Dietary regulation of the hepatic epigenome

肝脏表观基因组的饮食调节

基本信息

批准号：
10434846
负责人：
JOHN M DENU
金额：
$ 58.27万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10434846
关键词：
Address Adult Affect Alzheimer&apos s Disease American Amino Acids Animals Attention Biological Branched-Chain Amino Acids Caloric Restriction Calories Cardiovascular Diseases Cell Culture Techniques Cells Chemicals Chromatin Chromatin Structure Complex Complications of Diabetes Mellitus Consumption Development Diabetes Mellitus Diet Dietary Component Dietary Intervention Disease Eating Energy Intake Enzymes Epigenetic Process Essential Amino Acids Evolution FRAP1 gene Fasting Genetic Transcription Goals Health Health Benefit Hepatic Heterochromatin Histones Human In Vitro Individual Insulin Resistance Intake Intervention Isoleucine Knowledge Laboratories Leucine Link Long-Term Effects Longevity Macronutrients Nutrition Maintenance Malignant Neoplasms Mediating Metabolic Metabolic Control Metabolic syndrome Metabolism Methionine Methylation Modification Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity Epidemic Outcome Overweight Pathway interactions Persons Pharmacological Treatment Pharmacology Phosphotransferases Physiological Prevalence Proteins Regimen Regulation Risk Rodent Role S-Adenosylmethionine Thinness United States Valine Vegan Diet Work base detection of nutrient diabetes risk diet-induced obesity dietary dietary restriction disorder risk epigenetic memory epigenome experimental study feeding glycemic control histone methylation histone methyltransferase improved in vivo insulin sensitivity laboratory experiment metabolome novel strategies obesity prevention obesity treatment post SARS-CoV-2 infection preservation prevent protective effect response sensor targeted treatment transcriptome

项目摘要

Obesity is linked with an increased risk of diseases that include type 2 diabetes, cardiovascular disease, cancer, Alzheimer’s disease, and now emerging evidence indicates that obesity and diabetes are linked with worse outcomes following COVID-19 infection, even in the young. Type 2 diabetes affects over 29 million Americans, and the prevalence of diabetes, primarily driven by the obesity epidemic, continues to rise. Dietary interventions to control or prevent type 2 diabetes could be highly effective and affordable, but reduced calorie diets have proven to be unsustainable over the long term. New approaches to maintain metabolic health are therefore urgently needed. We and others have begun to investigate the role of specific dietary amino acids in the control of metabolic health, finding that in mice restriction of essential dietary amino acids, including methionine and the branched-chain amino acids (BCAAs; leucine, isoleucine and valine) can promote metabolic health and even reverse diet-induced obesity and insulin resistance. Understanding the physiological and molecular mechanisms by which restriction of calories or specific amino acids promotes metabolic health will permit the development of new pharmacological approaches to treat and prevent obesity and diabetes. Here, we will examine how dietary restriction of each of the nine essential amino acids alters the hepatic epigenome, metabolome, and transcriptome. We will examine the reversibility of methionine depletion (MD)- induced changes, and determine if MD alters the epigenome through depletion of epi-metabolites or by altering the activity of AA-responsive kinases. We will conduct in vitro and cell culture experiments to highlight the precise molecular pathways engaged by MD. Finally, we will investigate the contributions of reduced calorie intake and prolonged daily fasting, which calorie restricted (CR) animals are typically subjected to in most laboratory experiments, to the effects of a CR diet on the epigenome (chromatin structure, chemical modifications and gene transcription states) through altered metabolism. The proposed work will address long-standing questions regarding the molecular mechanisms by which dietary components regulate metabolic health. In terms of translatability, this work will enable our laboratories to develop a mechanistic understanding of how when, how much, and what we eat regulates health and disease vulnerability, and to identify new targets for the pharmacological treatment of obesity and diabetes.

肥胖与 2 型糖尿病、心血管疾病、癌症、阿尔茨海默氏病等疾病的风险增加有关，现在新出现的证据表明，肥胖和糖尿病与感染 COVID-19 后的较差结果有关，即使是在年轻人中也是如此。糖尿病影响着超过 2900 万美国人，并且主要由肥胖流行推动的糖尿病患病率持续上升，控制或预防 2 型糖尿病的饮食干预措施可能非常有效且负担得起，但事实证明，低热量饮食是不可持续的。这因此，从长远来看，我们和其他人已经开始研究特定膳食氨基酸在控制代谢健康中的作用，发现在小鼠中限制必需膳食氨基酸，包括蛋氨酸和氨基酸。支链氨基酸（BCAA；亮氨酸、异亮氨酸和缬氨酸）可以促进代谢健康，甚至逆转饮食引起的肥胖和胰岛素抵抗，了解限制热量或特定氨基酸促进代谢健康的生理和分子机制将有助于改善健康。开发新的治疗和预防肥胖和糖尿病的药理学方法在这里，我们将研究九种必需氨基酸的饮食限制如何改变肝脏表观基因组、代谢组和转录组，我们将研究蛋氨酸消耗（MD）引起的变化的可逆性。，并确定 MD 是否通过消耗表观代谢物或通过改变 AA 反应激酶的活性来改变表观基因组。我们将进行体外和细胞培养实验以突出显示。最后，我们将研究减少热量摄入和延长每日禁食（在大多数实验室实验中，热量限制（CR）动物通常会经历这种情况）对 CR 饮食对表观基因组的影响。拟议的工作将解决有关饮食成分调节代谢健康的分子机制的长期问题，这项工作将使我们的实验室能够开发一种机制。了解如何何时我们吃多少、吃什么调节健康和疾病脆弱性，并确定肥胖和糖尿病药物治疗的新目标。