Estudio del efecto de la cirugía de Bypass Gástrico en Y de Roux sobre los mecanismos moleculares asociados a la fisiopatología de la obesidad
- Autores: Zaida María Abad Jiménez
- Directores de la Tesis: Victor Manuel Victor González (dir. tes.), Milagros Rocha Barajas (codir. tes.)
- Lectura: En la Universitat de València ( España ) en 2022
- Idioma: español
- Tribunal Calificador de la Tesis: M. Carmen Gómez Cabrera (presid.), Jordi Muntané Relat (secret.), Pedro Escoll Guerrero (voc.)
- Programa de doctorado: Programa de Doctorado en Fisiología por la Universitat de València (Estudi General)
- Materias:
- Enlaces
- Tesis en acceso abierto en: TESEO
- Resumen
Obesity is a multifactorial and disabling disease characterized by metabolic overload in adipose tissue (AT), chronic low-grade inflammation, oxidative stress and endothelial dysfunction. Currently, the worldwide prevalence of obesity is increasing, with lifestyle having a significant influence on the resolution of this disease. In this context, there has been an increase in the demand for strategies to reverse comorbidities and to stop its increase. The Roux-en-Y gastric bypass (RYGB) procedure is an effective tool for weight loss and remission of the metabolic comorbidities of obesity, although the molecular mechanisms involving these improvements are unknown. Therefore, the main objective of the present PhD thesis was to determine how RYGB surgery modulates chronic low-grade inflammation, oxidative stress and endothelial dysfunction, by exploring its effect on the inflammasome complex, autophagy, mitochondrial dynamics and endoplasmic reticulum (ER) stress. The role of metformin, an alternative therapeutic approach to obesity and type 2 diabetes (T2D), was also addressed. Therefore, another aim of this study was to analyse the molecular mechanisms related to inflammation and autophagy in AT and the protective effect of metformin against metabolic alterations. Our hypothesis was that RYGB-induced weight loss modulates the response of leukocytes, primordial components of the immune system. To test this hypothesis, we analysed the various metabolic pathways that are altered by obesity and explored whether AT responds differentially to metformin. We observed that the weight loss produced after 1 year of RYGB was accompanied by an improvement in proatherogenic lipid profile and insulin sensitivity. This was accompanied by a decrease in proinflammatory cytokines and leukocyte reactive oxygen species production and an enhanced antioxidant response, resulting in less interaction between leukocytes and both the endothelium and markers of endothelial dysfunction. In addition, further analysis of molecular mechanisms in leukocytes after weight loss revealed an improvement in the homeostatic response as a result of an increase in AMPK, markers of autophagy, biogenesis and mitochondrial dynamics, along with a decrease in proinflammatory cytokines, markers of inflammation and ER stress. Considered together, these results help to shed light on the mechanisms underlying the protective effect of weight loss on metabolic control and cellular homeostasis in obesity. Moreover, through a cross-sectional study, we reported that obese T2D patients treated with metformin exhibit improved inflammatory and oxidative profile with respect to metabolically healthy obesity (MHO) subjects. This improvement seems to be modulated by changes in the activation of the inflammasome complex and autophagy in VAT, suggesting – despite common belief – that MHO subjects are not as cardiometabolically protected as expected. Future mechanistic studies should aim to determine the direct targets of metformin responsible for mediating these responses.
