Maresin 1 Exerts a Tissue-Specific Regulation of Adipo-Hepato-Myokines in Diet-Induced Obese Mice and Modulates Adipokine Expression in Cultured Human Adipocytes in Basal and Inflammatory Conditions.

ABSTRACT

This study analyses the effects of Maresin 1 (MaR1), a docosahexaenoic acid (DHA)-derived specialized proresolving lipid mediator with anti-inflammatory and insulin-sensitizing actions, on the expression of adipokines, including adiponectin, leptin, dipeptidyl peptidase 4 (DPP-4), cardiotrophin-1 (CT-1), and irisin (FNDC5), both in vitro and in in vivo models of obesity. The in vivo effects of MaR1 (50 µg/kg, 10 days, oral gavage) were evaluated in epididymal adipose tissue (eWAT), liver and muscle of diet-induced obese (DIO) mice. Moreover, two models of human differentiated primary adipocytes were incubated with MaR1 (1 and 10 nM, 24 h) or with a combination of tumor necrosis factor-α (TNF-α, 100 ng/mL) and MaR1 (1-200 nM, 24 h) and the expression and secretion of adipokines were measured in both models. MaR1-treated DIO mice exhibited an increased expression of adiponectin and Ct-1 in eWAT, increased expression of Fndc5 and Ct-1 in muscle and a decreased expression of hepatic Dpp-4. In human differentiated adipocytes, MaR1 increased the expression of ADIPONECTIN, LEPTIN, DPP4, CT-1 and FNDC5. Moreover, MaR1 counteracted the downregulation of ADIPONECTIN and the upregulation of DPP-4 and LEPTIN observed in adipocytes treated with TNF-α. Differential effects for TNF-α and MaR1 on the expression of CT-1 and FNDC5 were observed between both models of human adipocytes. In conclusion, MaR1 reverses the expression of specific adipomyokines and hepatokines altered in obese mice in a tissue-dependent manner. Moreover, MaR1 regulates the basal expression of adipokines in human adipocytes and counteracts the alterations of adipokines expression induced by TNF-α in vitro. These actions could contribute to the metabolic benefits of this lipid mediator.