Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN, United States.
Department of Surgery, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States.
Front Immunol. 2023 Jun 2;14:1213415. doi: 10.3389/fimmu.2023.1213415. eCollection 2023.
Obesity is a multifactorial disease characterized by an enhanced amount of fat and energy storage in adipose tissue (AT). Obesity appears to promote and maintain low-grade chronic inflammation by activating a subset of inflammatory T cells, macrophages, and other immune cells that infiltrate the AT. Maintenance of AT inflammation during obesity involves regulation by microRNAs (miRs), which also regulate the expression of genes implicated in adipocyte differentiation. This study aims to use and approaches to evaluate the role and mechanism of miR-10a-3p in adipose inflammation and adipogenesis.
Wild-type BL/6 mice were placed on normal (ND) and high-fat diet (HFD) for 12 weeks and their obesity phenotype, inflammatory genes, and miRs expression were examined in the AT. We also used differentiated 3T3-L1 adipocytes for mechanistic studies.
Microarray analysis allowed us to identify an altered set of miRs in the AT immune cells and Ingenuity pathway analysis (IPA) prediction demonstrated that miR-10a-3p expression was downregulated in AT immune cells in the HFD group as compared to ND. A molecular mimic of miR-10a-3p reduced expression of inflammatory M1 macrophages, cytokines, and chemokines, including transforming growth factor-beta 1 (TGF-β1), transcription factor Krüppel-like factor 4 (KLF4), and interleukin 17F (IL-17F) and induced expression of forkhead box P3 (FoxP3) in the immune cells isolated from AT of HFD-fed mice as compared to ND. In differentiated 3T3-L1 adipocytes, the miR-10a-3p mimics also reduced expression of proinflammatory genes and lipid accumulation, which plays a role in the dysregulation of AT function. In these cells, overexpression of miR-10a-3p reduced the expression of TGF-β1, Smad3, CHOP-10, and fatty acid synthase (FASN), relative to the control scramble miRs.
Our findings suggest that miR-10a-3p mimic mediates the TGF-β1/Smad3 signaling to improve metabolic markers and adipose inflammation. This study provides a new opportunity for the development of miR-10a-3p as a novel therapeutic for adipose inflammation, and its associated metabolic disorders.
肥胖是一种多因素疾病，其特征是脂肪和能量在脂肪组织（AT）中过度储存。肥胖似乎通过激活浸润 AT 的一小部分炎症 T 细胞、巨噬细胞和其他免疫细胞来促进和维持低度慢性炎症。肥胖期间 AT 炎症的维持涉及 microRNAs（miRs）的调节，miRs 还调节与脂肪细胞分化相关的基因的表达。本研究旨在使用 和 方法评估 miR-10a-3p 在脂肪炎症和脂肪生成中的作用和机制。
将野生型 BL/6 小鼠置于正常（ND）和高脂肪饮食（HFD）中 12 周，并检测 AT 中的肥胖表型、炎症基因和 miR 表达。我们还使用分化的 3T3-L1 脂肪细胞进行机制研究。
微阵列分析使我们能够鉴定出 AT 免疫细胞中一组改变的 miR，Ingenuity 通路分析（IPA）预测表明，与 ND 相比，HFD 组 AT 免疫细胞中的 miR-10a-3p 表达下调。miR-10a-3p 的分子模拟物降低了 HFD 喂养小鼠 AT 免疫细胞中炎症 M1 巨噬细胞、细胞因子和趋化因子的表达，包括转化生长因子-β1（TGF-β1）、转录因子 Krüppel 样因子 4（KLF4）和白细胞介素 17F（IL-17F），并诱导表达 FoxP3 在 ND 相比。在分化的 3T3-L1 脂肪细胞中，miR-10a-3p 模拟物还降低了促炎基因的表达和脂质积累，这在 AT 功能失调中起作用。在这些细胞中，与对照 scramble miRs 相比，miR-10a-3p 的过表达降低了 TGF-β1、Smad3、CHOP-10 和脂肪酸合酶（FASN）的表达。
我们的研究结果表明，miR-10a-3p 模拟物介导 TGF-β1/Smad3 信号传导，以改善代谢标志物和脂肪炎症。这项研究为 miR-10a-3p 作为治疗脂肪炎症及其相关代谢紊乱的新型治疗方法提供了新的机会。
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