Norathyriol reverses obesity- and high-fat-diet-induced insulin resistance in mice through inhibition of PTP1B
Norathyriol reverses obesity- and high-fat-diet-induced insulin resistance in mice through inhibition of PTP1B
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去甲甲状腺醇通过抑制 PTP1B 逆转肥胖和高脂饮食诱导的小鼠胰岛素抵抗
DOI：
10.1007/s00125-014-3315-8
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发表时间：
2014-10-01
期刊：
影响因子：
8.2
通讯作者：
Jiang, Xiaohong
中科院分区：
文献类型：
--
作者：
Ding, Hanying;Zhang, Yan;Jiang, Xiaohong
目的/假设：蛋白酪氨酸磷酸酶1B（PTP 1B）负调节胰岛素信号传导。PTP 1B缺乏改善肥胖诱导的胰岛素抵抗，从而改善小鼠的2型糖尿病。方法：采用双倒数底物法研究小分子去甲胸腺嘧啶醇（norathyriol）对PTP 1B的抑制作用。原代培养的肝细胞、成肌细胞和白色脂肪细胞被用来研究去甲甲状腺素对胰岛素信号传导的影响。通过葡萄糖和胰岛素耐量试验表征葡萄糖稳态和胰岛素敏感性。结果：去甲肾上腺素被鉴定为PTP 1B的竞争性抑制剂，IC 50为9.59 ± 0.39 μmol/l。在培养的肝细胞和成肌细胞中，去甲甲状腺素治疗阻断了PTP 1B介导的胰岛素受体去磷酸化。腹腔注射去甲甲状腺素抑制小鼠肝脏和肌肉PTP 1B活性，从而有助于改善葡萄糖稳态和胰岛素敏感性。然而，这些有益的效果在PTP 1B缺陷小鼠中被消除。值得注意的是，口服去甲胸腺酚保护小鼠通过抑制下丘脑PTP 1B activity.Conclusions/interpretation饮食诱导的肥胖和胰岛素抵抗：我们的研究结果表明，小分子去甲胸腺酚是一种有效的PTP 1B抑制剂，具有良好的细胞渗透性和口服利用率。
Aim/hypothesis:Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signalling. PTP1B deficiency improves obesity-induced insulin resistance and consequently improves type 2 diabetes in mice. Here, the small molecule norathyriol reversed obesity- and high-fat-diet-induced insulin resistance by inhibiting PTP1B.Methods:The inhibitory mode of PTP1B was evaluated by using the double-reciprocal substrate in the presence of norathyriol. Primary cultured hepatocytes, myoblasts and white adipocytes were used to investigate the effect of norathyriol on insulin signalling. Glucose homeostasis and insulin sensitivity were characterised by glucose and insulin tolerance tests.Results:Norathyriol was identified as a competitive inhibitor of PTP1B, with an IC50 of 9.59 ± 0.39 μmol/l. In cultured hepatocytes and myoblasts, norathyriol treatment blocked the PTP1B-mediated dephosphorylation of the insulin receptor. Intraperitoneal injection of norathyriol inhibited liver and muscle PTP1B activity in mice, thus contributing to the improved glucose homeostasis and insulin sensitivity. However, these beneficial effects were abolished in PTP1B-deficient mice. Notably, oral administration of norathyriol protected mice from diet-induced obesity and insulin resistance through inhibition of hypothalamic PTP1B activity.Conclusions/interpretation:Our results indicate that the small molecule norathyriol is a potent PTP1B inhibitor with good cell permeability and oral availability.