Changes in adipose tissue plasticity after bariatric surgery and their role in the improvement of obesity-associated comorbidities

Resumen

Adipose tissue (AT) is considered a plastic and dynamic endocrine organ with obesity driving changes in its biomechanical properties as well as in its extracellular matrix (ECM) remodelling, inflammation and mechanotransduction profiles, leading to the impairment of whole-body homeostasis. To achieve important and sustained weight loss as well as for the resolution of obesity-associated diseases, bariatric surgery (BS) is considered the most effective option in adequately selected patients. Despite great efforts to understand the processes involved in both, the development of dysfunctional AT and the favourable outcomes of BS, the underlying biological mechanisms have not been fully disentangled. Therefore, the objective of the present PhD thesis is to evaluate changes in AT plasticity together with their associations with the inflammation profile as well as ECM remodelling and mechanotransduction properties in an animal model of diet-induced obesity (DIO) and in patients with obesity. At the same time, we aimed to analyse the effect of BS on these biological processes, beyond the mere weight loss. We found that changes in the biomechanical properties of AT in obesity, including decreased Young’ modulus (E), ultimate tensile strength (UTS) and strain at UTS, were associated with the deterioration of body homeostasis. In this line, obesity induced changes in the inflammation, fibrosis and ECM remodelling profiles not only in AT but also in the liver being also related to the development of obesity comorbidities. Our findings also provide new insights into AT adaptation after BS beyond caloric restriction, being demonstrated by significant changes in the mechanotransduction and inflammatory profiles together with the decrease in the crosslinking and synthesis of collagens as well as an increase in its degradation. Our data also supports the notion that the higher blood vessel density found in AT after BS is involved in the increased E, UTS and strain at UTS values, providing at the same time higher stiffness and increased strain capacity. Furthermore, the inhibition of NLRP3, a key component of the inflammasome involved in the regulation of inflammation, in visceral adipocytes significantly blocked inflammation and fibrosis suggesting its potential to regulate the development of obesity-associated comorbidities. In terms of fibrosis-inducing factors, we also showed a novel role of dermatopontin in the pathological AT ECM remodelling during obesity. Finally, we proposed that the measurement of the Adiponectin/Leptin ratio after BS might constitute a significant factor for evaluating the remission of type 2 diabetes after bariatric procedures.