Endocrinology, Diabetes, and Nutrition Unit, Institute of Experimental and Clinical Research, Medical Sector, University of Louvain, Brussels, Belgium.
Endocrinology. 2012 Nov;153(11):5285-96. doi: 10.1210/en.2012-1623. Epub 2012 Sep 26.
A low-grade proinflammatory state contributes to the metabolic syndrome (MS). Adiponectin (ApN), which is reduced in the MS, has emerged as a master regulator of inflammation/immunity. We wanted to identify whether microRNAs (miRNAs) may mediate the antiinflammatory action of ApN on adipose tissue (AT). miRNA expression profiling was performed in mice overexpressing ApN specifically in AT and in wild-type controls. The role of specific miRNAs was analyzed by gain- or loss-of function approaches in 3T3-F442A (pre)-adipocytes and in de novo AT formed from engineered 3T3-F442A preadipocytes transplanted in nude mice. miRNA expression was compared in the omental AT of lean and obese subjects. The expression of miR532-5p and miR1983 was down-regulated, whereas that of miR883b-5p and miR1934 was up-regulated in AT of mice overexpressing ApN specifically in AT. We focused on miR883b-5p identified by computational analysis as being involved in inflammatory pathways. miR883b-5p overexpression down-regulated the lipopolysaccharide-binding protein (LBP) in 3T3-F442A cells, whereas miR883b-5p blockade had reverse effects. LBP aids in lipopolysaccharide binding to Toll-like receptor-4. miR883b-5p blockade also abolished the protective effects of ApN on proinflammatory adipokine induction. These data were recapitulated in the de novo AT in which miR883b-5p silencing induced LBP production and tissue inflammation. Eventually miR883b-5p expression was down-regulated in AT of obese subjects. We identified several novel miRNAs that are regulated by ApN in AT in vivo. miR883b-5p, which is up-regulated by ApN represses LBP and Toll-like receptor-4 signaling, acting therefore as a major mediator of the antiinflammatory action of ApN. These novel miRNAs may open new therapeutic perspectives for the MS.
低度炎症状态导致代谢综合征（MS）。脂联素（ApN）在 MS 中减少，它已成为炎症/免疫的主要调节剂。我们想确定是否 microRNAs（miRNAs）可能介导 ApN 对脂肪组织（AT）的抗炎作用。在特异性在 AT 中过表达 ApN 的小鼠和野生型对照中进行 miRNA 表达谱分析。通过 gain-或 loss-of function 方法在 3T3-F442A（前）脂肪细胞和从工程化的 3T3-F442A 前脂肪细胞移植到裸鼠中形成的新 AT 中分析特定 miRNA 的作用。在瘦人和肥胖受试者的网膜 AT 中比较 miRNA 表达。在特异性在 AT 中过表达 ApN 的小鼠的 AT 中，miR532-5p 和 miR1983 的表达下调，而 miR883b-5p 和 miR1934 的表达上调。我们通过计算分析确定 miR883b-5p 参与炎症途径，并将其作为重点。miR883b-5p 过表达可下调 3T3-F442A 细胞中的脂多糖结合蛋白（LBP），而 miR883b-5p 阻断则有相反的作用。LBP 有助于脂多糖与 Toll 样受体-4 结合。miR883b-5p 阻断也消除了 ApN 对促炎脂肪因子诱导的保护作用。这些数据在新形成的 AT 中得到了重现，其中 miR883b-5p 沉默诱导 LBP 产生和组织炎症。最终，肥胖受试者的 AT 中 miR883b-5p 的表达下调。我们在体内 AT 中鉴定出几种受 ApN 调节的新 miRNAs。由 ApN 上调的 miR883b-5p 抑制 LBP 和 Toll 样受体-4 信号，因此作为 ApN 抗炎作用的主要介质。这些新的 miRNAs 可能为 MS 开辟新的治疗前景。
