Abstract
Long noncoding RNA (lncRNA) is a crucial factor in the progression of insulin resistance (IR). Resveratrol (RSV) exhibits promising therapeutic potential for IR. However, there are few studies on whether RSV improves IR through lncRNA. This study aimed to determine whether RSV could influence the expression of lncRNA and to elucidate the underlying mechanism. Mice were divided into three groups: control group, high-fat diet (HFD) group, and HFD + RSV group. We conducted a high-throughput sequencing analysis to detect lncRNA and mRNA expression signatures and the ceRNA-network in the skeletal muscles of mice that were fed an HFD to induce IR. Hierarchical clustering, gene enrichment, and gene ceRNA-network analyses were subsequently conducted. Differentially expressed lncRNAs were selected and validated via reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The biological functions of the selected lncRNAs were investigated by silencing the target genes via lentivirus transfection of C2C12 mouse myotube cells. RSV treatment reversed the expression of 338 mRNAs and 629 lncRNAs in the skeletal muscles of mice with HFD-induced IR. The results of the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes database analyses indicated that the differentially expressed mRNAs modulated type II diabetes mellitus. After validating randomly selected lncRNAs via RT-qPCR, we identified a novel lncRNA, NONMMUT044897.2, which was upregulated in the HFD group and reversed with RSV treatment. Additionally, NONMMUT044897.2 was proven to function as a ceRNA of microRNA- (miR-) 7051-5p. Suppressor of Cytokine Signaling 1 (SOCS1) was confirmed as a target of miR-7051-5p. We further performed lentivirus transfection to knock down NONMMUT044897.2 in vitro and found that NONMMUT044897.2 silenced SOCS1 and potentiated the insulin signaling pathway. Hence, RSV mimicked the silencing effect of lentivirus transfection on NONMMUT044897.2. Our study revealed that RSV reduced IR in mouse skeletal muscles via the regulation of NONMMUT044897.2.
Highlights
Type 2 diabetes mellitus (T2DM) accounts for 90% of diabetes worldwide, and insulin resistance (IR) is a primary determinant of T2DM since it reduces glucose uptake and utilization [1]
high-fat diet (HFD), and HFD + RSV groups, no differences were found in the protein levels of AKT and GSK3β (Figures 1(a), 1(b), and 1(d)). e HFD group showed dramatic repression of p-AKT and p-GSK3β protein levels compared with those in the control group, while the RSV group showed a marked increase in p-AKT and p-GSK3β protein expression (Figures 1(a), 1(c), and 1(e))
Suppressor of Cytokine Signaling 1 (SOCS1) expression was abnormally elevated in the HFD group but decreased following RSV treatment (Figures 1(a) and 1(f )). ese results suggest that RSV improves the expression of genes on the insulin signaling pathway
Summary
Type 2 diabetes mellitus (T2DM) accounts for 90% of diabetes worldwide, and insulin resistance (IR) is a primary determinant of T2DM since it reduces glucose uptake and utilization [1]. Phosphatidylinositol-3-kinase (PI3K)/ protein kinase B (AKT) is the most important signaling pathway of insulin in glucose metabolism [3]. Activated AKT can promote phosphorylated GSK3β, inhibiting its activity to improve IR [4]. Researchers found that the Suppressor of Cytokine Signaling 1 (SOCS1) is an important negative regulator of the PI3K/AKT pathway [5, 6]. Overexpression of SOCS1 in the liver was found to reduce insulin sensitivity by downregulating the level of tyrosine phosphorylation of insulin receptor substrate in IR mice [5]. SOCS1 primarily inhibits the catalytic binding of insulin receptors to insulin receptor substrates to induce IR [6]
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