Study of the mechanisms of oxidative stress, mitochondrial function and endoplasmic reticulum stress in obesity. Role in subclinical atherosclerosis and therapeutic approaches

• Autores: Sandra Lopez Domenech
• Directores de la Tesis: Milagros Rocha Barajas (dir. tes.), Victor Manuel Victor González (codir. tes.), Antonio Hernández Mijares (codir. tes.)
• Lectura: En la Universitat de València ( España ) en 2019
• Idioma: español
• Tribunal Calificador de la Tesis: Nadezda Apostolova Atanasovska (presid.), José Antonio Rodríguez García (secret.), Giuseppe Poli (voc.)
• Programa de doctorado: Programa de Doctorado en Biomedicina y Biotecnología por la Universitat de València (Estudi General)
• Materias:
  • Ciencias de la vida
    • Fisiología humana
      • Fisiología endocrina
    • Biología molecular
  • Ciencias médicas
    • Medicina interna
      • Endocrinología
    • Patología
      • Arterioesclerosis
• Enlaces
  • Tesis en acceso abierto en: TESEO
• Resumen

  • The alarming rise in the prevalence of obesity worldwide and the associated heavy burden of the disease has generated a growing demand for strategies for slowing down the epidemic and/or mitigating the damaging effects of obesity on health. A massive commitment by social forces is required not only to develop preventive strategies but to further increase understanding of the pathological events and mechanisms involved. The main aim of the present doctoral thesis is to delve into the underlying mechanisms of obesity, especially those related to the increased risk of developing atherosclerosis, with a special focus on leukocyte activation and margination in the vessel wall and the role of certain mechanisms, including inflammation, oxidative stress, mitochondrial dysfunction and ER stress. We also address whether several therapeutic approaches such as diet-induced weight loss and pinitol (a botanical compound) can modulate these pathways and protect against metabolic disturbances. First, by means of a cross-sectional study, we show that adherence between leukocytes and the vascular endothelium is enhanced in obesity in parallel with the rising degree of adiposity. This response is associated with systemic conditions such as inflammation, IR and endothelial dysfunction, but also with increased oxidative stress and mitochondrial dysfunction in leukocytes, suggesting a role of altered redox balance within leukocytes in the onset of the atherosclerotic process. At the same time, we demonstrate that a worsening of the periodontal condition in a cohort of obese patients was associated with increasing systemic inflammation and oxidative stress in leukocytes, thus promoting their interaction with the endothelium. These results are an important contribution to our knowledge of the potential mechanisms underlying the relationship between obesity, chronic periodontitis and CV disease. Interestingly, when morbid obese patients underwent dietary weight-loss intervention we found that moderate weight loss partially reversed this situation by improving lipid profile, insulin sensitivity and reducing inflammatory and oxidative response both in leukocytes and at systemic level, resulting in enhanced endothelial function and lesser interactions between leukocytes and the endothelium. Further analysis of the modulation of intracellular stress responses in leukocytes after weight loss revealed ameliorated ER stress and mitochondrial dysfunction, which were associated with increased expression of chaperones and anti-inflammatory and antioxidant mediators. Altogether, these results shed light on the potential mechanisms underlying the protective role of weight loss on metabolic control and cellular homeostasis. Finally, we demonstrate that pinitol targets ER stress and inflammatory pathways in adipose tissue and leukocytes of obese patients and may represent a novel adjunctive treatment to reduce metabolic complications in this pathology.