Abstract
Regulator of G protein signaling 9–2 (RGS9–2) is a protein that is highly enriched in the striatum, a brain region that mediates motivation, movement and reward responses. We identified a naturally occurring 5 nucleotide deletion polymorphism in the human RGS9 gene and found that the mean body mass index (BMI) of individuals with the deletion was significantly higher than those without. A splicing reporter minigene assay demonstrated that the deletion had the potential to significantly decrease the levels of correctly spliced RGS9 gene product. We measured the weights of rats after virally transduced overexpression of RGS9–2 or the structurally related RGS proteins, RGS7, or RGS11, in the nucleus accumbens (NAc) and observed a reduction in body weight after overexpression of RGS9–2 but not RGS7 or 11. Conversely, we found that the RGS9 knockout mice were heavier than their wild-type littermates and had significantly higher percentages of abdominal fat. The constituent adipocytes were found to have a mean cross-sectional area that was more than double that of corresponding cells from wild-type mice. However, food intake and locomotion were not significantly different between the two strains. These studies with humans, rats and mice implicate RGS9–2 as a factor in regulating body weight.
Highlights
A large body of data indicates that brain circuits in the striatum that utilize opioid peptides and dopamine as neurotransmitters are important in i) the motivation to acquire food, ii) encoding food value and reward and iii) the orchestration of movements for acquiring food [1,2].Regulators of G-protein signaling (RGS) are a family of proteins that can accelerate GTP hydrolysis catalyzed by G protein coupled receptor (GPCR)-activated, Ga G protein subunits
On day 3 post-surgery, RGS11 overexpressing rats weighed on average 10.8 g (3.6% of total body mass) more than the LacZ controls. 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
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 (PTB), a protein involved in regulating the processing of RNA and ii) that the intronic variation can alter the splicing of the RGS9 gene product
Summary
Regulators of G-protein signaling (RGS) are a family of proteins that can accelerate GTP hydrolysis catalyzed by G protein coupled receptor (GPCR)-activated, Ga G protein subunits. They accelerate the termination of GPCR signals [3]. This study which investigates the role of the striatally enriched RGS protein, RGS9–2 [5], in regulating body weight was prompted by the following findings. Several studies have shown that altered RGS9–2 levels modulate the reward responses to drugs that activate brain opioid and dopamine receptors [15]
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