Ricerc@Sapienza

Type 2 diabetes (T2D) is characterized by chronic systemic low-grade inflammation which worsens insulin resistance (IR) and impairs vascular function, increasing the risk of organ damage and cardiovascular mortality. In condition of obesity, dysfunctional adipose tissue plays a key role in the development of T2D, as an insulin resistant organ per se and primary supplier of pro-inflammatory mediators, such as adipocytokines and fatty acids. Nonetheless, knowledge of causes leading to the onset of this condition is still limited. Gut and enterohepatic circulation are structurally and functionally entangled in processes leading from chronic caloric overload to fat mass expansion, inflammation and detrimental metabolic outcomes. Moreover, liver, besides being an obliged target of fatty acids overflow in presence of visceral adipose tissue inflammation (VAT-I), is a source of inflammatory mediators, further fuelling IR and increasing the risk of T2D and its complications. Starting from these premises, this study proposal aims to explore the relationship between obesity and its metabolic complications, impaired enterohepatic axis and its association with VAT-I. This project will 1) investigate the relationship between gastrointestinal peptides, in particular neurotensin (NT)/NTRs system and gut metabolites, as bile acids (BAs), and modifications in response to fat ingestion according to the degree of obesity and glucose tolerance; 2) study BAs and NT/NTRs axis in relation to systemic and VAT-associated inflammation, evaluated by VAT immunohistochemistry and gene expression analyses and 3) investigate if alterations in BAs are associated with gut bacterial translocation in bloodstream and VAT, and the relationship with biopsy-assessed NAFLD. Thus, this project will provide new insights into the changes occurring to the enterohepatic system in association with obesity and that have the potential to break out VAT homeostasis, leading to "VAT disease" and T2D.