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

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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.