Response to and signals of caloric restriction and intermittent feeding regimens

对热量限制和间歇性喂养方案的反应和信号

• 批准号: 7699465
• 负责人: MARC Kopel HELLERSTEIN
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7699465
• 关键词: Acetylation; Address; Adipose tissue; Agonist; Animal Model; Animals; Apolipoprotein E; Biochemical; Biogenesis; Biological Markers; Body Composition; Body Weight; Body Weight decreased; Caloric Restriction; Cell Proliferation; Clinical; Diabetes Mellitus; Diet; Dietary Intervention; Disease; Disease model; Eating; Employee Strikes; Energy Metabolism; Exercise; Fasting; Fatty acid glycerol esters; Food deprivation (experimental); Frequencies; Gene Expression; Genes; Genetic Models for Cancer; Glycogen; Goals; Health; Health Benefit; Heart Diseases; Hormones; Human; Insulin; Insulin Resistance; Insulin-Like-Growth Factor I Receptor; Intake; Intervention Studies; Islet Cell; Islets of Langerhans; Knockout Mice; Laboratories; Life; Liver; Longevity; Low Density Lipoprotein Receptor; Lymphocyte; Macronutrients Nutrition; Mammary gland; Measurement; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Mus; Nuclear; Nutrient; Obesity; Outcome; Outcome Measure; Oxidation-Reduction; Pathway interactions; Pattern; Periodicity; Pharmaceutical Preparations; Prostate; Public Health; Rodent; Rodent Model; Role; Signal Pathway; Signal Transduction; Skin; Testing; Time; Tissues; Translating; Treatment Protocols; base; cancer genetics; cancer risk; disorder risk; energy balance; fatty acid oxidation; feeding; in vivo; insulin sensitivity; macrophage; mimetics; nuclear factor 1; oxidation; programs; public health relevance; research study; response; stable isotope; transcription factor; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): Caloric restriction (CR) extends life-span and delays diseases in animal models. This remarkable observation has been difficult to translate into human health benefits, for two primary reasons. First, a life-time of food deprivation and reduced body weight is not practical for most people; and, second, it has not been easy to identify the underlying metabolic and molecular signals responsible for health benefits in rodent models when each experiment takes up to 3 years (to show that animals live longer). We recently applied a biomarker- based strategy, using highly sensitive, stable isotope-mass spectrometric measurements of fluxes through metabolic pathways in vivo as outcome measures, and looked for dietary regimens that may mimic the benefits of CR without requiring net negative energy balance, to address these limitations. Our studies have shown that intermittent feeding (IF) regimens such as modifed alternate-day fasting (mADF) reproduce many of the benefits of true CR in mice, without weight loss or change in body composition. Biomarkers that respond to CR and certain mADF regimens include global cell proliferation (mammary, prostate, skin, liver, lymphocytes), adipose tissue dynamics and fat distribution, insulin sensitivity, and vascular smooth muscle cell proliferation. We also observed similarities between IF and CR regimens with regard to striking cyclicity of whole-body fuel utilization and food intake, indicating that CR is itself a form of IF. In this project, we will use rapidly responsive biomarkers of disease risk to explore potentially more feasible dietary regimens and to identify underlying metabolic and molecular signals responsible for benefits. Specific aims are, 1) establish the pattern of IF required to reproduce the effects of CR (duration of fasting, feeding frequency, macronutrient content). 2) Identify metabolic signals (e.g., NADH/NAD, glycogen, fatty acid oxidation products) associated with effective IF regimens. 3) Identify changes in molecular signaling pathways (e.g., sirtuin pathway gene expression and target acetylation, IGF-1/insulin axis, PGC-1, nuclear factors) potentially mediating changes in biomarkers, including studies in gene knock-out mice (liver-specific SIRT3, IGF-1 receptor). 4) Evaluate combinations of exercise or CR-mimetic drugs with mADF, to assess amplification of beneficial effects. 5) Determine whether biomarker-based outcome measures predict effects on hard clinical outcomes, through longevity studies and studies in disease models (ApoE k.o. and LDL-receptor k.o., dietary-induced obese/insulin resistance, and genetic cancer models in mice). In all studies, different dietary interventions involving intermittent food intake will be compared to classic CR. The central hypothesis is that cyclic changes in intake and metabolism provide signals that turn on a conservation program, without requiring changes in body weight. The availability of biomarkers allows identification of dietary interventions and of metabolic and molecular correlates in an efficient, iterative manner. In summary, our goal is to better understand the metabolic and molecular signals underlying the effects of IF and CR, and to correlate effects on biomarkers with hard outcomes. PUBLIC HEALTH RELEVANCE: The findings that caloric restriction extends lifespan and delays diseases in animal models are remarkable, but have been difficult to translate into human public health benefits for two main reasons: first, because a lifetime of food deprivation and reduced body weight is not practical for most people, and second, because it has been easy to identify the underlying signals responsible for these benefits, when each experiment takes 3 or more years to show that animals live longer. We have identified and will explore here in detail dietary regimens (intermittent fasting alternated with ad-libitum intake) which may not result in weight loss and are likely to be much more feasible for long-term compliance in humans. Our discovery that sensitive, rapid turn-around tests developed in my laboratory may be used as markers of benefit opens the possibility of teasing out the biochemical and molecular signals that underlie the effects of diet, so that drugs which mimic these effects might be developed.

