Discovery of adipose specific glycerol channel and its application to obesity therapy

脂肪水通道蛋白是一种脂肪特异性甘油通道，我们在小鼠AQPap基因启动子区发现了过氧化物酶体增殖反应元件（PPRE）。AQPap mRNA的脂肪特异性表达可能与过氧化物酶体增殖物激活受体γ（peroxisome proliferator activated receptor γ，PPAR γ）的结合和激活有关。对160例健康人AQPap基因突变进行了研究，发现3种错义突变（R12C，V59L，G264V）和2种沉默突变（A103A，Q250G）。通过功能分析，G264V型AQPap不能利用爪蟾卵母细胞系统转运甘油。G264V AQPap基因纯合子小鼠在剧烈运动后血浆甘油浓度没有升高，而血浆肾上腺素浓度却有相当的升高，提示AQPap基因可能介导了人体运动后脂肪中甘油的释放。

Aquaporin adipose is a fat-specific glycerol channel.We identified the PPRE (peroxisome proliferator response element) in the promoter region of the mouse AQPap gene. Binding and activation of PPARγ (peroxisome proliferator activated receptor_γ) to this element was suggested to explain the fat-specific expression of AQPap mRNA.AQPap gene expression was negatively regulated by insulin in vivo and in tissue cultures. In the analysis of AQPap promoter, we showed there was an insulin negative response element composed of seven nucleotides.In the search of genetic mutations of AQPap in 160 human subjects, we found three types of missense mutation (R12C, V59L, G264V) and two types of silent mutations (A103A, Q250G). By the functional analysis, the G264V-type AQPap was not capable of transporting glycerol using the xenopus oocyte system. The homozygous subject for G264V AQPap failed to raise the concentrations of plasma glycerol in response to vigorous exercise, while there was an equivalent serge of plasma adrenalin, which suggested that the AQPap is mediating the glycerol release from fat by exercise in human.We are now investigating the phenotypes of AQPap knockout mice to clarify the physiological significance of AQPap and glycerol metabolism in whole body.