Effects of maresin 1 on adipose tissue inflammation and insulin resistance on obesitycharacterization of mechanisms involved

Resum

The present study aimed to evaluate the ability of Maresin 1 (MaR1) to reverse white adipose tissue (WAT) inflammation and insulin resistance in murine models of obesity as well as to further investigate the mechanisms involved in such effects. Moreover, MaR1 ability to modulate the expression/production of bioactive peptides in key metabolic tissues (WAT, skeletal muscle and liver) was also examined. MaR1 ameliorated WAT inflammation in two different models of obesity, diet-induced (DIO) and genetic (ob/ob) obese mice, which was associated with insulin-sensitizing effects. In DIO mice, MaR1 (2 µg/kg, i.p.; 10 days) reduced F4/80 positive cells in WAT and the proinflammatory M1 macrophage phenotype marker Cd11c expression. Moreover, MaR1 decreased Mcp-1, Tnf-α and Il-1ß expression along with the up-regulation of adiponectin and Glut-4, and the increase of Akt phosphorylation in WAT. In ob/ob mice MaR1 administration (2 µg/kg, i.p.; 20 days) did not modify macrophage recruitment but increased the M2 macrophage markers Cd163 and Il-10. Besides, MaR1 reduced Mcp-1, Tnf-α, Il-1ß and Dpp-4 and increased adiponectin gene expression in WAT. MaR1 treatment also improved the insulin tolerance test of ob/ob mice and increased Akt and AMPK phosphorylation in WAT. This proresolving lipid mediator also prevented the inhibitory effect of the proinflammatory cytokine TNF-α on insulin-stimulated glucose uptake and Akt phosphorylation in cultured human adipocytes from overweight/obese subjects. In addition, acute treatment with MaR1 (50 µg/kg, 3 h, i.p.) induced Akt phosphorylation in WAT and skeletal muscle of lean mice. Interestingly, intragastric chronic administration of MaR1 (50 µg/kg, 10 days) to DIO mice reduced the hyperglycemia induced by the high fat diet (HFD) and improved systemic insulin sensitivity. In parallel, MaR1 partially restored the impaired insulin response in skeletal muscle of DIO mice. Additionally, MaR1 reversed HFD-induced lower Akt phosphorylation in WAT in no insulin-stimulated DIO mice while did not restore the defective Akt activation in response to acute insulin observed in DIO mice. In summary, our results suggest that MaR1 attenuates the impaired insulin signaling and glucose uptake induced by proinflammatory cytokines. Furthermore, MaR1 (50 µg/ kg, 10 days intragastrically) modulated the production of bioactive proteins in human adipocytes as well as in WAT, skeletal muscle and liver of DIO mice. In cultured human adipocytes from overweight/obese subjects, MaR1 upregulated the expression of ADIPOQ, LEPTIN, DPP-4, CT-1 and FNDC5. Moreover, MaR1 counteracted the TNF-α-induced decrease of adiponectin as well as the upregulation of DPP-4, CT-1 and FNDC5 mRNA expression. Moreover, MaR1-treated DIO mice exhibited increased expression of adiponectin and Ct-1 in eWAT, and of Fndc5 and Ct-1 in muscle, while decreasing expression of hepatic Dpp-4. Additionally, in these mice MaR1 reduced circulating FGF21 levels in parallel with a decrease of HFD-induced hepatic Fgf21 mRNA expression. MaR1 also increased hepatic ß-Klotho and skeletal muscle Fgfr1 expression and counteracted the HFD-induced fall in the expression of both receptor components in WAT. In vitro experiments showed that MaR1 decreased Fgf21 expression in mouse primary hepatocytes in a concentration-dependent manner, in parallel with a downregulation in PPARα mRNA levels. Preincubation with the AMPK inhibitor, Compound C, and the PI3K inhibitor, LY294002, did not modify the inhibitory effect of MaR1 on Fgf21, suggesting that neither AMPK nor PI3K/AKT pathways are involved in MaR1 effects on FGF21. In summary, the outcomes of the current project have uncovered that MaR1 might constitute a novel therapeutic candidate to tackle obesity-associated inflammation and comorbidities such as insulin resistance and T2DM, in part through the regulation of the production of key metabolic adipokines and hepatokines.