No abstract

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.

Inflammation is involved in the pathophysiology of many chronic diseases, such as rheumatoid arthritis and neurodegenerative diseases. Several studies have evidenced important anti-inflammatory and immunomodulatory properties of omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs). This review illustrates current knowledge about the efficacy of n-3 LC-PUFAs (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), particularly) in preventing and/or treating several chronic inflammatory conditions (inflammatory bowel diseases and rheumatoid arthritis) as well as their potential benefits on neurodegenerative diseases. It is well established that n-3 LC-PUFAs are substrates for synthesis of novel series of lipid mediators (e.g., resolvins, protectins, and maresins) with potent anti-inflammatory and pro-resolving properties, which have been proposed to partly mediate the protective and beneficial actions of n-3 LC-PUFAs. Here, we briefly summarize current knowledge from preclinical studies analyzing the actions of EPA- and DHA-derived resolvins and protectins on pathophysiological models of rheumatoid arthritis, Alzheimer, and irritable bowel syndrome.

No abstract

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.

This article is available online at http://www.jlr.org effects by interacting with the glycoprotein 130 (gp130)/ leukemia inhibitory factor receptor heterodimer ( 1 ). Adipose tissue has been identifi ed as a source of CT-1 ( 2 ), and this cytokine is capable of activating major signaling pathways involved in metabolic control in adipocytes ( 3 ). Moreover, it has been reported that CT-1 levels are raised in obesity and metabolic syndrome ( 2 ), suggesting that CT-1 could be a new marker for obesity and related diseases. A recent study by our group has revealed that CT-1 is a key regulator of energy homeostasis, as well as of glucose and lipid metabolism ( 4 ). Thus, chronic recombinant CT-1 (rCT-1) treatment reduced body weight and corrected insulin resistance in ob/ob and high-fat-fed obese mice by reducing food intake and enhancing energy expenditure. Moreover, rCT-1 induced dramatic white adipose tissue remodeling characterized by the upregulation of genes implicated in the control of fatty acid oxidation, mitochondrial biogenesis, and lipolysis. In this context, it has been reported that adipocytes from rCT-1-treated mice exhibited an increased lipolytic response to isoproterenol, while adipocytes from old obese CT-1 -null mice responded poorly to isoproterenol, suggesting that CT-1 might play a role in the regulation of lipolysis ( 4 ). However, the mechanism underlying the lipolytic action of CT-1 still remains unknown.During lipolysis, intracellular triacylglycerol (TAG) is hydrolyzed through the consecutive action of three major lipases: adipose triglyceride lipase (ATGL/desnutrin), Abbreviations: AdPLA , adipocyte phospholipase A2; AICAR, aminoimidazole carboxamide ribonucleotide; ATGL, adipose triglyceride lipase (desnutrin); CGI-58, comparative gene identifi cation-58; cGMP, cyclic guanosine monophosphate; CT-1, cardiotrophin-1; DAG, diacylglycerol; Gi, inhibitory guanine nucleotide binding protein; gp130, glycoprotein 130; Gs, stimulatory guanine nucleotide binding protein; G0S2, G0/G1 switch gene 2; HPTLC, high-performance TLC; HSL, hormone sensitive lipase; IL, interleukin; MAG, monoacylglycerol; PDE3B, phosphodiesterase 3B; PK, protein kinase; rCT-1, recombinant cardiotrophin-1; TAG, triacylglycerol. 1 M. Bustos and M. J. Moreno-Aliaga contributed equally to the work.

ObjectivesNon-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. Protein tyrosine phosphatase 1B (PTP1B), a negative modulator of insulin and cytokine signaling, is a therapeutic target for type 2 diabetes and obesity. We investigated the impact of PTP1B deficiency during NAFLD, particularly in non-alcoholic steatohepatitis (NASH).MethodsNASH features were evaluated in livers from wild-type (PTP1BWT) and PTP1B-deficient (PTP1BKO) mice fed methionine/choline-deficient diet (MCD) for 8 weeks. A recovery model was established by replacing MCD to chow diet (CHD) for 2–7 days. Non-parenchymal liver cells (NPCs) were analyzed by flow cytometry. Oval cells markers were measured in human and mouse livers with NASH, and in oval cells from PTP1BWT and PTP1BKO mice.ResultsPTP1BWT mice fed MCD for 8 weeks exhibited NASH, NPCs infiltration, and elevated Fgf21, Il6 and Il1b mRNAs. These parameters decreased after switching to CHD. PTP1B deficiency accelerated MCD-induced NASH. Conversely, after switching to CHD, PTP1BKO mice rapidly reverted NASH compared to PTP1BWT mice in parallel to the normalization of serum triglycerides (TG) levels. Among NPCs, a drop in cytotoxic natural killer T (NKT) subpopulation was detected in PTP1BKO livers during recovery, and in these conditions M2 macrophage markers were up-regulated. Oval cells markers (EpCAM and cytokeratin 19) significantly increased during NASH only in PTP1B-deficient livers. HGF-mediated signaling and proliferative capacity were enhanced in PTP1BKO oval cells. In NASH patients, oval cells markers were also elevated.ConclusionsPTP1B elicits a dual role in NASH progression and reversion. Additionally, our results support a new role for PTP1B in oval cell proliferation during NAFLD.

Obesity is associated with high levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), which promotes inflammation in adipose tissue. The omega-3 PUFAs, and their derived lipid mediators, such as Maresin 1 (MaR1) have anti-inflammatory effects on adipose tissue. This study aimed to analyze if MaR1 may counteract alterations induced by TNF-α on lipolysis and autophagy in mature 3T3-L1 adipocytes. Our data revealed that MaR1 (1-100 nM) inhibited the TNF-α-induced glycerol release after 48 hr, which may be related to MaR1 ability of preventing the decrease in lipid droplet-coating protein perilipin and G0/G1 Switch 2 protein expression. MaR1 also reversed the decrease in 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 and phosphorylation of extracellular signal-regulated kinase 1/2 induced by TNF-α. Moreover, MaR1 counteracted the cytokine-induced decrease of p62 protein, a key autophagy indicator, and also prevented the induction of LC3II/LC3I, an important autophagosome formation marker. Current data suggest that MaR1 may ameliorate TNF-α-induced alterations on lipolysis and autophagy in adipocytes. This may also contribute to the beneficial actions of MaR1 on adipose tissue and insulin sensitivity in obesity.