Implication of ceramide 1-phosphate in obesity-associated processes. Role of PEMT
Ordoñez Zaragoza, Marta
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Obesity is the most common metabolic disease in developed nations and has become a global epidemic in recent years. Therefore, understanding the molecular mechanisms that regulate obesity-associated processes, such as cell migration, adipogenesis and inflammation, can be a crucial step for developing novel therapeutic strategies to control obesity and obesity-related pathologies. It is well known that sphingolipid content in tissue undergoes dramatic alterations in metabolic diseases suggesting that these lipids might mediate the pathology associated with metabolic disease. In this thesis, we demonstrate that C1P enhances macrophage migration, an action that requires the activation of matrix metalloprotease- 2 and -9. We also provide evidence suggesting that adipogenesis is associated with an increase in CERK protein expression and activity. In addition, we demonstrate that exogenous C1P inhibits adipocyte differentiation of 3T3-L1 cells, as confirmed by a reduction in triglyceride accumulation and a reduction in the expression of adipocyte specific genes. This action of C1P implicates the activation of extracellular signal-regulated kinases (ERK1/2). We have also found that lack of phosphatidylethanolamine N-methyltransferase (PEMT), the enzyme responsible for phosphatidylcholine biosynthesis in liver and whose expression is blocked by C1P, attenuates obesity-associated inflammation. This occurs by decreasing both, the number of classically activated M1 proinflammatory macrophages and pro-inflammatory cytokine levels in adipose tissue. Moreover, we also demonstrate that PEMT over expression induces macrophage migration, an action that requires the activation of PI3K/Akt1/mTOR pathway. These findings may help to develop new therapeutic strategies for the treatment of obesity and obesity-related diseases.