Insulin resistance and related metabolic disorders can be favoured by genetic predisposition and are promoted by environmental factors, which impact the cell’s metabolic control via epigenetic mechanisms. Advances in epigenetics opened new points of view on the deciphering of the molecular mechanisms regulating insulin action and metabolic control. In the field of pharmaceutical discovery, the majority of first-in-class newly therapeutics falls within the class of regulators of the epigenomes, molecules that act to activate or inhibit epigenetic writers (enzymes adding acetyl, methyl or other chemical groups to histones and DNA), readers (effectors acting upon interaction with the modified histones and DNA) and erasers (enzymes removing the histone post-translational modification (PTM). While the alterations on DNA methylation patterns in various conditions of altered metabolism have been investigated, in situation such as obesity, insulin resistance and diabetes, the evidence supporting an association, or causality, between epigenetic changes of histone post-translational modifications and metabolic dysfunction, especially in human studies, is scant. Our project aims to generate a deeper mechanistic description of the relation between insulin signalling and histone PTMs (acetylation and other acylations), and to investigate whether defects in histone acylations take place in diabetes. While insulin-dependency of histone acetylation in cell culture and on a few selected genes have been investigated, the regulation at the genome-wide level is an exciting future field of research that we aim to explore. In spite of these gaps in the understanding of the interaction between insulin action and the cell’s epigenetic response, some preclinical investigations in rodents already suggest that inhibition of one class of epigenetic erasers, the histone deacetylases, can be a therapeutic option to alleviate insulin resistance and Type 2 Diabetes. The aim of our project is threefold: from the discovery point of view, we aim to shed light on the relationship between the action of insulin on the epigenome and the possible dysregulation of such control in metabolic disease. From a translation phase into preclinical discovery, we aim to harness the richness of newly described epigenetic modulators (most of which are at advanced preclinical testing and/or already evaluated in oncology clinical trials) towards a validation of their potential in the metabolic and diabetes field. From a public-health and societal point of view, we are aware that epigenetics is a trending word in the news, the internet and social platforms. The understanding of how epigenetics can influence our health and how both "genes and environment" in turn play a role in shaping such epigenetic influence is still limited in the general population and often distorted by input from low quality or misleading sources. Questions like "Would this epigenetic treatment change my genome?", "Should I follow this dietary regime if it changes my genes?" are not uncommon. With an eye to future pharmacological or nutritional interventions for obesity, metabolic diseases and cancer that rely on alterations of the patient's epigenome, we deem it timely to accompany our scientific research with insight from a social scientist (to be recruited as a partner in our network). In particular, we will seek to attract a group interested in identifying and analysing the implications, perception and acceptance of such interventions.