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肥胖受试者内脏脂肪组织中通过WNT5A激活非经典Wnt信号传导与炎症相关。

Activation of noncanonical Wnt signaling through WNT5A in visceral adipose tissue of obese subjects is related to inflammation.

作者信息

Catalán Victoria, Gómez-Ambrosi Javier, Rodríguez Amaia, Pérez-Hernández Ana I, Gurbindo Javier, Ramírez Beatriz, Méndez-Giménez Leire, Rotellar Fernando, Valentí Víctor, Moncada Rafael, Martí Pablo, Sola Iosu, Silva Camilo, Salvador Javier, Frühbeck Gema

机构信息

Metabolic Research Laboratory (V.C., J.G.-A., A.R., A.I.P.-H., J.G., B.R., L.M.-G., G.F.) and Departments of Surgery (F.R., V.V., P.M.), Anesthesia (R.M.), Pathology (I.S.), and Endocrinology and Nutrition (C.S., J.S., G.F.), Clínica Universidad de Navarra, 31008 Pamplona, Spain; and CIBER de la Obesidad y Nutrición (V.C., J.G.-A., A.R., B.R., F.R., V.V., C.S., J.S., G.F.), Instituto de Salud Carlos III, 31008, Pamplona, Spain.

出版信息

J Clin Endocrinol Metab. 2014 Aug;99(8):E1407-17. doi: 10.1210/jc.2014-1191. Epub 2014 May 19.

DOI:10.1210/jc.2014-1191

PMID:24840810

Abstract

CONTEXT

Wingless-type mouse mammary tumor virus integration site family (WNT)-5A is a glycoprotein involved in the regulation of the inflammatory response by activating the noncanonical Wnt signaling pathway. Secreted frizzled-related protein (SFRP)-5 acts as a decoy receptor that binds and sequesters WNT5A, preventing activation of frizzled receptors and attenuating the noncanonical Wnt signaling.

OBJECTIVE

The aim of the study was to evaluate the involvement of WNT5A and SFRP5 in obesity and obesity-related comorbidities as well as to explore their effect in visceral adipose tissue inflammation.

PATIENTS AND METHODS

Samples obtained from 90 subjects were used. Circulating and gene expression levels of WNT5A and SFRP5 were analyzed in different metabolic tissues. The effect of TNF-α and lipopolysaccharide on the transcript levels of WNT5A and SFRP5 in adipocytes was explored. We also investigated whether WNT5A itself can activate an inflammatory response.

RESULTS

Increased circulating levels of WNT5A in obese patients (P < .05) were decreased (P < .001) after gastric bypass. In this line, WNT5A mRNA in visceral adipose tissue was increased (P < .05) in obese patients with gene expression levels of SFRP5 being down-regulated (P < .05). WNT5A mRNA expression was significantly enhanced (P < .01) by lipopolysaccharide and TNF-α treatment, whereas no effects were found in SFRP5 gene expression levels. Furthermore, exogenous WNT5A induced (P < .05) IL-6, IL1B, MMP2, MMP9, and SSP1 mRNA expression in human adipocyte cultures.

CONCLUSIONS

Activation of noncanonical Wnt signaling through the up-regulation of WNT5A and down-regulation of SFRP5 may promote a proinflammatory state in visceral adipose tissue contributing to the development of obesity-associated comorbidities.

摘要

背景

无翅型小鼠乳腺肿瘤病毒整合位点家族（WNT）-5A是一种糖蛋白，通过激活非经典Wnt信号通路参与炎症反应的调节。分泌型卷曲相关蛋白（SFRP）-5作为一种诱饵受体，可结合并隔离WNT5A，阻止卷曲受体的激活并减弱非经典Wnt信号。

目的

本研究旨在评估WNT5A和SFRP5在肥胖症及肥胖相关合并症中的作用，并探讨它们在内脏脂肪组织炎症中的影响。

患者与方法

使用从90名受试者获取的样本。分析了不同代谢组织中WNT5A和SFRP5的循环水平和基因表达水平。探讨了肿瘤坏死因子-α（TNF-α）和脂多糖对脂肪细胞中WNT5A和SFRP5转录水平的影响。我们还研究了WNT5A本身是否能激活炎症反应。

结果

肥胖患者中WNT5A的循环水平升高（P < 0.05），胃旁路手术后降低（P < 0.001）。同样，肥胖患者内脏脂肪组织中的WNT5A信使核糖核酸（mRNA）增加（P < 0.05），而SFRP5的基因表达水平下调（P < 0.05）。脂多糖和TNF-α处理显著增强了WNT5A mRNA表达（P < 0.01），而SFRP5基因表达水平未受影响。此外，外源性WNT5A诱导人脂肪细胞培养物中白细胞介素（IL）-6、IL1B、基质金属蛋白酶（MMP）2、MMP9和SSP1 mRNA表达（P < 0.05）。