Therefore, one hypothesis explaining the relative increase in weight produced by RGS7 or RGS11 overexpression, is that RGS7 and RGS11 competes with WZ8040 RGS9-2 for the available Gb5 and R7BP, destabilizing native RGS9-2 protein and producing an effect on weight similar to that seen in RGS9 knock-out mice. Results similar to those we report have been observed at the cellular level: previous studies have reported that, despite their structural similarity, RGS7 and RGS11 produce opposite effects to those produced by RGS9 on cellular signaling pathways. While there is one report of RGS9 transcript expression in blood lymphocytes, all other studies examining the tissue distribution and function of RGS9 gene products have reported only on the expression of RGS9 in the brain and the retina. Thus, the absence of reports of RGS9 expression in peripheral tissue, interpreted in conjunction with, i) our observations with rats demonstrating that RGS9-2 overexpression in the NAc lowers body weight compared to control animals and ii) undetectable levels of RGS9 protein expression in fat tissue, suggest that the RGS9 acts to regulate body-weight and adiposity via expression in the brain. RGS9-2 exhibits extremely dense expression in rodent striatum, and pleasure, desire and reward circuits operating in the striatum are thought to be important in obesity and eating disorders. However, the actions of RGS9-2 in regulating body-weight and adiposity are likely to involve alternative striatal connections, since we report that the food intake of the heavier RGS9 knockout mice was similar to that of wild-type mice. The dopamine-sensitive NAc reward centers are densely interconnected with the hypothalamus, a brain region that is critical for regulating energy expenditure. Hypothalamic neurons, including orexin and melanin concentrating hormone neurons, make connections with the NAc, and the NAc can influence hypothalamic functions. Thus, RGS9-2 via expression in the NAc could modulate the activity of hypothalamic centers that control energy expenditure and future experiments will examine the total and resting oxygen consumption in the RGS9 knockout mice. Interestingly, in addition to extremely dense expression in striatum, RGS9-2 is also localized to medial hypothalamus. However, it is clear from our experiments that modulating RGS9-2 levels specifically in the NAc can alter body weight. Human genetic studies have CT99021 side effects linked variations in two other R7 RGS proteins, RGS6 and RGS7 to obesity. The above human genetic studies provide a precedent for R7 RGS family proteins regulating body-weight through their expression in the brain since these proteins have been reliably detected only in the brain or in excitable tissue such as retina and heart.