Dopamine D(2) receptor signaling modulates pancreatic beta cell circadian rhythms.
Dopamine D(2) receptor signaling modulates pancreatic beta cell circadian rhythms.
复制标题
DOI：
10.1016/j.psyneuen.2019.104551
复制
发表时间：
2020-03
影响因子：
3.7
通讯作者：
McCarthy MJ
中科院分区：
文献类型：
--
作者：
Wei H;Zapata RC;Lopez-Valencia M;Aslanoglou D;Farino ZJ;Benner V;Osborn O;Freyberg Z;McCarthy MJ
抗精神病药物（APD）在临床上具有重要的代谢不良作用，限制了它们的治疗效用。胰腺细胞产生多巴胺并表达D2多巴胺受体（D2R）。作为D2R拮抗剂，apd改变葡萄糖刺激的胰岛素分泌，表明多巴胺可能在apd诱导的代谢功能障碍中发挥作用。细胞分泌的胰岛素也受到生物钟的调节。昼夜节律紊乱引起的代谢紊乱与在apd治疗对象中观察到的相似。鉴于多巴胺和昼夜节律对β细胞的重要性，我们假设β细胞多巴胺系统和昼夜节律钟相互作用并双重调节胰岛素分泌，昼夜节律操纵可能改变apd的代谢影响。我们使用生物发光报告仪测量了昼夜节律、胰岛素释放和多巴胺对β细胞这些过程的影响。然后，我们评估了昼夜节律对小鼠体重增加和代谢结果的影响，这些小鼠在光照或黑暗开始时接受APD舒必利治疗。我们发现多巴胺系统的分子成分在β细胞中有节奏地表达。内源性多巴胺或激动剂溴隐亭刺激D2R可降低昼夜节律幅度，并改变胰岛素分泌的时间分布。与光照期相比，在黑暗期给予舒必利会导致小鼠体重增加和高胰岛素血症。d2r作用药物影响昼夜节律-多巴胺相互作用并调节β细胞代谢功能。这些发现确定了昼夜节律是apd诱导的代谢功能障碍的一个新的重要机制，为治疗干预提供了新的可能性
Antipsychotic drugs (APD) have clinically important, adverse effects on metabolism that limit their therapeutic utility. Pancreatic beta cells produce dopamine and express the D2 dopamine receptor (D2R). As D2R antagonists, APDs alter glucose-stimulated insulin secretion, indicating that dopamine likely plays a role in APD-induced metabolic dysfunction. Insulin secretion from beta cells is also modulated by the circadian clock. Disturbed circadian rhythms cause metabolic disturbances similar to those observed in APD-treated subjects. Given the importance of dopamine and circadian rhythms for beta cells, we hypothesized that the beta cell dopamine system and circadian clock interact and dually regulate insulin secretion, and that circadian manipulations may alter the metabolic impact of APDs. We measured circadian rhythms, insulin release, and the impact of dopamine upon these processes in beta cells using bioluminescent reporters. We then assessed the impact of circadian timing on weight gain and metabolic outcomes in mice treated with the APD sulpiride at the onset of light or dark. We found that molecular components of the dopamine system were rhythmically expressed in beta cells. D2R stimulation by endogenous dopamine or the agonist bromocriptine reduced circadian rhythm amplitude, and altered the temporal profile of insulin secretion. Sulpiride caused greater weight gain and hyperinsulinemia in mice when given in the dark phase compared to the light phase. D2R-acting drugs affect circadian-dopamine interactions and modulate beta cell metabolic function. These findings identify circadian timing as a novel and important mechanism underlying APD-induced metabolic dysfunction, offering new possibilities for therapeutic interventions
登录
查看更多内容
影响因子：
3.7
作者：
Farino ZJ;Morgenstern TJ;Vallaghe J;Gregor N;Donthamsetti P;Harris PE;Pierre N;Freyberg R;Charrier-Savournin F;Javitch JA;Freyberg Z
通讯作者：
Freyberg Z
影响因子：
16.2
作者：
Cincotta, AH;Meier, AH
通讯作者：
Meier, AH
影响因子：
5.3
作者：
Ebdrup, Bjorn H.;Knop, Filip K.;Lublin, Henrik
通讯作者：
Lublin, Henrik
影响因子：
17.7
作者：
Graham, KA;Gu, HB;Perkins, DO
通讯作者：
Perkins, DO
影响因子：
29
作者：
Hatori M;Vollmers C;Zarrinpar A;DiTacchio L;Bushong EA;Gill S;Leblanc M;Chaix A;Joens M;Fitzpatrick JA;Ellisman MH;Panda S
通讯作者：
Panda S