Effects of Maresin 1 (MaR1) on Colonic Inflammation and Gut Dysbiosis in Diet-Induced Obese Mice

The aim of this study was to characterize the effects of Maresin 1 (MaR1), a DHA-derived pro-resolving lipid mediator, on obesity-related colonic inflammation and gut dysbiosis in diet-induced obese (DIO) mice. In colonic mucosa of DIO mice, the MaR1 treatment decreased the expression of inflammatory genes, such as Tnf-α and Il-1β. As expected, the DIO mice exhibited significant changes in gut microbiota composition at the phylum, genus, and species levels, with a trend to a higher Firmicutes/Bacteroidetes ratio. Deferribacteres and Synergistetes also increased in the DIO animals. In contrast, these animals exhibited a significant decrease in the content of Cyanobacteria and Actinobacteria. Treatment with MaR1 was not able to reverse the dysbiosis caused by obesity on the most abundant phyla. However, the MaR1 treatment increased the content of P. xylanivorans, which have been considered to be a promising probiotic with healthy effects on gut inflammation. Finally, a positive association was found between the Deferribacteres and Il-1β expression, suggesting that the increase in Deferribacteres observed in obesity could contribute to the overexpression of inflammatory cytokines in the colonic mucosa. In conclusion, MaR1 administration ameliorates the inflammatory state in the colonic mucosa and partially compensates changes on gut microbiota caused by obesity

Effects of Maresin 1 (MaR1) on Colonic Inflammation and Gut Dysbiosis in Diet-Induced Obese Mice

The aim of this study was to characterize the effects of Maresin 1 (MaR1), a DHA-derived pro-resolving lipid mediator, on obesity-related colonic inflammation and gut dysbiosis in diet-induced obese (DIO) mice. In colonic mucosa of DIO mice, the MaR1 treatment decreased the expression of inflammatory genes, such as Tnf-α and Il-1β. As expected, the DIO mice exhibited significant changes in gut microbiota composition at the phylum, genus, and species levels, with a trend to a higher Firmicutes/Bacteroidetes ratio. Deferribacteres and Synergistetes also increased in the DIO animals. In contrast, these animals exhibited a significant decrease in the content of Cyanobacteria and Actinobacteria. Treatment with MaR1 was not able to reverse the dysbiosis caused by obesity on the most abundant phyla. However, the MaR1 treatment increased the content of P. xylanivorans, which have been considered to be a promising probiotic with healthy effects on gut inflammation. Finally, a positive association was found between the Deferribacteres and Il-1β expression, suggesting that the increase in Deferribacteres observed in obesity could contribute to the overexpression of inflammatory cytokines in the colonic mucosa. In conclusion, MaR1 administration ameliorates the inflammatory state in the colonic mucosa and partially compensates changes on gut microbiota caused by obesity

Maresin 1 activates brown adipose tissue and promotes browning of white adipose tissue in mice

Objective: Maresin 1 (MaR1) is a docosahexaenoic acid-derived proresolving lipid mediator with insulin-sensitizing and anti-steatosis properties. Here, we aim to unravel MaR1 actions on brown adipose tissue (BAT) activation and white adipose tissue (WAT) browning. Methods: MaR1 actions were tested in cultured murine brown adipocytes and in human mesenchymal stem cells (hMSC)-derived adipocytes. In vivo effects of MaR1 were tested in diet-induced obese (DIO) mice and lean WT and Il6 knockout (Il6 / ) mice. Results: In cultured differentiated murine brown adipocytes, MaR1 reduces the expression of inflammatory genes, while stimulates glucose uptake, fatty acid utilization and oxygen consumption rate, along with the upregulation of mitochondrial mass and genes involved in mitochondrial biogenesis and function and the thermogenic program. In Leucine Rich Repeat Containing G Protein-Coupled Receptor 6 (LGR6)-depleted brown adipocytes using siRNA, the stimulatory effect of MaR1 on thermogenic genes was abrogated. In DIO mice, MaR1 promotes BAT remodeling, characterized by higher expression of genes encoding for master regulators of mitochondrial biogenesis and function and iBAT thermogenic activation, together with increased M2 macrophage markers. In addition, MaR1-treated DIO mice exhibit a better response to cold-induced BAT activation. Moreover, MaR1 induces a beige adipocyte signature in inguinal WAT of DIO mice and in hMSC-derived adipocytes. MaR1 potentiates Il6 expression in brown adipocytes and BAT of cold exposed lean WT mice. Interestingly, the thermogenic properties of MaR1 were abrogated in Il6 / mice. Conclusions: These data reveal MaR1 as a novel agent that promotes BAT activation and WAT browning by regulating thermogenic program in adipocytes and M2 polarization of macrophages. Moreover, our data suggest that LGR6 receptor is mediating MaR1 actions on brown adipocytes, and that IL-6 is required for the thermogenic effects of MaR1