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

Identifier:  TDX:2583

Handle: https://hdl.handle.net/20.500.11797/TDX2583

Authors:  Riera Borrull, Marta

Abstract:
Current lifestyle patterns, like exposure to excessive amounts of nutrients and lack of physical activity, promote the development of metabolic pathologies. In the case of obesity, chronic over nutrition exceed the storage capacity of metabolic tissues and activate metabolic pathways involved in the development of inflammatory responses and insulin resistance. Macrophages are considered as triggers of the inflammatory responses underlying metabolic diseases like obesity. By virtue of their plasticity, macrophages can display a wide spectrum of functional “polarization” states. An excessive amount of fat induces a macrophage polarization switch that leads to the acquisition of pro-inflammatory effector functions that exacerbate the obesity-associated inflammation state. In the first study, we addressed the consequences of excessive nutrient intake in energy metabolism. Since mitochondrial dysfunction is a common feature in metabolic disorders, we develop a GC-EI-QTOF-MS method to identify and quantify metabolites in biological samples as a mean to predict mitochondrial alterations. The second study focused on the identification of therapeutic strategies to ameliorate the metabolic disturbances induced by high-fat diet in low density lipoprotein receptor-deficient mice. Our findings reveal that the combination of metformin and caloric restraint provides a better alternative against the metabolic damage and might be a therapeutic strategy to ameliorate the metabolic dysfunction induced by excessive nutrient intake. The effects of palmitate (saturated fatty acid) on the human macrophage polarization are reported in the third study. We observed that exposure of M-CSF-dependent monocyte-derived human macrophages to palmitate lowers the expression of transcription factors that drive “anti-inflammatory gene set” expression 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. Importantly, we also report that the transcriptional and functional effects of palmitate differ from those triggered by LPS.