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

Martínez-Fernández, Leyre; González‐Muniesa, Pedro; Laiglesia, Laura M.; Sáinz, Neira; Prieto-Hontoria, Pedro L.; Escoté, Xavier; Odriozola, Leticia; Corrales, Fernando J.; Arbonés-Mainar, José M.; Martínéz, J. Alfredo; Moreno-Aliaga, María J.

doi:10.1096/fj.201600859r

Cited by 82 publications

(61 citation statements)

References 49 publications

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“…In our model of obese mice, GLUT12 and GLUT4 did not respond to insulin. In the same animals, previous studies of our group showed increased levels of serum leptin together with a decrease on the ratio serum adiponectin/amount of fat, and increase on TNF‐α mRNA in epididymal adipose tissue . Other authors found reduction of AMPK phosphorylation and oxygen levels in obesity .…”

Section: Discussionsupporting

confidence: 70%

“…Here, we show that GLUT12 and GLUT4 protein expression, as well as AKT phosphorylation, were diminished in visceral adipose tissue from obese mice. In the same animals, decrease of GLUT4 mRNA and p‐AKT was also found in epidydimal adipose tissue . The reduction of GLUT12 and GLUT4 was confirmed in visceral (omental) adipose tissue from obese subjects.…”

Section: Discussionsupporting

confidence: 54%

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GLUT12 and adipose tissue: Expression, regulation and its relation with obesity in mice

et al. 2019

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Aim:The facilitative glucose transporter GLUT12 was isolated from the breast cancer cell line MCF-7 by its homology with GLUT4. GLUT12 is expressed in insulin-sensitive tissues such as adipose tissue. The aim of this work was to investigate GLUT12 expression and hormonal regulation in 3T3-L1 adipocytes and in adipose tissue of lean and diet-induced obese mice. Methods: Uptake studies were performed using radio-labelled sugars; α-methyld-glucose (αMG) was used as specific substrate of GLUT12. Expression and localization of GLUT12 in adipocytes were investigated by western blot and immunohistochemical methods. Results: GLUT12 is expressed in the peri-nuclear region of mouse adipocytes.Insulin, by AKT activation, and TNF-α, by AMPK activation, increase αMG uptake by inducing GLUT12 translocation to the membrane. In contrast, leptin and adiponectin decrease GLUT12 activity through its internalization. Under hypoxia conditions GLUT12 expression is upregulated. The response of GLUT12 to TNF-α, leptin, adiponectin and hypoxia is the opposite to that of GLUT4. In diet-induced obese mice and obese subjects, GLUT12 protein is decreased. Intraperitoneal injection of insulin increases AKT phosphorylation and GLUT12 expression, but this effect is lost in obese animals. Conclusion: We hypothesize that GLUT12 would contribute to modulate sugar absorption in physiological and pathophysiological situations such as obesity.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionsupporting

confidence: 54%

GLUT12 and adipose tissue: Expression, regulation and its relation with obesity in mice

et al. 2019

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“…A model based on the structure of RORα and MaR1 suggested that MaR1 fit well in the ligand binding pocket of RORα through interaction with Arg370, Tyr290, and Val364, which was comparable to the binding pattern of cholesterol sulfate to RORα (Figure 4, C and D) (28). To show the importance of these interactions, 2 RORα mutants, C288L and A330L, were examined with respect to their responsiveness to the (20,21). Moreover, M2 macrophages increase the biosynthesis of specific SPMs such as MaR1 (22).…”

Section: Introductionmentioning

confidence: 94%

A maresin 1/RORα/12-lipoxygenase autoregulatory circuit prevents inflammation and progression of nonalcoholic steatohepatitis

