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.
Obesity is one of the greatest public health challenges of the 21st century and, among many other physical and psychosocial disabilities, it drastically increases the risk of type 2 diabetes and cardiovascular diseases. The latest data from the WHO Regional Office for Europe, describe a prevalence of overweight between 30 and 70% and obesity up to 30% in adults, making the identification of strategies for reducing the burden of obesity and its complications, a major challenge for Western societies and healthcare systems. The adipose tissue stress and inflammation (VAT-I) resulting from chronic caloric overload, is nowadays considered one of the leading causes of metabolic impairment in obesity. Many convincing investigations have carefully described pathophysiological processes occurring in inflamed VAT, inducing insulin resistance and increasing the risk of type 2 diabetes. However, the knowledge of causes leading to the onset of this condition is still limited. Moreover, since the possibility of detecting VAT-I may result in more accurate risk stratification in individuals with overweight and obesity, the development of non-invasive tools for its identification is a major challenge to address for improving efficacy and efficiency in diabetes prevention and care. Alterations of the gut - liver axis, chronically overwhelmed and stressed by excessive food intake and unbalanced nutrient rates, have been gaining new attention from the scientific community as a forge of metabolites potentially triggering the dysmetabolic cascade in obesity. Starting from this experimental evidence, this project will provide, in a clinical setting, new insights on the relationship among overfeeding/high fat diet and changes in the enterohepatic system, focusing on gastrointestinal peptide secretion and gut metabolites, in association to the presence of systemic and VAT-associated inflammation. Indeed, these investigations will allow to select biomarkers of VAT-I to be used for risk stratification in larger cohorts of dysmetabolic individuals. This project will depict aspects, not yet investigated, of gut hormones secretion, with a focus on NT, a peptide involved in the central regulation of energy balance and in lipids absorption/bile acids circulation, whose plasma levels strongly predict type 2 diabetes and cardiovascular mortality. Moreover, we will investigate the relationship between impaired gut metabolites/hormone secretion, endotoxemia and detrimental metabolic outcomes, such as VAT-I in obesity. Altogether these findings will add new insights into pathophysiological changes which occur in obesity and have the potential to break out the VAT homeostasis, leading to "VAT disease" and development of type 2 diabetes.