Endocannabinoid Signaling at Hypothalamic Steroidogenic Factor-1/Proopiomelanocortin Synapses Is Sex- and Diet-Sensitive
Endocannabinoid Signaling at Hypothalamic Steroidogenic Factor-1/Proopiomelanocortin Synapses Is Sex- and Diet-Sensitive
复制标题
DOI：
10.3389/fnmol.2018.00214
复制
发表时间：
2018-06-19
影响因子：
4.8
通讯作者：
Wagner, Edward J.
中科院分区：
文献类型：
--
作者：
Fabelo, Carolina;Hernandez, Jennifer;Wagner, Edward J.
我们测试了以下假设：下丘脑腹内侧核 (VMN) 中的类固醇生成因子 (SF)-1 神经元向阿片黑皮质素原 (POMC) 神经元提供性别不同的内源性大麻素 (EC) 和饮食敏感的谷氨酸能输入。在完整和去势豚鼠的下丘脑切片中进行电生理记录，并对完整雄性以及循环和卵巢切除的雌性 NR5A1-Cre 小鼠进行体外光遗传学实验。在去势雄性和雌性豚鼠的切片中，去极化诱导的兴奋抑制 (DSE) 时间依赖性地降低了 POMC 神经元中通过电刺激背内侧 VMN 产生的诱发兴奋性突触后电流 (eEPSC) 的幅度。雄激素刺激迅速增强了这种 DSE，这种情况在胰岛素抵抗、高脂肪饮食 (HFD) 喂养的男性中也发现了。相比之下，在排卵期女性中，VMN/ARC POMC 突触的逆行信号明显减弱。 HFD 增强了男性和女性中枢大麻素引起的食欲亢进，但对大麻素引起的能量消耗增加产生了不同的影响。在 NR5A1-Cre 小鼠中，与完整雄性小鼠相比，循环雌性小鼠突触后去极化引起的光诱发 EPSC 振幅降低幅度较小。雌二醇减弱了卵巢切除女性切片中光诱发 EPSC 振幅的 DSE。此外，在高脂饮食的雄性中，传播的逆行抑制进一步加剧。 SF-1 神经元的化学遗传学激活抑制了雄性的食欲并增加了能量消耗，而 HFD 减弱了这种影响。相反，雌二醇治疗的卵巢切除女性的能量消耗增加，但媒介物治疗的能量消耗没有增加。与我们之前的研究一起表明 POMC 神经元中的 DSE 是 EC 介导的，这些发现表明 VMN SF-1/ARC POMC 突触代表下丘脑能量平衡回路内的性别分化、EC 和饮食敏感的厌食成分。
We tested the hypotheses that steroidogenic factor (SF)-1 neurons in the hypothalamic ventromedial nucleus (VMN) provide sexually disparate, endocannabinoid (EC)and diet-sensitive glutamatergic input onto proopiomelanocortin (POMC) neurons. Electrophysiological recordings were performed in hypothalamic slices from intact and castrated guinea pigs, along with in vitro optogenetic experiments in intact male as well as cycling and ovariectomized female NR5A1-Cre mice. In slices from castrated male and female guinea pigs, depolarized-induced suppression of excitation (DSE) time-dependently reduced the amplitude of evoked excitatory postsynaptic currents (eEPSCs) in POMC neurons generated by electrically stimulating the dorsomedial VMN. Androgen stimulation rapidly enhanced this DSE, which was also found in insulinresistant, high-fat diet (HFD)-fed males. By contrast, retrograde signaling at VMN/ARC POMC synapses was markedly attenuated in periovulatory females. HFD potentiated central cannabinoid-induced hyperphagia in both males and females, but exerted differential influences on cannabinoid-induced increases in energy expenditure. In NR5A1-Cre mice, the reduction in light-evoked EPSC amplitude caused by postsynaptic depolarization in cycling females was modest in comparison to that seen in intact males. Estradiol attenuated the DSE in light-evoked EPSC amplitude in slices from ovariectomized females. Moreover, the retrograde inhibition of transmission was further accentuated in HFD-fed males. Chemogenetic activation of SF-1 neurons suppressed appetite and increased energy expenditure in males, effects which were attenuated by HFD. Conversely, energy expenditure was increased in estradiol- but not vehicle-treated ovariectomized females. Together with our previous studies indicating that DSE in POMC neurons is EC-mediated, these findings indicate that VMN SF-1/ARC POMC synapses represent a sexually differentiated, EC- and diet-sensitive anorexigenic component within the hypothalamic energy balance circuitry.