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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

基本信息

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
项目类别：
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

项目摘要

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.

在模式生物中，热量限制是最保守的延长寿命的行为干预。