Turaihi Alexander H, Bakker Wineke, van Hinsbergh Victor W M, Serné Erik H, Smulders Yvo M, Niessen Hans W M, Eringa Etto C
Department of Physiology, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, Netherlands.
Department of Internal Medicine, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, Netherlands.
Front Physiol. 2018 Mar 23;9:245. doi: 10.3389/fphys.2018.00245. eCollection 2018.
Insulin signaling in adipose tissue has been shown to regulate insulin's effects in muscle. In muscle, perivascular adipose tissue (PVAT) and vascular insulin signaling regulate muscle perfusion. Insulin receptor substrate (IRS) 2 has been shown to control adipose tissue function and glucose metabolism, and here we tested the hypothesis that IRS2 mediates insulin's actions on the vessel wall as well as the vasoactive properties of PVAT. We studied PVAT and muscle resistance arteries (RA) from littermate IRS2 and IRS2 mice and vasoreactivity by pressure myography, vascular insulin signaling, adipokine expression, and release and PVAT morphology. As insulin induced constriction of IRS2 RA in our mouse model, we also exposed RA's of C57/Bl6 mice to PVAT from IRS2 and IRS2 littermates to evaluate vasodilator properties of PVAT. IRS2 RA exhibited normal vasomotor function, yet a decreased maximal diameter compared to IRS2 RA. IRS2 vessels unexpectedly constricted endothelin-dependently in response to insulin, and this effect was absent in IRS2 RA due to reduced ERK1/2activation. For evaluation of PVAT function, we also used C57/Bl6 vessels with a neutral basal effect of insulin. In these experiments insulin (10.0 nM) increased diameter in the presence of IRS2 PVAT (17 ± 4.8, = 0.014), yet induced a 10 ± 7.6% decrease in diameter in the presence of IRS2 PVAT. Adipocytes in IRS2 PVAT (1314 ± 161 μm) were larger ( = 0.0013) than of IRS2 PVAT (915 ± 63 μm). Adiponectin, IL-6, PAI-1 secretion were similar between IRS2 and IRS2 PVAT, as were expression of pro-inflammatory genes (TNF-α, CCL2) and adipokines (adiponectin, leptin, endothelin-1). Insulin-induced AKT phosphorylation in RA was similar in the presence of IRS2 and IRS2 PVAT. In muscle, IRS2 regulates both insulin's vasoconstrictor effects, mediating ERK1/2-ET-1 activation, and its vasodilator effects, by mediating the vasodilator effect of PVAT. The regulatory role of IRS2 in PVAT is independent from adiponectin secretion.
脂肪组织中的胰岛素信号已被证明可调节胰岛素在肌肉中的作用。在肌肉中，血管周围脂肪组织（PVAT）和血管胰岛素信号调节肌肉灌注。胰岛素受体底物（IRS）2已被证明可控制脂肪组织功能和葡萄糖代谢，在此我们测试了一个假设，即IRS2介导胰岛素对血管壁的作用以及PVAT的血管活性特性。我们研究了同窝出生的IRS2和IRS2小鼠的PVAT和肌肉阻力动脉（RA），并通过压力肌动描记法、血管胰岛素信号传导、脂肪因子表达、释放以及PVAT形态来研究血管反应性。由于在我们的小鼠模型中胰岛素诱导了IRS2 RA的收缩，我们还将C57/Bl6小鼠的RA暴露于IRS2和IRS2同窝小鼠的PVAT中，以评估PVAT的血管舒张特性。IRS2 RA表现出正常的血管运动功能，但与IRS2 RA相比最大直径减小。IRS2血管对胰岛素的反应意外地出现了内皮素依赖性收缩，而由于ERK1/2激活减少，这种效应在IRS2 RA中不存在。为了评估PVAT功能，我们还使用了对胰岛素具有中性基础效应的C57/Bl6血管。在这些实验中，胰岛素（10.0 nM）在存在IRS2 PVAT的情况下增加了直径（17±4.8，P = 0.014），而在存在IRS2 PVAT的情况下诱导直径下降了10±7.6%。IRS2 PVAT中的脂肪细胞（1314±161μm）比IRS2 PVAT中的脂肪细胞（915±63μm）更大（P = 0.0013）。IRS2和IRS2 PVAT之间脂联素、IL-6、PAI-1的分泌相似，促炎基因（TNF-α、CCL2）和脂肪因子（脂联素、瘦素、内皮素-1）的表达也相似。在存在IRS2和IRS2 PVAT的情况下，胰岛素诱导的RA中AKT磷酸化相似。在肌肉中，IRS2通过介导PVAT的血管舒张作用来调节胰岛素的血管收缩作用和血管舒张作用，介导ERK1/2-ET-1激活。IRS2在PVAT中的调节作用独立于脂联素分泌。
