Regulation of energy and glucose metabolism by the central nervous system through the SHPS-1/SHP-2 signaling

蛋白酪氨酸磷酸酶(PTP)催化的下丘脑瘦素受体(OB-Rb)去磷酸化可抑制瘦素的作用。我们继续研究了SHP-2及其底物SHPS-1的生理功能，SHP-2是一种可以脱磷的OB-RB的PTP。在本研究中，我们利用缺乏SHPS-1基因(KO)的小鼠，研究了SHPS-1/SHP-2信号通路在中枢神经系统控制的能量代谢中的潜在作用。我们目前的研究结果如下：1)在标准饲料条件下，KO小鼠在26周龄后体重明显变小；在32周龄时，KO小鼠的体重比野生型小鼠轻约15%。2)从8周龄开始喂食高脂饮食8周所引起的体重增加在KO小鼠中明显小于野生型小鼠。3)这种体重增加的减少与体脂质量的大幅下降有关。4)反映下丘脑瘦素作用的食物摄入量在两种基因型之间相似，而不考虑饮食。5)两组之间的血糖水平没有显著差异，然而，KO小鼠的血清胰岛素水平往往较低。我们还试图确定一种先前未知的SHP-2底物，它可能调节中枢神经系统中的瘦素活动。然而，到目前为止，还没有找到有希望的目标。因此，我们的结果可能提示SHPS-1/SHP-2信号通路在控制能量代谢和肥胖症的发生中具有潜在的调节作用，尽管这种调节机制是否由下丘脑瘦素信号介导尚不清楚。

The dephosphorylation of hypothalamic leptin receptor (OB-Rb) catalyzed by protein-tyrosine phosphatase (PTP) has been proposed to suppress leptin action. We have continued to study physiological function of SHP-2, a PTP which can dephosphorylate OB-Rb, and its substrate SHPS-1. In the present study, we investigated a potential role of the SHPS-1/SHP-2 signaling pathway in energy metabolism controlled by the CNS with the use of mice lacking SHPS-1 gene (KO). Our present findings are as follows :1)Under standard diet, KO mice were significantly smaller in body weight after 26 weeks of age ; the KO mice weighed approximately 15% less than wild-type mice at 32 weeks of age.2)The increase in body weight induced by feeding a high-fat diet for 8 weeks starting at 8 weeks of age was significantly smaller in KO mice as compared to wild-type mice.3)Such reduction in body weight gain was associated with a substantial decrease in body fat mass.4)Food intake, which reflects hypothalamic leptin action, was similar between the two genotypes irrespective of the diet.5)There was no significant difference in blood glucose level between the two groups, whereas serum insulin level tends to be lower in KO mice.We have also tried to identify a previously unidentified substrate for SHP-2 potentially regulating leptin action in the CNS. However, promising targets have not been found until now. Thus, our results may suggest a potential regulatory role of the SHPS-1/SHP-2 signaling pathway in the control of energy metabolism and the development of obesity, although whether such a regulatory mechanism, if any, is mediated by hypothalamic leptin signaling is unclear.