Institute of Medical Sciences, School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
Diabetologia. 2013 Oct;56(10):2286-96. doi: 10.1007/s00125-013-2992-z. Epub 2013 Jul 6.
AIMS/HYPOTHESIS: Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin signalling. Hepatic PTP1B deficiency, using the Alb-Cre promoter to drive Ptp1b deletion from birth in mice, improves glucose homeostasis, insulin sensitivity and lipid metabolism. The aim of this study was to investigate the therapeutic potential of decreasing liver PTP1B levels in obese and insulin-resistant adult mice.
Inducible Ptp1b liver-specific knockout mice were generated using SA-Cre-ER(T2) mice crossed with Ptp1b floxed (Ptp1b(fl/fl)) mice. Mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity and insulin resistance. Tamoxifen was administered in the HFD to induce liver-specific deletion of Ptp1b (SA-Ptp1b(-/-) mice). Body weight, glucose homeostasis, lipid homeostasis, serum adipokines, insulin signalling and endoplasmic reticulum (ER) stress were examined.
Despite no significant change in body weight relative to HFD-fed Ptp1b(fl/fl) control mice, HFD-fed SA-Ptp1b(-/-) mice exhibited a reversal of glucose intolerance as determined by improved glucose and pyruvate tolerance tests, decreased fed and fasting blood glucose and insulin levels, lower HOMA of insulin resistance, circulating leptin, serum and liver triacylglycerols, serum NEFA and decreased HFD-induced ER stress. This was associated with decreased glycogen synthase, eukaryotic translation initiation factor-2α kinase 3, eukaryotic initiation factor 2α and c-Jun NH2-terminal kinase 2 phosphorylation, and decreased expression of Pepck.
CONCLUSIONS/INTERPRETATION: Inducible liver-specific PTP1B knockdown reverses glucose intolerance and improves lipid homeostasis in HFD-fed obese and insulin-resistant adult mice. This suggests that knockdown of liver PTP1B in individuals who are already obese/insulin resistant may have relatively rapid, beneficial therapeutic effects.
目的/假设：蛋白酪氨酸磷酸酶 1B（PTP1B）是胰岛素信号的关键负调控因子。使用 Alb-Cre 启动子从出生时驱动 Ptp1b 在小鼠中缺失，可改善葡萄糖稳态、胰岛素敏感性和脂代谢。本研究旨在探讨在肥胖和胰岛素抵抗的成年小鼠中降低肝 PTP1B 水平的治疗潜力。
使用 SA-Cre-ER(T2) 小鼠与 Ptp1b 基因敲除（Ptp1b(fl/fl)）小鼠杂交，生成诱导型肝特异性 Ptp1b 敲除小鼠。将小鼠用高脂肪饮食（HFD）喂养 12 周以诱导肥胖和胰岛素抵抗。用他莫昔芬在 HFD 中诱导肝特异性 Ptp1b 缺失（SA-Ptp1b(-/-) 小鼠）。检测体重、葡萄糖稳态、脂代谢、血清脂肪因子、胰岛素信号和内质网（ER）应激。
尽管与 HFD 喂养的 Ptp1b(fl/fl) 对照小鼠相比，体重无明显变化，但 HFD 喂养的 SA-Ptp1b(-/-) 小鼠葡萄糖耐量试验改善，表现为葡萄糖和丙酮酸耐量试验改善，空腹和餐后血糖及胰岛素水平降低，HOMA 胰岛素抵抗指数降低，循环瘦素、血清和肝脏三酰甘油、血清非酯化脂肪酸降低，HFD 诱导的 ER 应激降低。这与糖原合酶、真核翻译起始因子 2α 激酶 3、真核起始因子 2α 和 c-Jun NH2 末端激酶 2 磷酸化降低以及 Pepck 表达降低有关。
结论/解释：诱导型肝特异性 PTP1B 敲低可逆转 HFD 喂养肥胖和胰岛素抵抗成年小鼠的葡萄糖不耐受，并改善脂代谢。这表明，在已经肥胖/胰岛素抵抗的个体中敲低肝 PTP1B 可能具有相对较快、有益的治疗效果。
