Spred2 Regulates High Fat Diet-Induced Adipose Tissue Inflammation, and Metabolic Abnormalities in Mice

Ohkura, Takahiro; Yoshimura, Teizo; Fujisawa, Masayoshi; Ohara, Toshiaki; Marutani, Rie; Usami, Kaya; Matsukawa, Akihiro

doi:10.3389/fimmu.2019.00017

Cited by 33 publications

(25 citation statements)

References 64 publications

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“…The MAPK pathway can also regulate glucose metabolism, and its activation could lead to a high level of blood glucose [8]. By inhibiting the ERK/MAPK pathway, HFD-induced obesity, adipose tissue inflammation, metabolic abnormalities, and insulin resistance would be improved [72]. Due to its pleiotropic functions, the MAPK pathway (in this case, the most significantly changed pathway) represents a potential therapeutic target for morbid obesity and the resulting metabolic problems encountered by obese patients.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA Expression Profiles in the Subcutaneous Adipose Tissues of Morbidly Obese Chinese Women

Wang¹,

Chen²,

Pan³

et al. 2021

Obes Facts

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Introduction: Obesity is a main global health issue and an outstanding cause of morbidity and mortality. Exploring miRNA profiling may help further studies on obesity. Methods: Three morbidly obese and 5 normal-weight Chinese women were enrolled in the microarray testing group. Abdominal subcutaneous adipose tissue (SAT) samples were excised. Total RNAs including miRNAs were extracted. Affymetrix GeneChip miRNA 4.0 Array was used to compare the expression profiles of miRNAs between the 2 groups. Two algorithms, miRanda and TargetScan, were used to predict target messenger RNAs (mRNAs). Bioinformatics analysis was then done based on the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The sample sizes were further expanded to 8 morbidly obese and 9 normal-weight subjects, and quantitative real-time PCR (qRT-PCR) was utilized to verify the expression of differential miRNAs and target genes. Results: As per the microarray assay, 58 miRNAs were differentially expressed in the SAT from the morbidly obese and normal-weight groups (Fold >4, p < 0.01, FDR <0.05); 54 of these were downregulated and 4 were upregulated in morbidly obese subjects. A total of 1,333 target genes were jointly predicted by miRanda and TargetScan. Further bioinformatics analysis showed that the differential miRNAs were involved in 269 significant biological functions and 89 significant signaling pathways. The validation experiment by qRT-PCR showed that the expression levels of miRNA-143-5p, miRNA-143-3p, miRNA-145-5p, and let-7a-5p were downregulated in morbidly obese subjects, consistent with the microarray detection. High-mobility group A2 (HMGA2), a target gene of the downregulated miRNA let-7a-5p, was first found to be upregulated 3.19-fold in the SAT of morbidly obese Chinese women when compared to normal-weight controls. Conclusions: MiRNA downregulation is a hallmark of intact SAT in a morbidly obese state. Transcription (DNA-dependent), small-molecule metabolic processes, the MAPK signaling pathway, and cancer-related pathways may play important roles in the occurrence and development of obesity. For the first time, we proved that HMGA2, a target gene of let-7a-5p, is upregulated in the SAT of morbidly obese Chinese women.

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Section: Discussionmentioning

confidence: 99%

MicroRNA Expression Profiles in the Subcutaneous Adipose Tissues of Morbidly Obese Chinese Women

Wang¹,

Chen²,

Pan³

et al. 2021

Obes Facts

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“…Circulating evidences showed that Sprouty-related EVH1 domain-2(SPRED2) was potent inhibitors for cytokines and growth factors [23]. SPRED2 was reported to be involved in various diseases [24].…”

Section: Discussionmentioning

confidence: 99%

Thrombin-activated platelet rich plasma (PRP) enhanced osteogenic differentiation of bone marrow mesenchymal stem cells by activing autophagy through miR-140-3p/SPRED2 axis

