Assessment of pathophysiological mechanisms in obesity-related diseases through metabolomics, transcriptomics and mouse models of disease

• Autores: Marta Riera Borrull
• Directores de la Tesis: Ángel Luis Corbi Lopez (dir. tes.), Jorge Joven Maried (dir. tes.)
• Lectura: En la Universitat Rovira i Virgili ( España ) en 2017
• Idioma: inglés
• Tribunal Calificador de la Tesis: Juan Rubiés Prat (presid.), Juan Carlos Pedro Botet Montoya (secret.), Fátima Sabench Pereferrer (voc.)
• Materias:
  • Química
    • Bioquímica
  • Ciencias de la vida
    • Fisiología humana
      • Metabolismo humano
    • Inmunología
• Enlaces
  • Tesis en acceso abierto en:  hdl.handle.net  TDX 
• Resumen

  • Nutrient management and energy balance are involved in maintenance of metabolic homeostasis systems. Current lifestyle patterns, like exposure to excessive amounts of nutrients and lack of physical activity, promote the disruption of homeostatic mechanisms and are the basis for the development of numerous pathologies. In the case of obesity, chronic over nutrition and reduced energy expenditure exceed the storage capacity of metabolic tissues and activate several metabolic pathways involved in the development of inflammatory responses and insulin resistance. Thus, as a contributor to disruption of homeostasis, low-grade chronic inflammation has a crucial role in the development of metabolic diseases, such as obesity, type 2 diabetes, cardiovascular diseases and non-alcoholic fatty liver disease. Moreover, maintenance and reinforcement of an inflammatory state results in the development of chronic metabolic diseases.

    A close link exists between the function of metabolic tissues and the presence of immune cells. Specifically, macrophages are considered as triggers of the inflammatory responses underlying metabolic diseases like obesity. By virtue of their huge plasticity to adapt to different microenvironments, macrophages can display a wide spectrum of functional “polarization” states. In lean adipose tissue, macrophages exhibit an anti-inflammatory phenotype that contributes to insulin sensitivity. Conversely, an excessive amount of fat induces a macrophage polarization switch that leads to the acquisition of pro-inflammatory effector functions, best exemplified by the release of pro-inflammatory cytokines, and the ability to recruit other immune cells that impair insulin sensitivity and further exacerbate the obesity-associated inflammation state.

    In the first study (Journal of The American Society for Mass Spectrometry), we addressed the consequences of excessive nutrient intake in energy metabolism. Since mitochondrial dysfunction is a common feature in metabolic disorders, we develop a method to identify and quantify metabolites in biological samples as a mean to predict mitochondrial alterations. Specifically, we developed a GC-EI-QTOF-MS method to measure a wide range of intermediate metabolites from energy metabolism. The method was validated in cell-culture lysates, plasma from patients and tissues from mice models of disease, and was confirmed as a valid analytical platform to assess the energy metabolism in biological samples.

    The second study (Nutrients) focused on the identification of therapeutic strategies to ameliorate the metabolic disturbances induced by high-fat diet (HFD) in low density lipoprotein receptor-deficient mice (Ldlr-/-). Specifically, the effects of metformin in HFD- or chow diet-fed mice, as well as the effect of “diet reversal” with or without metformin in HFD-fed mice, were assessed on liver and adipose tissue through the use of biochemical, histological and metabolomic analysis. Our findings reveal that the combination of metformin and caloric restraint provides a better alternative against metabolic damage and might be a therapeutic strategy to ameliorate the metabolic dysfunction induced by excessive nutrient intake.

    The effects of the saturated fatty acid (SFA) palmitate on human macrophage polarization are reported in the third study (Molecular Metabolism). We observed that exposure of M-CSF-dependent monocyte-derived human macrophages to palmitate (200µM) lowers the expression of transcription factors that drive “anti-inflammatory gene set” expression (MAFB, AhR) and simultaneously promote the acquisition of a pro-inflammatory transcriptional and functional profile via JNK activation. Besides, palmitate was found to prime macrophages for exacerbated inflammatory responses towards a pathogenic stimulus like LPS, a process also mediated by JNK activation. Importantly, we report that the transcriptional and functional effects of palmitate differ from those triggered by LPS, with stimuli oppositely regulating the expression of CCL19 and TRIB3. These results have established that palmitate induces a specific pro-inflammatory polarization state in human macrophages.