新的脂肪因子 WISP1 与胰岛素抵抗相关，并损害人类肌管和小鼠肝细胞中的胰岛素作用。
The novel adipokine WISP1 associates with insulin resistance and impairs insulin action in human myotubes and mouse hepatocytes.
机构信息
Institute for Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany.
German Center for Diabetes Research (DZD), Muenchen-Neuherberg, Germany.
出版信息
Diabetologia. 2018 Sep;61(9):2054-2065. doi: 10.1007/s00125-018-4636-9. Epub 2018 May 12.
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.
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 WISP1 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 AML12 hepatocytes, recombinant WISP1 impaired insulin action by inhibiting phosphorylation of insulin receptor, Akt and its substrates glycogen synthase kinase 3β, FOXO1 and p70S6 kinase, and inhibiting insulin-stimulated glycogen synthesis and suppression of gluconeogenic genes.
CONCLUSIONS/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.
目的/假设：Wnt 诱导信号通路蛋白-1（WISP1）最近被鉴定为一种促炎脂肪因子。我们研究了 2 型糖尿病患者中 WISP1 的表达和循环水平是否发生改变，以及 WISP1 是否影响肌肉细胞和肝细胞中的胰岛素信号。
方法
收集正常体重男性（对照组，n=33）、肥胖伴 2 型糖尿病男性（n=46）和肥胖不伴 2 型糖尿病男性（n=56）的血清和内脏脂肪组织（VAT）活检，通过 ELISA 检测循环 WISP1 水平，实时定量 RT-PCR 检测 WISP1 mRNA 表达。将原发性人骨骼肌细胞（hSkMCs）和鼠 AML12 肝细胞与 WISP1 和胰岛素孵育后，通过 Western 印迹分析胰岛素信号。在 hSkMCs 和鼠肝细胞中分别研究 WISP1 对胰岛素刺激的糖原合成和糖异生的影响。
结果
与正常体重男性相比，肥胖男性（无论是否合并糖尿病）的循环 WISP1 水平更高（平均[95%置信区间]：70.8[55.2，86.4]ng/l 比 42.6[28.5，56.6]ng/l；p<0.05）。与正常体重男性相比，肥胖男性的 VAT WISP1 表达高 1.9 倍（p<0.05）。循环 WISP1 水平与 OGTT 中的血糖呈正相关，与循环血红素氧合酶-1 呈负相关，与脂联素水平呈负相关。在 hSkMCs 和 AML12 肝细胞中，重组 WISP1 通过抑制胰岛素受体、Akt 及其底物糖原合酶激酶 3β、FOXO1 和 p70S6 激酶的磷酸化，抑制胰岛素刺激的糖原合成和抑制糖异生基因的表达，从而损害胰岛素作用。
结论/解释：肥胖患者的循环 WISP1 水平和 VAT 中的 WISP1 表达增加，与血糖状态无关。此外，WISP1 损害了肌肉和肝细胞中的胰岛素信号。
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