Han

Shin

Kim

et al. 2019

Journal of Clinical Investigation

114

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Figure 6. RORα activates Alox12-dependent MaR1 synthesis. (A) Seven-week-old C57BL/6 mice were fed with either LFD or HFD for 12 weeks (n = 4) or fed with MCS or MCD for 4 weeks (n = 5) (first and second panels). The LFD-fed C57BL/6 mice were treated with 5 mg/kg BW SR1078 for 5 days (n = 5) (third panel). Seven-week-old LFD-fed floxed and RORα-MKO mice were sacrificed (n = 11) (fourth panel). (B) Liver samples were obtained from the floxed and RORα-MKO mice those described in Supplemental Figure 1 (n = 5). Levels of MaR1 and RvD1 in liver tissues were measured. *P < 0.05 and **P < 0.01; ## P < 0.01 for A and B. (C) DHA-treated peritoneal macrophages (PM) and Raw 264.7 cells were treated with 5 μM SR1078 for 24 hours, or the cells were infected by lenti-shGFP or lenti-shRORα for 48 hours. Intracellular amount of MaR1 were measured. *P < 0.05 (n = 3). (D) A scheme for biosynthesis of MaR1 by LOX family. (E) Expression levels of 12-LOX protein (Alox12 mRNA) and 12/15-LOX protein (Alox15 mRNA) in liver macrophages (LM), PM, Raw 264.7, bone marrow-derived macrophages (BMDM), and hepatocytes were measured by Western blotting and qRT-PCR. (F) mRNA levels of Alox genes in the isolated LMs from floxed and RORα-MKO mice as shown in A were measured by qRT-PCR. (G) LMs were treated with SR1078 or MaR1 (left). LMs were infected by AAV-GFP/AAV-RORα or lenti-shGFP/lenti-shRORα as indicated (right). The mRNA levels of Alox12 were measured by qRT-PCR. *P < 0.05 (n = 3) for F and G. (H) Schematic representation of the mouse Alox12 promoter with the putative ROREs shown as red boxes (top). Raw 264.7 cells were transfected with the deleted Alox12 promoter-Luc reporter with empty vector (EV) or Myc-RORα. Luciferase activity was measured and normalized by β-galactosidase activity. *P < 0.05 (n = 3) (middle). Raw 264.7 cells were transfected with Myc-RORα, or cells were treated with SR1078 or MaR1. DNA fragments that contain flanking region of the ROREs on the Alox12 promoter were immunoprecipitated with indicated antibodies and then amplified by PCR (bottom). (I) DHA-treated PMs were treated with 5 μM SR1078, 5 μM baicalein, or 10 μM NCTT-956. Intracellular MaR1 content was measured. (J) LMs were treated with baicalein, or NCTT-956 in the presence or absence of DHA. The mRNA levels of Rora were measured by qRT-PCR (left). The CD206 + /CD80 + ratio of F4/80 + cells was determined by flow cytometry (right). *P < 0.05 and # P < 0.05 (n = 3) for I and J. The data represent mean ± SD. Data were analyzed by Mann-Whitney U test for simple comparisons or Kruskal-Wallis test for multiple groups.

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“…Notably, the results from individual SPM treatments in adipose tissue explants and rodent obesity models (summarized in Table ) suggest that the impaired biosynthesis of certain SPMs contributes to adipose tissue inflammation and obesity‐related insulin resistance . Intraperitoneal administration of 17‐HDHA (50 µg kg −1 body weight) significantly attenuated adipose inflammation (decrease in adipose expression of inflammatory genes, MCP‐1 , IL‐6 , TNF‐α , and NF‐κB ) and improved the glucose tolerance (increase in adipose expression of adiponectin , peroxisome proliferator‐activated receptor‐α , peroxisome proliferator‐activated receptor‐γ , and glucose transporter type‐4 as well as decrease in plasma insulin levels) in diet‐induced obese mice compared to results for the vehicle control .…”

Section: Preventive Effects Of Omega‐3 Fatty Acids In Metabolic Syndrmentioning

confidence: 99%

“…In addition, the treatment of another DHA‐derived SPM, MaR1 (2 µg kg −1 bodyweight), improved insulin sensitivity, determined with an insulin tolerance test. MaR1 also increased adiponectin gene expression and Akt phosphorylation in the adipose tissues and attenuated adipose tissue inflammation (decrease in adipose expression of IL‐1β , MCP‐1 , and TNF‐α ) in both ob / ob and diet‐induced obese mice . PD1 treatment (100 n m ) acutely increased the adiponectin transcripts in adipose tissue explants isolated from ob/ob mice .…”

Section: Preventive Effects Of Omega‐3 Fatty Acids In Metabolic Syndrmentioning

confidence: 99%

Immuno‐Resolving Ability of Resolvins, Protectins, and Maresins Derived from Omega‐3 Fatty Acids in Metabolic Syndrome

Kwon

2019

Molecular Nutrition Food Res

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Omega‐3 fatty acid consumption has been suggested to be beneficial for the prevention of type 2 diabetes mellitus (T2DM). Its effects have been attributed to anti‐inflammatory activity, with the inhibition of arachidonic acid metabolism playing a central role. However, a more recent view is that omega‐3 fatty acids play an active role as the precursors of potent, specialized pro‐resolving mediators (SPMs), such as resolvins, protectins, and maresins. Docosahexaenoic acid (DHA)‐ and eicosapentaenoic‐acid‐derived SPMs are identified in the adipose tissue but the levels of certain SPMs (e.g., protectin D1) are markedly reduced with obesity, suggesting adipose SPM deficiency, potentially resulting in unresolved inflammation. Supplementation of the biosynthetic intermediates of SPM (e.g., 17‐hydroxy‐DHA) or omega‐3 fatty acids increases the level of adipose SPMs, reduces adipose inflammation (decrease in macrophage accumulation and change to less inflammatory macrophages), and enhances insulin sensitivity. The findings from studies using rodent obesity models must be translated to humans. It will be important to further elucidate the underlying mechanisms by which obesity reduces the levels of and the sensitivity to SPM in adipose tissues. This will enable the development of nutrition therapy to enhance the effects of omega‐3 fatty acids in the prevention and/or treatment of T2DM.

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

Cited by 82 publications

References 49 publications

GLUT12 and adipose tissue: Expression, regulation and its relation with obesity in mice

GLUT12 and adipose tissue: Expression, regulation and its relation with obesity in mice

A maresin 1/RORα/12-lipoxygenase autoregulatory circuit prevents inflammation and progression of nonalcoholic steatohepatitis

Immuno‐Resolving Ability of Resolvins, Protectins, and Maresins Derived from Omega‐3 Fatty Acids in Metabolic Syndrome

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