Dietary regulation of the hepatic epigenome

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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.