Laura M. Laiglesia

Universidad de Navarra

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María J. Moreno‐Aliaga

Instituto de Salud Carlos III

J. Alfredo Martínéz

Universidad de Navarra

Neira Sáinź

Universidad de Navarra

Leyre Martínez‐Fernández

Universidad de Navarra

Silvia Lorente‐Cebrián

Centro de Investigación y Tecnología Agroalimentaria de Aragón

Xavier Escoté

Technological Center of Nutrition and Health

ÁM

Ángela M. Valverde

Universidad Autónoma de Madrid

Marta Fernández‐Galilea

Universidad de Navarra

José M. Arbones-Mainar

Instituto de Investigación Sanitaria Aragón

Miguel Lópeź‐Yoldi

Universidad de Navarra

Cooperative Institutions

Instituto de Salud Carlos III

Universidad de Navarra

Centro de Investigación Biomédica en Red

Navarre Institute of Health Research

Universidad Autónoma de Madrid

Consejo Superior de Investigaciones Científicas

Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas

Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

Clinica Universidad de Navarra

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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

Biomolecules (2023)

Leyre Martínez‐Fernández Miguel Burgos Neira Sáinź Laura M. Laiglesia José M. Arbones-Mainar

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.

Myokine

Basal (medicine)

Proinflammatory cytokine

10.3390/biom13060919

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Maresin 1 improves insulin sensitivity and attenuates adipose tissue inflammation in ob/ob and diet‐induced obese mice

The FASEB Journal (2017)

Leyre Martínez‐Fernández Pedro González‐Muniesa Laura M. Laiglesia Neira Sáinź Pedro L. Prieto‐Hontoria

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 (ob/ob) obese mice. In DIO mice, MaR1 (2 mg/kg; 10 d) reduced F4/80-positive cells and expression of the proinflammatory M1 macrophage phenotype marker Cd11c in white adipose tissue (WAT). Moreover, MaR1 decreased Mcp-1, Tnf-a, and Il-1b expression, upregulated adiponectin and Glut-4, and increased Akt phosphorylation in WAT. MaR1 administration (2 mg/kg; 20 d) to ob/ob mice did not modify macrophage recruitment but increased the M2 macrophage markers Cd163 and Il-10. MaR1 reduced Mcp-1, Tnf-a, Il-1b, 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. 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 ob/ob and diet-induced obese mice. FASEB J. 31, 2135–2145 (2017). www.fasebj.org

Proinflammatory cytokine

10.1096/fj.201600859r

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Dual role of protein tyrosine phosphatase 1B in the progression and reversion of non-alcoholic steatohepatitis

Molecular Metabolism (2017)

Águeda González‐Rodríguez M. Pilar Valdecantos Patricia Rada Annalisa Addante Inés Barahona

Non-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).NASH 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.PTP1BWT 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.PTP1B elicits a dual role in NASH progression and reversion. Additionally, our results support a new role for PTP1B in oval cell proliferation during NAFLD.

Steatohepatitis

10.1016/j.molmet.2017.10.008

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Citations (27)

Maresin 1 inhibits TNF‐alpha‐induced lipolysis and autophagy in 3T3‐L1 adipocytes

Journal of Cellular Physiology (2017)

Laura M. Laiglesia Silvia Lorente‐Cebrián Miguel Lópeź‐Yoldi Raquel Lanas Neira Sáinź

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.

Perilipin

Lipid droplet

3T3-L1

Proinflammatory cytokine

10.1002/jcp.26096

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Maresin 1 Regulates Hepatic FGF21 in Diet‐Induced Obese Mice and in Cultured Hepatocytes

Molecular Nutrition & Food Research (2019)

Leticia Martínez-Fernández Pedro González‐Muniesa Neira Sáinź Laura M. Laiglesia Xavier Escoté

Scope To 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 results Diet‐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. Conclusion The ability of MaR1 to modulate FGF21 can contribute to its beneficial metabolic effects.

FGF21

10.1002/mnfr.201900358

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Maresin 1 activates brown adipocytes metabolism

Laura M. Laiglesia Xavier Escoté Ángela M. Valverde María J. Moreno‐Aliaga

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Omega-3 fatty acids and adipose tissue function in obesity and metabolic syndrome

Prostaglandins & Other Lipid Mediators (2015)

Leyre Martínez‐Fernández Laura M. Laiglesia Ana E. Huerta J. Alfredo Martínéz María J. Moreno‐Aliaga