Effects of hepatic protein tyrosine phosphatase 1B and methionine restriction on hepatic and whole-body glucose and lipid metabolism in mice.
Effects of hepatic protein tyrosine phosphatase 1B and methionine restriction on hepatic and whole-body glucose and lipid metabolism in mice.
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DOI：
10.1016/j.metabol.2014.10.038
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发表时间：
2015-02
期刊：
影响因子：
--
通讯作者：
Delibegovic M
中科院分区：
文献类型：
--
作者：
Lees EK;Krol E;Shearer K;Mody N;Gettys TW;Delibegovic M
蛋氨酸限制（MR）和肝脏蛋白酪氨酸磷酸酶1B （PTP1B）敲低均可通过靶向胰岛素信号通路内的不同蛋白来改善肝脏胰岛素敏感性，并通过减少肝脏脂肪生成来降低肝脏甘油三酯含量。我们假设肝脏PTP1B抑制和蛋氨酸限制的联合方法可能导致葡萄糖稳态和脂质代谢改善的协同作用。雄性和雌性肝脏- ptp1b敲除小鼠（Alb-Ptp1b−/−）和对照野生型小鼠（Ptp1bfl/fl）分别饲喂对照组饲粮（蛋氨酸含量为0.86%）或MR饲粮（蛋氨酸含量为0.172%）8周。记录体重和食物摄入量，并进行全身葡萄糖稳态生理测试。血清和组织进行生化分析。正如预期的那样，MR降低了Ptp1bfl/fl小鼠的体重，增加了食物摄入量，但没有改变PTP1B蛋白的表达水平或活性。在雌性小鼠中，单独MR治疗可改善Ptp1bfl/fl小鼠的糖耐量，这在肝脏ptp1b缺乏时进一步增强。然而，其他葡萄糖稳态指标在磁共振喂养组之间是相似的。在雄性小鼠中，MR在Alb-Ptp1b−/−和野生型Ptp1bfl/fl小鼠中改善葡萄糖稳态的程度相似。与单独MR治疗相比，肝脏- ptp1b抑制联合MR治疗不能进一步增强胰岛素刺激的肝蛋白激酶B/Akt磷酸化，因此不会导致肝脏胰岛素信号传导进一步增加。与单独MR饮食相比，联合治疗并没有进一步改善脂质代谢。蛋氨酸限制改善葡萄糖和脂质稳态；然而，在MR中加入肝脏PTP1B抑制剂不太可能产生任何额外的保护作用。
Methionine restriction (MR) and hepatic protein tyrosine phosphatase 1B (PTP1B) knockdown both improve hepatic insulin sensitivity by targeting different proteins within the insulin signaling pathway, as well as diminishing hepatic triglyceride content through decreasing hepatic lipogenesis. We hypothesised that a combined approach of hepatic PTP1B inhibition and methionine restriction could lead to a synergistic effect on improvements in glucose homeostasis and lipid metabolism. Male and female hepatic-PTP1B knockout (Alb-Ptp1b−/−) and control wild-type (Ptp1bfl/fl) mice were maintained on control diet (0.86% methionine) or MR diet (0.172% methionine) for 8 weeks. Body weight and food intake were recorded and physiological tests for whole-body glucose homeostasis were performed. Serum and tissues were analysed biochemically. MR decreased body weight and increased food intake in Ptp1bfl/fl mice as expected, without changing PTP1B protein expression levels or activity. In females, MR treatment alone improved glucose tolerance in Ptp1bfl/fl mice, which was further amplified with hepatic-PTP1B deficiency. However, other markers of glucose homeostasis were similar between MR-fed groups. In males, MR improved glucose homeostasis in both, Alb-Ptp1b−/− and wild-type Ptp1bfl/fl mice to a similar extent. Hepatic-PTP1B inhibition in combination with MR could not further enhance insulin-stimulated hepatic protein kinase B/Akt phosphorylation compared to MR treatment alone and therefore led to no further increase in hepatic insulin signaling. The combined treatment did not further improve lipid metabolism relative to MR diet alone. Methionine restriction improves glucose and lipid homeostasis; however, adding hepatic PTP1B inhibition to MR is unlikely to yield any additional protective effects.
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影响因子：
7.7
作者：
Delibegovic M;Zimmer D;Kauffman C;Rak K;Hong EG;Cho YR;Kim JK;Kahn BB;Neel BG;Bence KK
通讯作者：
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3.5
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Owen C;Czopek A;Agouni A;Grant L;Judson R;Lees EK;Mcilroy GD;Göransson O;Welch A;Bence KK;Kahn BB;Neel BG;Mody N;Delibegović M
通讯作者：
Delibegović M
影响因子：
4.4
作者：
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通讯作者：
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影响因子：
7.7
作者：
Hasek BE;Boudreau A;Shin J;Feng D;Hulver M;Van NT;Laque A;Stewart LK;Stone KP;Wanders D;Ghosh S;Pessin JE;Gettys TW
通讯作者：
Gettys TW