Jiang

Liu

Zhu

et al. 2020

Preprint

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Background Mesenchymal stem cells transplantation gradually become a potential treatment for bone defect in clinic practice. This study aimed to investigate the molecular mechanism of PRP and autophagy for osteogenic differentiation in bone marrow mesenchymal stem cells (BMSCs). Methods Thrombin activated PRP was prepared and the BMSCs were treated with activated PRP with different concentration and transfected with miR-140-3p vector (mimics or inhibitor), si-SPRED2 or co-transfected with miR-140-3p inhibitor and si-SPRED2, respectively. qRT-PCR and Western blotting were used to determine the mRNA expression and protein expression. A luciferase reporter assay was conducted to identified the targeting relationship between iR-140-3p and SPRED2 Subsequently, cell proliferation was detected by MTT and ALP activity was also determined. Alizarin red staining was used for the evaluating the formation of calcium nodules. Results MiR-140-3p expression was found to be inhibited by PRP in a dose-dependent manner, besides, cell proliferation, ALP activity, the expression of COL-I, OPN, Runx2 and OCN, and the formation of calcium nodules related to osteogenic differentiation were enhanced by PRP. Subsequently, we found that PRP activated autophagy and up-regulated SPRED2 expression in BMSCs through suppressing miR-140-3p expression. Moreover, we confirmed that miR-140-3p targeted SPRED2 and negatively regulation its expression. Finally, the findings showed that inhibition of miR-140-3p enhanced cell proliferation, osteogenic differentiation and autophagy of BMSCs by negatively regulating SPRED2 expression. Conclusion Thrombin activated PRP accelerated osteogenic differentiation of BMSCs by activing autophagy through miR-140-3p/SPRED2 axis.

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“…Reduced BML-induced PF development in Spred2 −/− mice is not due to Spred2-deficiency in myeloid cells. We previously demonstrated that the production of proinflammatory mediators was up-regulated in Spred2 −/− resident or M-CSF-induced BM-derived macrophages 22,23 . Here, we examined the production of TNFα and MCP-1 by inflammatory macrophages obtained by intraperitoneal injection of thioglycolate (TG) in response to BLM or LPS.…”

Section: Spred2-deficiency Increases the Proliferation Of Bronchial Ementioning

confidence: 99%

Spred2-deficiency enhances the proliferation of lung epithelial cells and alleviates pulmonary fibrosis induced by bleomycin

Kawara

Mizuta

Fujisawa

et al. 2020

Sci Rep

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The mitogen-activated protein kinase (MAPK) pathways are involved in many cellular processes, including the development of fibrosis. Here, we examined the role of Sprouty-related EVH-1-domain-containing protein (Spred) 2, a negative regulator of the MAPK-ERK pathway, in the development of bleomycin (BLM)-induced pulmonary fibrosis (PF). Compared to WT mice, Spred2−/− mice developed milder PF with increased proliferation of bronchial epithelial cells. Spred2−/− lung epithelial cells or MLE-12 cells treated with spred2 siRNA proliferated faster than control cells in vitro. Spred2−/− and WT macrophages produced similar levels of TNFα and MCP-1 in response to BLM or lipopolysaccharide and myeloid cell-specific deletion of Spred2 in mice had no effect. Spred2−/− fibroblasts proliferated faster and produced similar levels of MCP-1 compared to WT fibroblasts. Spred2 mRNA was almost exclusively detected in bronchial epithelial cells of naïve WT mice and it accumulated in approximately 50% of cells with a characteristic of Clara cells, 14 days after BLM treatment. These results suggest that Spred2 is involved in the regulation of tissue repair after BLM-induced lung injury and increased proliferation of lung bronchial cells in Spred2−/− mice may contribute to faster tissue repair. Thus, Spred2 may present a new therapeutic target for the treatment of PF.

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Spred2 Regulates High Fat Diet-Induced Adipose Tissue Inflammation, and Metabolic Abnormalities in Mice

Cited by 33 publications

References 64 publications

MicroRNA Expression Profiles in the Subcutaneous Adipose Tissues of Morbidly Obese Chinese Women

MicroRNA Expression Profiles in the Subcutaneous Adipose Tissues of Morbidly Obese Chinese Women

Thrombin-activated platelet rich plasma (PRP) enhanced osteogenic differentiation of bone marrow mesenchymal stem cells by activing autophagy through miR-140-3p/SPRED2 axis

Spred2-deficiency enhances the proliferation of lung epithelial cells and alleviates pulmonary fibrosis induced by bleomycin

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