Lees Emma Katherine, Krol Elzbieta, Shearer Kirsty, Mody Nimesh, Gettys Thomas W, Delibegovic Mirela
Institute of Medical Sciences, School of Medical Sciences, University of Aberdeen, Aberdeen, UK.
School of Biological Sciences, University of Aberdeen, Aberdeen, UK.
Metabolism. 2015 Feb;64(2):305-14. doi: 10.1016/j.metabol.2014.10.038. Epub 2014 Nov 5.
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 hypothesized 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 (Ptp1b(fl/fl)) mice were maintained on control diet (0.86% methionine) or MR diet (0.172% methionine) for 8weeks. Body weight and food intake were recorded and physiological tests for whole-body glucose homeostasis were performed. Serum and tissues were analyzed biochemically.
MR decreased body weight and increased food intake in Ptp1b(fl/fl) mice as expected, without changing PTP1B protein expression levels or activity. In females, MR treatment alone improved glucose tolerance in Ptp1b(fl/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 Ptp1b(fl/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.
蛋氨酸限制（MR）和肝脏蛋白酪氨酸磷酸酶1B（PTP1B）基因敲低均通过作用于胰岛素信号通路中的不同蛋白来改善肝脏胰岛素敏感性，同时通过减少肝脏脂肪生成降低肝脏甘油三酯含量。我们推测，联合应用肝脏PTP1B抑制和蛋氨酸限制可能会对改善葡萄糖稳态和脂质代谢产生协同效应。
雄性和雌性肝脏PTP1B基因敲除（Alb-Ptp1b(-/-)）小鼠和对照野生型（Ptp1b(fl/fl)）小鼠分别给予对照饮食（0.86%蛋氨酸）或MR饮食（0.172%蛋氨酸）8周。记录体重和食物摄入量，并进行全身葡萄糖稳态的生理测试。对血清和组织进行生化分析。
正如预期的那样，MR降低了Ptp1b(fl/fl)小鼠的体重并增加了食物摄入量，而未改变PTP1B蛋白表达水平或活性。在雌性小鼠中，单独的MR治疗改善了Ptp1b(fl/fl)小鼠的葡萄糖耐量，肝脏PTP1B缺乏进一步增强了这种作用。然而，MR喂养组之间的其他葡萄糖稳态指标相似。在雄性小鼠中，MR在Alb-Ptp1b(-/-)和野生型Ptp1b(fl/fl)小鼠中均在相似程度上改善了葡萄糖稳态。与单独的MR治疗相比，联合肝脏PTP1B抑制和MR并不能进一步增强胰岛素刺激的肝脏蛋白激酶B/Akt磷酸化，因此不会导致肝脏胰岛素信号进一步增加。与单独的MR饮食相比，联合治疗并未进一步改善脂质代谢。
蛋氨酸限制可改善葡萄糖和脂质稳态；然而，在MR基础上增加肝脏PTP1B抑制不太可能产生任何额外的保护作用。
