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：
10211950
负责人：
JOHN M DENU
金额：
$ 58.89万
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/10211950
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 Pharmacological Treatment Pharmacology Phosphotransferases Physiological Prevalence Proteins Regimen Regulation Risk Rodent Role S-Adenosylmethionine SARS-CoV-2 infection 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 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.

肥胖与包括2型糖尿病，心血管疾病，癌症，阿尔茨海默氏病的疾病风险增加有关，现在新出现的证据表明，即使在年轻人中，肥胖症和糖尿病与COVID-19感染后的结局较差。 2型糖尿病会影响超过2900万美国人，而肥胖症流行驱动的主要糖尿病患病率仍在继续上升。控制或预防2型糖尿病的饮食干预措施可能是非常有效且负担得起的，但是从长远来看，降低的卡路里饮食已被证明是不可持续的。因此，迫切需要新的维持代谢健康的方法。我们和其他人已经开始研究特定饮食氨基酸在代谢健康中的作用，发现在小鼠限制基本饮食氨基酸（包括甲基氨酸和分支链氨基酸（BCAAS； Leucine，Isolecine and Isolecine and valine和Valine））的限制可以促进饮食健康，甚至可以促进饮食诱导的obe蛋白和胰岛素。了解卡路里或特定氨基酸促进代谢健康的物理和分子机制将允许开发新的药物方法来治疗和预防肥胖和糖尿病。在这里，我们将研究九种必需氨基酸中每一个的饮食限制如何改变肝性表现基因组，代谢组和转录组。我们将检查甲基氨酸耗竭（MD）诱导的变化的可逆性，并确定MD是否通过epi-亚赛代谢产物的耗竭或通过改变AA反应性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MD参与的精确分子途径。最后，我们将研究减少卡路里摄入量和延长日常禁食的贡献，在大多数实验室实验中，卡路里限制（CR）动物通常会受到CR饮食对Epegenome（染色质结构，化学修饰和基因转录状态）的影响的影响。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。在可翻译性方面，这项工作将使我们的实验室能够对何时，多少和我们饮食的何时，多少和饮食进行机械理解，从而调节健康和疾病的脆弱性，并确定肥胖和糖尿病药物治疗的新目标。