Dietary regulation of the hepatic epigenome

肥胖与包括2型糖尿病、心血管疾病、癌症、阿尔茨海默病在内的疾病风险增加有关，现在新出现的证据表明，肥胖和糖尿病与COVID-19感染后的不良后果有关，即使在年轻人中也是如此。2型糖尿病影响着超过2900万美国人，糖尿病的患病率主要由肥胖流行病驱动，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，但减少热量的饮食已被证明是长期不可持续的。因此，迫切需要维持代谢健康的新方法。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，甚至逆转饮食诱导的肥胖和胰岛素抵抗。了解限制卡路里或特定氨基酸促进代谢健康的生理和分子机制将允许开发新的药理学方法来治疗和预防肥胖和糖尿病。在这里，我们将研究如何饮食限制的九种必需氨基酸改变肝脏表观基因组，代谢组和转录组。我们将研究蛋氨酸耗竭（MD）诱导的变化的可逆性，并确定MD是否通过耗竭表观代谢物或通过改变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每日禁食的贡献，其中卡路里限制（CR）动物通常在大多数实验室实验中进行，通过改变代谢，CR饮食对表观基因组（染色质结构，化学修饰和基因转录状态）的影响。拟议的工作将解决长期存在的问题，即饮食成分调节代谢健康的分子机制。在可翻译性方面，这项工作将使我们的实验室能够对我们何时、吃多少、吃什么调节健康和疾病脆弱性的机制性理解，并确定肥胖和糖尿病药物治疗的新靶点。

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.