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

点击翻译按钮获取中文摘要

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.