Aging is a complex phenomenon characterized by the progressive loss of tissue and organ function. The oxidative-stress theory of aging postulates that age-associated functional losses are due to the accumulation of ROS-induced damage. Liver function impairment and non-alcoholic fatty liver disease (NAFLD) are common among the elderly. NAFLD can progress to non-alcoholic steatohepatitis (NASH) and evolve to hepatic cirrhosis or hepatic carcinoma. Oxidative stress, lipotoxicity, and inflammation play a key role in the progression of NAFLD. A growing body of evidence supports the therapeutic potential of omega-3 polyunsaturated fatty acids (n-3 PUFA), mainly docosahaexenoic (DHA) and eicosapentaenoic acid (EPA), on metabolic diseases based on their antioxidant and anti-inflammatory properties. Here, we performed a systematic review of clinical trials analyzing the efficacy of n-3 PUFA on both systemic oxidative stress and on NAFLD/NASH features in adults. As a matter of fact, it remains controversial whether n-3 PUFA are effective to counteract oxidative stress. On the other hand, data suggest that n-3 PUFA supplementation may be effective in the early stages of NAFLD, but not in patients with more severe NAFLD or NASH. Future perspectives and relevant aspects that should be considered when planning new randomized controlled trials are also discussed.

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The beneficial actions of n-3 fatty acids on obesity-induced insulin resistance and inflammation have been related to the synthesis of specialized proresolving lipid mediators (SPMs) like resolvins. The aim of this study was to evaluate the ability of one of these SPMs, maresin 1 (MaR1), to reverse adipose tissue inflammation and/or insulin resistance in two models of obesity: diet-induced obese (DIO) mice and genetic ( obese mice. In DIO mice, MaR1 (2 μg/kg; 10 d) reduced F4/80-positive cells and expression of the proinflammatory M1 macrophage phenotype marker in white adipose tissue (WAT). Moreover, MaR1 decreased, and expression, upregulated adiponectin and, and increased Akt phosphorylation in WAT. MaR1 administration (2 μg/kg; 20 d) to mice did not modify macrophage recruitment but increased the M2 macrophage markers and MaR1 reduced, ,, and and increased adiponectin gene expression in WAT. MaR1 treatment also improved the insulin tolerance test of mice and increased Akt and AMPK phosphorylation in WAT. These data suggest that treatment with MaR1 can counteract the dysfunctional inflamed WAT and could be useful to improve insulin sensitivity in murine models of obesity.-Martínez-Fernández, L., González-Muniesa, P., Laiglesia, L. M., Sáinz, N., Prieto-Hontoria, P. L., Escoté, X., Odriozola, L., Corrales, F. J., Arbones-Mainar, J. M., Martínez, J. A., Moreno-Aliaga, M. J. Maresin 1 improves insulin sensitivity and attenuates adipose tissue inflammation in and diet-induced obese mice.

MaR1 ameliorates liver steatosis by decreasing lipogenic enzymes, while inducing fatty acid oxidation genes and autophagy, which could be related to AMPK activation. Thus, MaR1 may be a new therapeutic candidate for reducing fatty liver in obesity.

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ScopeTo study the effects of Maresin 1 (MaR1), a docosahexaenoic‐acid‐derived lipid mediator, on fibroblast growth factor 21 (FGF21) production and to characterize the tissue‐specific regulation of Fgf21 and its signaling pathway in liver, skeletal muscle, and white adipose tissue (WAT).Methods and resultsDiet‐induced obese (DIO) mice are treated with MaR1 (50 µg kg−1, 10 days, oral gavage) and serum FGF21 levels and liver, muscle and WAT Fgf21, β‐Klotho, Fgfr1, Egr1, and cFos mRNA expression are evaluated. Additionally, MaR1 effects are tested in mouse primary hepatocytes, HepG2 human hepatocytes, C2C12 myotubes, and 3T3‐L1 adipocytes. In DIO mice, MaR1 decreases circulating FGF21 levels and HFD‐induced hepatic Fgf21 mRNA expression. MaR1 increases hepatic β‐Klotho, Egr1, and cFos in DIO mice. In WAT, MaR1 counteracts the HFD‐induced downregulation of Fgf21, Fgfr1, and β‐Klotho. In muscle, MaR1 does not modify Fgf21 but promoted Fgfr1 expression. In mouse primary hepatocytes, MaR1 decreases Fgf21 expression and downregulated Pparα mRNA levels. In HepG2 cells, MaR1 reverses the increased production of FGF21 and the downregulation of FGFR1, Β‐KLOTHO, EGR1, and cFOS induced by palmitate. Preincubation with a PPARα antagonist prevents MaR1 effects on FGF21 secretion.ConclusionThe ability of MaR1 to modulate FGF21 can contribute to its beneficial metabolic effects.

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Scope: Omega-3 fatty acids (FAs) from oily fish reduce cardiovascular disease. This may be partly due to modulation of endothelial cell (EC) inflammation. Fish stocks are declining and there is a need for sustainable alternative FAs. Gamma-linolenic acid (GLA) and pinolenic acid (PLA) are plant-derived FAs, which can fulfil this role. Methods and results: EA.hy926 cells are exposed GLA and PLA prior to stimulation with tumor necrosis factor (TNF)-. GLA and PLA are incorporated into ECs, resulting in increases in long-chain derivatives produced by elongase 5, dihomo-gamma-linolenic acid (DGLA), and eicosatrienoic acid (ETA). Both GLA and PLA (50 µm) decrease production of soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemoattractant protein 1 (MCP-1), and regulated on activation, normal T cell expressed and secreted (RANTES). However, decreases in these mediators are not seen after pre-treatment with GLA or PLA in elongase 5 silenced EA.hy926 cells. DGLA and ETA (10 µm) decrease EC production of sICAM-1, MCP-1, RANTES, and IL-6. All FAs reduce adhesion of THP-1 monocytes to EA.hy926 cells. Both PLA (50 µm) and ETA (10 µm) decrease NF Bp65 phosphorylation. Conclusion: These effects suggest potential for GLA, PLA and their long-chain derivatives, DGLA and ETA, as sustainable anti-inflammatory alternatives to fish-derived FAs.