Effects of Maresin 1, an omega-3 fatty acid-derived lipid mediator, on adipose tissue and liver function in obesity
Materias Investigacion::Ciencias de la Salud::Nutrición y dietética
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LAIGLESIA, Laura María. “Effects of Maresin 1, an omega-3 fatty acid-derived lipid mediator, on adipose tissue and liver function in obesity”. Moreno-Aliaga, M.J. y Lorente-Cebrian, S. (dir.). Tesis doctoral. Universidad de Navarra, Pamplona, 2017.
This research demonstrated the ability of the n-3 PUFA EPA to increase mitochondrial content, and to activate master regulators of mitochondrial biogenesis and to promote the expression of genes that typify beige adipocytes in cultured fully differentiated human subcutaneous adipocytes from overweight subjects. Moreover, EPA up-regulated genes involved in fatty acid oxidation while down-regulated lipogenic genes. These data suggest that EPA promotes a remodelling of adipocyte metabolism which could be in part responsible for EPA beneficial effects in obesity. Moreover, this research revealed for the first time that MaR1 inhibits TNF-a-induced lipolysis. This effect seems to be associated to MaR1 ability to prevent the reduction of perilipin and ATGL-inhibitor G0S2 protein expression induced by the cytokine. MaR1 also reversed the decrease on total hormone sensitive lipase (total HSL), and the ratio of phosphoHSL at Ser-565/total HSL, while preventing the increased ratio of phosphoHSL at Ser-660/total HSL as well as the phosphorylation of ERK1/2 induced by TNF-a. Moreover, MaR1 counteracted the cytokine-induced decrease of p62 protein content, and also prevented the induction of LC3II/LC3I ratio. These data point out that MaR1 ameliorate TNF-a-induced alterations on lipolysis and autophagy in adipocytes, which may contribute to the beneficial actions of MaR1 on adipose tissue inflammation and insulin sensitivity. The current study also demonstrated that MaR1 reverses obesity-related liver steatosis in two different models of obesity (ob/ob and diet-induced obese (DIO) mice) and characterized the mechanisms involved. Remarkably, oral gavage of MaR1 decreased serum transaminases, reduced liver weight and TG content. MaR1-treated mice exhibited reduced hepatic lipogenic enzymes content (FAS) or activation (by phosphorylation of ACC), accompanied by upregulation of genes involved in fatty acid oxidation (Cpt1a and Acox1) and autophagy (Atg 5 and Atg7), along with increased number of autophagic vacuoles and reduced p62 protein levels. MaR1 also induced AMPK phosphorylation in DIO mice and in primary hepatocytes, and preincubation of hepatocytes with the AMPK inhibitor Compound C reversed MaR1 effects on Cpt1a, Acox1, Atg5 and Atg7 expression, suggesting the implication of AMPK in MaR1 actions. The present study also reported that MaR1 treatment by oral gavage to DIO mice increased brown adipose tissue (BAT) UCP1 levels and upregulated other thermogenic-related genes along with an increase in the mRNA levels of glucose transporters and fatty acid oxidation-related genes. Indeed, in cultured brown adipocytes MaR1 also promoted glucose uptake and fatty acid utilization, in parallel with the upregulation of thermogenic genes and oxygen consumption rates. Interestingly, microPET studies with 18F-FDG revealed that acute treatment with MaR1 potentiates cold-induced BAT activation in mice. Furthermore, MaR1 induced beige adipocyte markers (Ucp1, Pgc-1a, Tmem26 and Tbx1) in subcutaneous white adipose tissue (WAT) of DIO mice as well as in human mesenchymal cells (hMSC)-derived adipocytes treated with MaR1 along the differentiation process. The fact that this effect was not observed when MaR1 treatment was tested on mature adipocytes, point toward that MaR1 exerts its browning effect via recruiting brite adipocytes and not by promoting transdifferentiation from mature white to beige adipocytes. Nevertheless, mature white adipocytes treated acutely with MaR1 exhibited higher fatty acid oxidation rates. These data reveal MaR1 as a novel agent able to promote BAT activation and WAT browning, which could also contribute to its insulin-sensitizing properties in obesity. In summary, the outcomes of the current project regarding the metabolic actions of MaR1 have uncover that MaR1 might constitutes a novel therapeutic candidate to tackle obesity comorbidities such as insulin resistance, type 2 diabetes and non-alcoholic fatty liver disease.

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