Voltage-sensor domain only protein, VSOP/Hv1, consists of the voltage-sensor domain lacking pore domain. It functions as voltage-gated proton channel (Sasaki et al, Science. 2006) and its expression is specific to microglia in mice brain. In phagocytes such as neutrophil, VSOP has a crucial role in the production of reactive oxygen species (ROS) by compensating for charge imbalance upon electron extrusion by NADPH oxidase. In the present study, we focused on the function of VSOP in mouse microglia using primary cultured cells. In these cells, numerous small VSOP-containing vesicles were observed in the intracellular compartments, while their function on plasma membrane were also observed by electrophysiology and pH imaging. We also analyzed the basic property of primary cultured microglia from VSOP-KO mice. We observed that F-actin signal is stronger at the periphery of microglia from VSOP-KO mice. Furthermore, our preliminary results suggest that TNFα release was slightly increased in KO microglia. More surprisingly, ROS production was not decreased but increased in VSOP-KO microglia, which may promote neuroinflammation in VSOP-KO mice. We found that female VSOP-KO mice show metabolic phenotype at the age of 6 month and over. Recently, it has been reported that neuroinflammation in hypothalamus is closely associated with obesity. Thus, VSOP deficiency in mice microglia may facilitate the initiation of inflammation in mice hypothalamus. The mechanism underlying the metabolic phenotype in VSOP-KO mice is also to be discussed.