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Mechanisms underlying the antiinflammatory and thermogenic effects of fish oil in obesity and associated metabolic diseases


We propose herein to investigate the mechanisms by which n-3 fatty acids protect from obesity and associated metabolic diseases. More specifically, we will investigate in two integrated research programs the mechanisms underlying the pro-energy expenditure (Aim 1) and anti-inflammatory (Aim 2) actions of n-3 fatty acids. In Aim 1, the following processes will be investigated as possible underlying causes of the increase in energy expenditure induced by n-3 fatty acids in liver, skeletal muscle and white and brown adipose tissues: 1- uncoupling proteins 2 and 3 (UCP2 and 3) dependent and independent mitochondrial uncoupling; 2- peroxisomal n-3 fatty acid oxidation; 3- metabolic (futile) cycling; 4- SERCA mediated calcium cycling; and 4- creatine driven substrate cycle. For this, both mice and cells (murine and human brown, beige and white adipocytes, myocytes and hepatocytes) bearing either genetic or pharmacological loss of function of proteins that are essential to the above mentioned processes will be treated with n-3 fatty acids and evaluated for energy balance and glucose and lipid metabolism. In Aim 2, we will test the hypothesis that the anti-inflammatory actions of n-3 fatty acids are mediated by changes in microbiota, as well as by the generation of antiinflammatory lipid mediators and products of n-3 oxidation (oxylipids). To address this, we will use genetically modified mice and cells (human and murine adipocytes and hepatocytes), dietary interventions, microbiota transfer experiments and state of art omic approaches (transcriptomic and meta-transcriptomic, proteomic and lipidomic). (AU)

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