Beneficial reprogramming of lipid metabolism with intermittent fasting

间歇性禁食对脂质代谢进行有益的重新编程

• 批准号: 10660477
• 负责人: Pouneh Khadejeh Fazeli
• 金额: $ 69.17万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660477
• 关键词: Adherence; Adipose tissue; Aging; Behavior Therapy; Biochemical; Blood; Blood Pressure; Body Composition; Body Weight; Body Weight Changes; Body Weight decreased; Bone Density; Caloric Restriction; Calories; Carbon; Cardiometabolic Disease; Clinical; Clinical Research; Control Groups; Coupling; Data; Diabetes Mellitus; Diet; Dose; Dual-Energy X-Ray Absorptiometry; Energy Intake; Event; Fasting; Fatty acid glycerol esters; Foundations; Future; Glucose Clamp; Goals; Health; Hour; Human; Hyperinsulinism; Inflammation; Interdisciplinary Study; Intermittent fasting; Intervention; Life; Lipids; Longevity; Low-Density Lipoproteins; Measures; Mediating; Metabolic; Methods; Modeling; Molecular; Overweight; Pathway interactions; Patients; Peripheral; Physiological; Protocols documentation; Randomized; Religion; Research Design; Resolution; Risk; Sampling; Surrogate Endpoint; Testing; Time-restricted feeding; Triglycerides; arm; blood glucose regulation; blood lipid; bone; bone loss; bone metabolism; bone turnover; cardiometabolism; clinical phenotype; design; diabetes risk; dietary; epidemiology study; feeding; frailty; glucose metabolism; high risk; improved; insulin sensitivity; lipid metabolism; lipidomics; metabolomics; model organism; multidisciplinary; multiple omics; novel; pharmacologic; pi bond; programs; randomized, clinical trials; randomized, controlled study; response; secondary analysis; serial imaging; subcutaneous; volunteer; weight maintenance

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.

热量限制是延长模型生物中寿命的最保守的行为干预措施。 通过饮食处方或通过识别因果途径来捕获热量限制的好处 可以通过药理学进行操纵，有望改善心脏代谢健康。测试是否 生命的效果可以翻译成人类是挑战。但是，多种研究，采用各种方法 为了热量限制，已经证明了体重减轻，脂质和葡萄糖等替代终点的好处 稳态。一个重要的问题是热量限制的好处是由于重量 损失 - 我。我们都会从热量限制中受益还是最适用于患者的好处 超重？此外，长期遵守需要每天遵守的饮食是挑战。 禁食已成为不需要每日遵守的替代方案，早期研究表明代谢 好处。我们的多学科研究小组的重点是研究禁食，因为有理论上的好处 独立于减肥。通过将临床表型与多摩学分析耦合，我们定义了 代谢反应是禁食持续时间和与关键生理事件的关系，例如 体重减轻和骨代谢的变化，因为对骨骼的分解代谢作用是 热量限制与体重减轻。我们已经发现了脂质成分的明显禁食转变 - 持续 即使在重新喂食后，也通过降低的低碳含量，饱和甘油三酸酯的特征来表征并增加了高 - 碳含量，不饱和甘油三酸酯；流行病学研究中显示的甘油三酸酯的转移 未来的心脏代谢疾病和脆弱。值得注意的是，甘油三酸酯质量的有益转变已经是证据 在第一个禁食日，在体重减轻或骨转换标记的负面变化之前。因此，我们的中心 假设是，禁食驱动心脏代谢益处独立于减肥，而收益可以是 如果每个禁食剂量仅限于一天，则不会对骨骼负面影响。我们提出了一种机械 临床研究，糖尿病高风险的随机志愿者，3组之一：1）对照组，2）禁食 每周一天3个月，或3）每周禁食，每天使用热量处方以保持身体 重量。在AIM 1中，我们将执行代谢组学以测试间歇性禁食是否有益地重新编程脂质 代谢，重编程预测是否改善了胰岛素敏感性以及这些变化是否发生 独立于减肥。认识到任何方法的最重要的负面后果 热量限制是对骨骼的分解代谢作用，在AIM 2中，我们将评估对骨骼的影响，包括状态 骨微体系结构的艺术分析。如果成功，这项研究将为一次提供证明 每周禁食干预以改善心脏代谢健康，而不会损害骨骼完整性。而且， 通过将随机控制研究设计与严格的临床表型和代谢组学合并，该项目 保持有望识别基于禁食的好处的新型代谢机制。