Pituitary adenylate cyclase-activating polypeptide receptor activation in the hypothalamus recruits unique signaling pathways involved in energy homeostasis.
Pituitary adenylate cyclase-activating polypeptide receptor activation in the hypothalamus recruits unique signaling pathways involved in energy homeostasis.
复制标题
下丘脑中垂体腺苷酸环化酶激活多肽受体的激活会招募参与能量稳态的独特信号通路。
DOI：
10.1152/ajpendo.00320.2021
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Choi,SuJean
中科院分区：
文献类型：
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作者：
Maunze,Brian;Bruckner,KatherineWood;Desai,NikhilNilesh;Chen,Christopher;Chen,Fanghong;Baker,David;Choi,SuJean
垂体腺苷环化酶激活多肽(PACAP)通过其I型PAC1受体(PAC1R)对下丘脑腹内侧核(VMN)发挥多效性作用，控制摄食和能量消耗。然而，PAC1Rs在VMN中的内源性作用以及PACAP对能量平衡的影响的下游信号转导机制尚不清楚。大量研究表明，PAC1Rs既与GαS/腺苷环化酶/蛋白激酶A(GαS/AC/PKA)和GαQ/磷脂酶C/蛋白激酶C(GαQ/PLC/PKC)偶联，又在刺激后发生转运。为了确定PAC1Rs的内源性作用和可能解释PACAP的多效性的下游信号，我们使用RNA干扰来敲除VMN PAC1Rs，并从药物上抑制PKA、PKC和PAC1R的运输。敲掉PAC1Rs会增加进餐数量，减少进餐总次数，并导致体重增加。在清醒的雄性SD大鼠中，单独抑制PKA或PKC，可减弱PACAP在黑暗阶段的低噬和厌食效应。然而，PKA或PKC抑制增强了PACAP在光期的生热效应。运动活性分析显示，抑制PKA可增强PACAP的运动效应，而抑制PKC对PACAP的运动无影响。最后，在VMN内给予PACAP可诱导表面PAC1R转运到胞浆中，而胞吞作用抑制剂可以阻止这种转运。随后，抑制PAC1R进入胞浆的运输减弱了PACAP诱导的低噬菌体反应。这些结果表明，内源性PAC1Rs独特地参与PKA、PKC和受体转运，介导PACAP在VMN控制摄食和代谢中的多效性。内源性PAC1受体是VMN管理摄食行为和体重调节的组成部分，独特地参与PKA、PKC和受体转运，介导下丘脑腹内侧核对摄食和代谢的控制。PACAP似乎使用不同的信号机制从其对新陈代谢的影响来调节摄食行为。
Pituitary adenylate cyclase activating polypeptide (PACAP) exerts pleiotropic effects on ventromedial nuclei (VMN) of the hypothalamus and its control of feeding and energy expenditure through the type I PAC1 receptor (PAC1R). However, the endogenous role of PAC1Rs in the VMN and the downstream signaling responsible for PACAP’s effects on energy balance are unknown. Numerous studies have revealed that PAC1Rs are coupled to both Gαs/adenylyl cyclase/protein kinase A (Gαs/AC/PKA) and Gαq/phospholipase C/protein kinase C (Gαq/PLC/PKC), while also undergoing trafficking following stimulation. To determine the endogenous role of PAC1Rs and downstream signaling that may explain PACAP’s pleiotropic effects, we used RNA interference to knockdown VMN PAC1Rs and pharmacologically inhibited PKA, PKC, and PAC1R trafficking. Knocking down PAC1Rs increased meal sizes, reduced total number of meals, and induced body weight gain. Inhibition of either PKA or PKC alone in awake male Sprague–Dawley rats, attenuated PACAP’s hypophagic and anorectic effects during the dark phase. However, PKA or PKC inhibition potentiated PACAP’s thermogenic effects during the light phase. Analysis of locomotor activity revealed that PKA inhibition augmented PACAP’s locomotor effects, whereas PKC inhibition had no effect. Finally, PACAP administration in the VMN induces surface PAC1R trafficking into the cytosol which was blocked by endocytosis inhibitors. Subsequently, inhibition of PAC1R trafficking into the cytosol attenuated PACAP-induced hypophagia. These results revealed that endogenous PAC1Rs uniquely engage PKA, PKC, and receptor trafficking to mediate PACAP’s pleiotropic effects in VMN control of feeding and metabolism.NEW & NOTEWORTHYEndogenous PAC1 receptors, integral to VMN management of feeding behavior and body weight regulation, uniquely engage PKA, PKC, and receptor trafficking to mediate the hypothalamic ventromedial nuclei control of feeding and metabolism. PACAP appears to use different signaling mechanisms to regulate feeding behavior from its effects on metabolism.