描述（由申请人提供）：热量限制（CR）扩展了寿命并延迟动物模型中的疾病。由于两个主要原因，这种非凡的观察很难转化为人类健康益处。首先，对于大多数人来说，食物剥夺和减轻体重的终身是不切实际的。其次，当每个实验最多占3年时（表明动物寿命更长）时，识别啮齿动物模型中负责健康益处的基本代谢和分子信号并不容易。最近，我们采用了一种基于生物标志物的策略，使用了高度敏感的同位素质量光谱测量通过体内代谢途径作为结果测量方法，并寻找饮食方案，这些饮食方案可能会模仿CR的好处而无需净负能量平衡，以解决这些限制。我们的研究表明，间歇性喂养（如果）方案（例如修饰的替代日禁食（MADF））在小鼠中重现了真正CR的许多好处，而没有体重减轻或身体组成的变化。对CR和某些MADF方案反应的生物标志物包括全球细胞增殖（乳腺，前列腺，皮肤，肝脏，淋巴细胞），脂肪组织动力学和脂肪分布，胰岛素敏感性和血管平滑肌细胞增殖。我们还观察到IF和CR方案之间关于全身燃料利用和食物摄入的惊人循环性的相似之处，这表明CR本身就是IF的一种形式。在这个项目中，我们将使用疾病风险的快速响应式生物标志物来探索潜在的更可行的饮食方案，并确定负责利益的基本代谢和分子信号。具体目的是，1）建立如果需要重现CR的影响的模式（禁食持续时间，进食频率，大量营养素含量）。 2）确定与有效IF方案相关的代谢信号（例如NADH/NAD，糖原，脂肪酸氧化产物）。 3）确定分子信号通路的变化（例如，SIRTUIN途径基因表达和靶乙酰化，IGF-1/胰岛素轴，PGC-1，核因子）可能介导生物标志物的变化，包括基因敲除小鼠的研究（肝脏特异性SIRT3，IGF-1受体）。 4）评估运动或CR模拟药物与MADF的组合，以评估有益效果的放大。 5）确定基于生物标志物的结果度量是否通过疾病模型中的寿命研究和研究（APOE K.O.和LDL受体K.O.，饮食诱导的肥胖/胰岛素耐药性以及小鼠的遗传癌模型）来预测对硬临床结果的影响。在所有研究中，将涉及间歇性食物摄入的不同饮食干预措施与经典CR进行比较。中心假设是，摄入量和代谢的循环变化提供了打开保护程序的信号，而无需体重改变。生物标志物的可用性允许以有效的迭代方式鉴定饮食干预措施以及代谢和分子的相关性。总而言之，我们的目标是更好地了解IF和CR效应的代谢和分子信号，并将对具有硬性结果的生物标志物的影响相关联。公共卫生相关性：热量限制会延长动物模型中的寿命和延长疾病的发现是显着的，但是很难转化为人类公共卫生的好处，这是有两个主要原因：首先，因为食物剥夺和体重的寿命减轻对大多数人来说并不实用，其次对每种动物的效果都很容易出现，因为在每种效果上都可以享受3个经验，而更长时间才能展现3个或更多的时间。我们已经确定并将在这里详细探索饮食方案（与脂肪摄入量交替交替进行饮食方案（间歇性禁食），这可能不会导致体重减轻，并且对于长期依从性人类的依从性可能会更可行。我们发现，在我的实验室中开发的敏感，快速的转弯测试可能被用作福利的标志，这可能会使嘲笑饮食作用的生化和分子信号取消生化和分子信号，从而可以开发出模仿这些作用的药物。