Beneficial reprogramming of lipid metabolism with intermittent fasting

热量限制是延长模式生物寿命的最保守的行为干预。 获取热量限制的好处，无论是通过饮食处方还是通过确定因果途径， 可以随意操作，有望改善心脏代谢健康。测试是否 延长寿命的效果是具有挑战性的人类翻译;然而，多项研究，各种方法 热量限制，已证明对替代终点（如体重减轻、血脂和血糖）有益 体内平衡一个重要的问题是热量限制的好处在多大程度上是由于体重 损失-即我们都将受益于热量限制或最适用于以下患者的好处 超重？此外，长期遵守需要每天坚持的饮食是具有挑战性的。间歇 禁食已经成为一种不需要每天坚持的替代方案，早期研究表明代谢 效益我们的多学科研究小组专注于研究禁食，因为它有理论上的好处。 与体重减轻无关。通过将临床表型与多组学分析相结合，我们定义了 作为禁食持续时间的函数以及与关键生理事件的关系的代谢反应，例如 体重减轻和骨代谢的变化，因为对骨的分解代谢作用是 热量限制和减肥。我们已经发现了一个明显的空腹脂肪成分的变化-持续 即使在重新进料后-其特征在于低碳含量降低、饱和甘油三酯和高- 碳含量，不饱和甘油三酯;流行病学研究显示甘油三酯的变化，以防止 未来的心脏代谢疾病和虚弱。值得注意的是，甘油三酯质量的有益转变已经很明显 在禁食的第一天，体重减轻或骨转换标志物出现负变化之前。因此，我们的中央 一种假设是，禁食驱动心脏代谢的好处独立于体重减轻，这些好处可以是 如果每次空腹给药仅限于一天，则捕获的剂量不会对骨骼产生负面影响。我们提出了一个机械的 临床研究，将糖尿病高危志愿者随机分为3组：1）对照组，2）空腹组 每周一天，持续3个月，或3）每周禁食一天，服用热量处方，以维持身体健康 重量.在目标1中，我们将进行代谢组学研究，以测试间歇性禁食是否有益于脂质重编程 代谢，是否重新编程预测改善胰岛素敏感性，以及这些变化是否发生 与体重减轻无关。认识到，任何解决办法最重要的负面后果是， 热量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 每周进行一次禁食干预，以改善心脏代谢健康，而不影响骨骼完整性。此外，委员会认为， 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， 有望发现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.