组学来测试间歇性禁食是否有益于重新编程脂质。 新陈代谢，这种重新编程是否预示着胰岛素敏感性的改善，以及这些变化是否发生 不受体重减轻的影响。认识到任何解决办法的最重要的负面后果 卡路里限制是对骨骼的分解代谢作用，在目标2中，我们将评估对骨骼的影响，包括 骨微结构的艺术分析。如果成功，这项研究将提供一次概念验证 每周禁食干预，在不损害骨骼完整性的情况下改善心脏代谢健康。此外， 通过将随机对照研究设计与严格的临床表型和代谢组学相结合，该项目 有希望确定支持禁食益处的新代谢机制。

Caloric restriction is the most conserved behavioral intervention that prolongs lifespan in model organisms. Capturing benefits of caloric restriction, either through dietary prescription or by identifying causal pathways that can be manipulated pharmacologically, holds promise to improve cardiometabolic health. Testing whether the life-prolonging effect is translatable to humans is challenging; however, multiple studies, with various approaches to caloric restriction, have demonstrated benefits to surrogate endpoints such as weight loss, lipids, and glucose homeostasis. One important question is the degree to which benefits of caloric restriction are due to weight loss—i.e. would we all benefit from caloric restriction or are the benefits most applicable to patients who are overweight? Moreover, long-term compliance with a diet requiring daily adherence is challenging. Intermittent fasting has emerged as an alternative that does not require daily adherence and early studies suggest metabolic benefit. Our multi-disciplinary research group has focused on studying fasting because there is theoretical benefit independent of weight loss. Through coupling of clinical phenotyping with multi-omics analyses, we have defined metabolic responses as a function of fasting duration and in relationship to key physiological events, such as weight loss and changes in bone metabolism, as catabolic effects on bone are a consistent negative result of caloric restriction with weight loss. We have discovered a marked fasting shift in lipid composition— sustained even after re-feeding—characterized by reduced low carbon-content, saturated triglycerides and increased high- carbon content, unsaturated triglycerides; a triglyceride shift shown in epidemiologic studies to protect against future cardiometabolic disease and frailty. Remarkably, the beneficial shift in triglyceride quality is already evident in the first fasting day, before weight loss or negative changes in bone turnover markers. Therefore, our central hypothesis is that fasting drives cardiometabolic benefits independent of weight loss and the benefits can be captured without negative effects to bone if each fasting dose is limited to one day. We propose a mechanistic clinical study, randomizing volunteers at high risk of diabetes, to one of 3 groups: 1) Control group, 2) Fasting one day per week for 3 months, or 3) Fasting one day per week with a caloric prescription to maintain body weight. In Aim 1 we will perform metabolomics to test whether intermittent fasting beneficially reprograms lipid metabolism, whether that reprogramming predicts improved insulin sensitivity and whether these changes occur independent of weight loss. Recognizing that the most important negative consequence of any approach to caloric restriction is the catabolic effect on bone, in Aim 2 we will assess the effects on bone, including state of the art analyses of bone microarchitecture. If successful, this study will provide proof-of-concept for a once weekly fasting intervention to improve cardiometabolic health without compromising bone integrity. Moreover, by merging a randomized-control study design with rigorous clinical phenotyping and metabolomics, this project holds promise to identify novel metabolic mechanisms underpinning the benefits of fasting.