The novel adipokine WISP1 associates with insulin resistance and impairs insulin action in human myotubes and mouse hepatocytes
The novel adipokine WISP1 associates with insulin resistance and impairs insulin action in human myotubes and mouse hepatocytes
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DOI：
10.1007/s00125-018-4636-9
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发表时间：
2018-09-01
期刊：
影响因子：
8.2
通讯作者：
Ouwens, D. Margriet
中科院分区：
文献类型：
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作者：
Hoerbeit, Tina;Tacke, Christopher;Ouwens, D. Margriet
无翅型（Wnt）诱导的信号通路蛋白1（WISP 1）最近被鉴定为促炎性脂肪因子。我们研究了WISP 1的表达和循环水平是否在2型糖尿病中改变，以及WISP 1是否影响肌细胞和肝细胞中的胰岛素信号传导。在肝细胞中，重组WISP 1通过抑制胰岛素受体的磷酸化而损害胰岛素作用。Akt及其底物糖原合成酶激酶3 β、FOXO 1和p70 S6激酶，并抑制胰岛素刺激的糖原合成和抑制促胰岛素生成基因。方法收集正常体重男性的血清和内脏脂肪组织（VAT）活检，通过ELISA分析循环WISP 1水平，通过实时定量RT-PCR分析WISP 1 mRNA表达。（对照组，n= 33）和患有（n = 46）和不患有2型糖尿病（n = 56）的肥胖男性接受手术。将原代人骨骼肌细胞（hSkMCs）和鼠AML 12肝细胞与WISP 1和胰岛素孵育后，通过蛋白质印迹法分析胰岛素信号传导。分别在hSkMCs和小鼠肝细胞中研究了WISP 1对胰岛素刺激的糖原合成和糖原生成的影响。（独立于糖尿病状态）比正常体重男性（平均值[95%CI]：分别为70.8 [55.2，86.4] ng/l和42.6 [28.5，56.6] ng/l; p < 0.05）。肥胖男性中VAT WISPI表达是正常体重男性的1.9倍（p < 0.05）。循环WISP 1水平与OGTT中的血糖和循环血红素氧合酶-1呈正相关，与脂联素水平呈负相关。在hSkMCs和AML 12中结论/解释循环WISP 1水平和VAT中WISP 1表达在肥胖者中增加，与血脂状态无关。此外，WISP 1损害肌肉和肝细胞中的胰岛素信号传导。
Aims/hypothesis Wingless-type (Wnt) inducible signalling pathway protein-1 (WISP1) has been recently identified as a proinflammatory adipokine. We examined whether WISP1 expression and circulating levels are altered in type 2 diabetes and whether WISP1 affects insulin signalling in muscle cells and hepatocytes. hepatocytes, recombinant WISP1 impaired insulin action by inhibiting phosphorylation of insulin receptor. Akt and its substrates glycogen synthase kinase 3 beta, FOXO1 and p70S6 kinase, and inhibiting insulin-stimulated glycogen synthesis and suppression of gluconeogenic genes.Methods Serum and visceral adipose tissue (VAT) biopsies, for analysis of circulating WISP1 levels by ELISA and WISP1 mRNA expression by real-time quantitative RT-PCR, were collected from normal-weight men (control group, n= 33) and obese men with (n = 46) and without type 2 diabetes (n = 56) undergoing surgery. Following incubation of primary human skeletal muscle cells (hSkMCs) and murine AML12 hepatocytes with WISP1 and insulin, insulin signalling was analysed by western blotting. The effect of WISP1 on insulin-stimulated glycogen synthesis and gluconeogenesis was investigated in hSkMCs and murine hepatocytes, respectively.Results Circulating WISP1 levels were higher in obese men (independent of diabetes status) than in normal-weight men (mean [95% CI]: 70.8 [55.2, 86.4] ng/l vs 42.6 [28.5, 56.6] ng/l, respectively; p < 0.05). VAT WISPI expression was 1.9-fold higher in obese men vs normal-weight men (p < 0.05). Circulating WISP1 levels were positively associated with blood glucose in the OGTT and circulating haem oxygenase-1 and negatively associated with adiponectin levels. In hSkMCs and AML12Conclusions/interpretation Circulating WISP1 levels and WISP1 expression in VAT are increased in obesity independent of glycaemic status. Furthermore, WISP1 impaired insulin signalling in muscle and liver cells.