Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons
Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons
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DOI：
10.1073/pnas.1219485110
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发表时间：
2013-06-11
影响因子：
11.1
通讯作者：
Di Marzo, Vincenzo
中科院分区：
文献类型：
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作者：
Cristino, Luigia;Busetto, Giuseppe;Di Marzo, Vincenzo
能量状态的急性或慢性改变改变了兴奋性和抑制性突触传递之间的平衡以及相关的突触可塑性，以允许能量代谢适应新的稳态要求。这种变化对内源性大麻素和大麻素受体1型（CB 1）介导的突触传递和强度调节的影响尚不清楚，尽管这种信号传导系统是开发抗肥胖新药的重要靶点。我们研究了CB 1表达的兴奋性与抑制性输入到下丘脑外侧含食欲素A的神经元是否在肥胖症中改变，以及这如何改变这些神经元的内源性大麻素控制。在瘦老鼠中，这些输入主要是兴奋性的。通过共聚焦和超微结构显微镜分析，我们观察到，在瘦素敲除（ob/ob）肥胖小鼠，并在小鼠饮食诱导的肥胖，食欲素能神经元主要接受抑制CB 1表达输入和过表达的内源性大麻素2-花生四烯酸甘油，这逆行抑制突触传递在CB 1表达轴突终端的生物合成酶。膜片钳记录也显示增加CB 1敏感的抑制性神经支配的orexinergic神经元在ob/ob小鼠。这些改变逆转瘦素管理，部分通过激活哺乳动物靶雷帕霉素途径的神经肽-Y-能神经元的弓状核，并伴随着CB 1介导的增强食欲素能神经支配的目标脑区。我们建议，增强食欲素-A神经元的抑制控制，和CB 1介导的去抑制，是弓状核瘦素信号障碍的结果。我们还提供了初步的证据表明，这种现象的参与，在暴食症和激素失调的肥胖。
Acute or chronic alterations in energy status alter the balance between excitatory and inhibitory synaptic transmission and associated synaptic plasticity to allow for the adaptation of energy metabolism to new homeostatic requirements. The impact of such changes on endocannabinoid and cannabinoid receptor type 1 (CB1)-mediated modulation of synaptic transmission and strength is not known, despite the fact that this signaling system is an important target for the development of new drugs against obesity. We investigated whether CB1-expressing excitatory vs. inhibitory inputs to orexin-A-containing neurons in the lateral hypothalamus are altered in obesity and how this modifies endocannabinoid control of these neurons. In lean mice, these inputs are mostly excitatory. By confocal and ultrastructural microscopic analyses, we observed that in leptin-knockout (ob/ob) obese mice, and in mice with diet-induced obesity, orexinergic neurons receive predominantly inhibitory CB1-expressing inputs and overexpress the biosynthetic enzyme for the endocannabinoid 2-arachidonoylglycerol, which retrogradely inhibits synaptic transmission at CB1-expressing axon terminals. Patch-clamp recordings also showed increased CB1-sensitive inhibitory innervation of orexinergic neurons in ob/ob mice. These alterations are reversed by leptin administration, partly through activation of the mammalian target of rapamycin pathway in neuropeptide-Y-ergic neurons of the arcuate nucleus, and are accompanied by CB1-mediated enhancement of orexinergic innervation of target brain areas. We propose that enhanced inhibitory control of orexin-A neurons, and their CB1-mediated disinhibition, are a consequence of leptin signaling impairment in the arcuate nucleus. We also provide initial evidence of the participation of this phenomenon in hyperphagia and hormonal dysregulation in obesity.