The Takeda G-protein-coupled receptor 5 (TGR5) is a functional receptor which mediates a variety of metabolic and immune processes and is involved in the regulation of adipocyte pathophysiology. Experimental data from animal models show that TGR5 promotes mitochondrial function and increases ¿-oxidation and lipolysis in the adipose tissue, overall reducing lipid accumulation. Moreover, TGR5 activation is demonstrated to increase the energy expenditure and displays central anorexigenic effects in mice. Conversely, data on the expression of TGR5 in humans are very limited.
Therefore, this study proposal aims to explore the expression of TGR5 in human visceral adipose tissue (VAT) and to investigate correlates of differential VAT TGR5 expression in obese patients. This project will be carried out in a population of 50 obese individuals candidate to bariatric surgery for clinical purposes. Specific objectives will be: 1) to study the relationship between VAT TGR5 and presence of insulin resistance-associated disorders, i.e. abnormal glucose metabolism and impaired lipid profile; 2) to investigate the association between the TGR5 expression and the presence of signs of VAT dysfunction, as indicated by local inflammation and impaired lipid trafficking; 3) to test whether VAT TGR5 expression at baseline may predict metabolic outcomes of bariatric surgery at the 6-month post-intervention evaluation.
TGR5 represents a primary regulator of adipose tissue homeostasis and is a pharmacologically targetable receptor; therefore, this study will add insights on VAT pathophysiology in human obesity and might open a new scenario towards novel treatments for metabolic disorders.
Obesity is one of the greatest public health challenges of this Century since its prevalence has reached pandemic proportions in both Western countries and emerging economies. The obesity spread parallels the mounting incidence of insulin resistance-related disorders, such as type diabetes and metabolic syndrome, all associated with severely increased risk of cardiovascular disease, overall and cardiovascular mortality. Therefore, the identification of strategies for reducing the burden of obesity and its complications has become a major goal for societies and healthcare systems.
Alterations of the adipose tissue micro-environment, as those occurring in presence of chronic caloric overload and reduced energy expenditure, have been largely demonstrated to play a causal role in the development of metabolic complications in overweight and obese individuals.
In this context, the modulation of metabolic pathways which exert favourable effects on lipid trafficking and inflammation in the adipose tissue, may potentially represent an innovative therapeutic strategy for reverting processes triggered by the excessive lipid accumulation, adipocyte hypoxia and tissue dysfunction.
Data from experimental models have recently shown that the modulation of TGR5 displays positive effects on lipid accumulation and adipose tissue homeostasis in mice. In particular, TGR5 was demonstrated to promote energetic metabolism, to increase lipid ¿-oxidation and to induce lipogenesis in mice, overall activating mitochondrial function, tissue remodelling and adipose tissue browning.
Starting from these initial evidence obtained in vitro and in animal models, we will carry out an exploratory investigation on TGR5 and lipid metabolism in human adipose tissue.
We will correlate histological and functional features of the omental adipose tissue from individuals affected by severe obesity, with the presence of overt metabolic diseases, in particular referring to alterations of glucose and lipid metabolism. Indeed, this investigation will provide novel evidence on the expression pattern of this receptor in humans and will first answer the question whether differential TGR5 expression occurs in presence of metabolically unhealthy obesity, and then will unravel whether TGR5 levels may represent a marker of metabolic outcomes after bariatric surgery. Altogether these findings will add new insights into pathophysiological changes occurring in visceral adipose tissue in presence of obesity and might contribute to design innovative therapeutic approaches for the treatment of obesity-related dysmetabolic disorders.