Effects of Maresin 1, an omega-3 fatty acid-derived lipid mediator, on adipose tissue and liver function in obesity
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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.
The present study aimed to determine the potential ability of EPA to remodel metabolism and phenotype of human subcutaneous adipocytes, as well as to characterize the ability of MaR1 to counteract inflammation-induced adipocyte disorders and to elucidate MaR1 actions on brown/beige adipose tissue and liver function in animal models of obesity and in culture cells. 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 was able to inhibit TNF-α-induced lipolysis. This effect seems to be associated to MaR1 ability to prevent the reduction of lipid droplet-coating protein 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-α. Moreover, MaR1 counteracted the cytokine-induced decrease of p62 protein content, a key autophagy indicator, and also prevented the induction of LC3II/LC3I ratio, an important autophagosome formation marker. These data point out that MaR1 might ameliorate TNF-α-induced alterations on lipolysis and autophagy in adipocytes, which could also contribute to the beneficial actions of MaR1 on adipose tissue inflammation and insulin sensitivity. Furthermore, the current study also demonstrated the beneficial effects of MaR1 in reversing obesity-related liver steatosis in two different models of obesity (ob/ob and diet-induced obese (DIO) mice) and characterized the mechanisms involved. Interestingly, in ob/ob mice, MaR1 (2-10 μg/kg i.p., 20 days) reduced liver triglycerides content, FAS and SCD-1, while increased ACC phosphorylation and LC3II protein expression, in parallel with a drop in p62 levels. Similar effects on hepatic TG, ACC phosphorylation, p62 and LC3II were observed in DIO mice after MaR1 i.p. injection (2 μg/kg i.p., 10 days). Interestingly, oral gavage of MaR1 (50 μg/kg, 10 days) also 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 (50 μg/kg, 10 days) to DIO mice increased brown adipose tissue (BAT) UCP1 levels and upregulated other thermogenic-related genes such as Pgc-1α, Prdm16 and Dio2, along with an increase in the mRNA levels of glucose transporters and fatty acid oxidation-related genes. In this line, in cultured brown adipocytes MaR1 also promoted glucose uptake and fatty acid utilization, in parallel with the upregulation of thermogenic genes and oxygen consumption rate. 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-1α, 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 hMSC-derived 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 rate. 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 nonalcoholic fatty liver disease.

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