Does the Drd2 receptor play a causal role in obesity?

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In the U.S., approximately one-third of the adult population is obese. Compounding this problem is the fact that obesity is associated with increased risk for developing other serious medical conditions 3. Thus, there is an urgent need to determine the underlying genetic and/or environmental contributors to obesity in order to mitigate obesity-related health and economic costs to society. In the striatum, D2Rs are expressed by striatopallidal, indirect pathway medium spiny neurons (iMSNs) and D2Rs exert inhibitory control over the firing of iMSNs. The iMSNs are involved in various behavioral and emotional functions. For example, stimulation of iMSNs impairs motor function, raising the possibility that they are directly involved in the impaired physical activity associated with obesity. Stimulation of iMSNs also induces a negative affective state similar to states that are often comorbid with obesity. Finally, D2R downregulation is associated with reward deficiency and compulsive eating behavior in rats. Together these data suggest that striatal D2Rs regulate iMSN activity and influence behavioral and emotional functions related to obesity. Based on these data, we have formed a hypothesis that mechanistically explains how changes in D2R availability affects iMSNs, and contributes to symptoms of obesity: obese individuals have impaired D2R signaling, causing overactivation of iMSNs. This results in increased depression, anxiety and decreased motor function ultimately leading to weight gain. Based these date indicating that 1) D2Rs exert inhibitory control over iMSNs. 2) Obese individuals have reduced striatal D2R expression. 3) Brain reward systems, including striatal DA and iMSN, are involved in depression anxiety, motor function, feeding behavior and motivation, we hypothesize that decreased D2R expression in striatum causes hyperactivation of iMSNs, altering striatal signaling and increasing behaviors that contribute to obesity.