Does the Drd2 receptor play a causal role in obesity?

在美国，大约三分之一的成年人患有肥胖症。3.因此，迫切需要确定导致肥胖的潜在遗传和/或环境因素，以减轻与肥胖相关的健康和经济成本。 在纹状体，D2Rs由纹状体苍白球表达，间接通路中棘神经元(IMSN)和D2Rs对iMSN的放电起抑制作用。IMSN参与各种行为和情感功能。例如，iMSN的刺激会损害运动功能，增加了它们直接参与与肥胖相关的受损体力活动的可能性。对iMSN的刺激也会导致一种负面的情感状态，类似于经常与肥胖并存的状态。最后，D2R的下调与大鼠的奖赏不足和强迫进食行为有关。总之，这些数据表明，纹状体D2Rs调节IMSN的活动，并影响与肥胖相关的行为和情感功能。基于这些数据，我们形成了一个假说，从机械上解释了D2R可用性的变化如何影响iMSN，并导致肥胖症状：肥胖者D2R信号受损，导致iMSN过度激活。这会导致抑郁、焦虑增加，运动功能下降，最终导致体重增加。 这些数据表明：1)D2Rs对iMSN具有抑制控制作用。2)肥胖个体纹状体D2R表达降低。3)脑奖赏系统，包括纹状体DA和IMSN，参与抑郁焦虑、运动功能、摄食行为和动机，我们假设纹状体D2R表达减少导致iMSN过度激活，改变纹状体信号，增加导致肥胖的行为。

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.