RGS9�C2 is BAY-60-7550 expressed specifically in the brain and is highly enriched in striatum neurons while RGS9-1is thought to be expressed specifically in the retina. RGS9�C1 and 2 are members of the R7 RGS protein subfamily whose members are defined by the presence of two N-terminal domains: i) a DEP domain and ii) Gc-like domain that binds Gb5, an outlying member of the G protein beta subunit family. Here, we identify a polymorphism in the human RGS9 gene likely to alter functional levels of RGS9�C2. Based on our observations that RGS9 knockout mice were heavier than their wild-type littermates we asked if this human RGS9 gene polymorphism was associated with altered body mass index. We also Selumetinib tested the effects of virallymediated overexpression of RGS9�C2 in the rat nucleus accumbens on body weight. The results from these experiments, involving humans, rats and mice, suggest that alterations in functional levels of RGS9�C2 can affect body weight. In this manuscript we provide data from human, mouse and rat studies that suggest that RGS9-2, a brain specific RGS family member, can regulate body weight and adiposity. First we link an intronic deletion in the RGS9 gene to increased body mass index in humans. We provide mechanistic insights into this association by showing i) that the intronic deletion is coincident with a binding motif for the polypyrimidine tract binding protein, a protein involved in regulating the processing of RNA and ii) that the intronic variation can alter the splicing of the RGS9 gene product. Further confirmation for a role of RGS9 in regulating body weight is provided by observations showing that RGS9 knockout mice are heavier than their wild-type littermates, have increased adiposity and adipocytes with approximately doubled cross-sectional area. Finally we identify a possible site for the action of RGS9-2 in regulating body-weight by showing that overexpression of RGS9-2 in the nucleus accumbens of rats can decrease body-weight. A major finding of our study is that an intronic deletion polymorphism in the RGS9 gene is associated with significantly increased body mass index in humans. The increase in mean BMI represents an increase in weight from 68.2 kg to 70 kg, or a 2.7% increase in weight, for an individual 168 cm tall. Thus, the influence of the DTTTCT deletion polymorphism on body weight is quite mild: a World Health Organization panel has suggested that the obesity cut-off definition for Asians should be lowered to a BMI of 25, compared to 35 for Caucasians, but the mean BMI of the DTTTCT deletion positive East Asian individuals in our study is less than even this lowered BMI value. An examination of Table 1 shows that the increase in mean BMI of the DTTTCT deletion positive subjects relative to the deletion negative individuals is greatest among the Chinese, is very small in Pacific Islanders and is reversed in Southeast Asians.