Belanger-Willoughby N, Linehan V, Hirasawa M
Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, Newfoundland A1B 3V6, Canada.
Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, Newfoundland A1B 3V6, Canada.
Neuroscience. 2016 Jun 2;324:82-91. doi: 10.1016/j.neuroscience.2016.03.003. Epub 2016 Mar 8.
In homeotherms, the hypothalamus controls thermoregulatory and adaptive mechanisms in energy balance, sleep-wake and locomotor activity to maintain optimal body temperature. Orexin neurons may be involved in these functions as they promote thermogenesis, food intake and behavioral arousal, and are sensitive to temperature and metabolic status. How thermal and energy balance signals are integrated in these neurons is unknown. Thus, we investigated the cellular mechanisms of thermosensing in orexin neurons and their response to a change in energy status using whole-cell patch clamp on rat brain slices. We found that warming induced an increase in miniature excitatory postsynaptic current (EPSC) frequency, which was blocked by the transient receptor potential vanilloid-1 (TRPV1) receptor antagonist AMG9810 and mimicked by its agonist capsaicin, suggesting that the synaptic effect is mediated by heat-sensitive TRPV1 channels. Furthermore, warming inhibits orexin neurons by activating ATP-sensitive potassium (KATP) channels, an effect regulated by uncoupling protein 2 (UCP2), as the UCP2 inhibitor genipin abolished this response. These properties are unique to orexin neurons in the lateral hypothalamus, as neighboring melanin-concentrating hormone neurons showed no response to warming within the physiological temperature range. Interestingly, in rats fed with western diet for 1 or 11weeks, orexin neurons had impaired synaptic and KATP response to warming. In summary, this study reveals several mechanisms underlying thermosensing in orexin neurons and their attenuation by western diet. Overeating induced by western diet may in part be due to impaired orexin thermosensing, as post-prandial thermogenesis may promote satiety and lethargy by inhibiting orexin neurons.
在恒温动物中，下丘脑控制能量平衡、睡眠 - 觉醒和运动活动中的体温调节及适应性机制，以维持最佳体温。食欲素神经元可能参与这些功能，因为它们促进产热、食物摄入和行为觉醒，并且对温度和代谢状态敏感。尚不清楚热和能量平衡信号如何在这些神经元中整合。因此，我们使用大鼠脑片的全细胞膜片钳技术，研究了食欲素神经元中温度感受的细胞机制及其对能量状态变化的反应。我们发现，升温诱导微小兴奋性突触后电流（EPSC）频率增加，该增加被瞬时受体电位香草酸受体1（TRPV1）拮抗剂AMG9810阻断，并被其激动剂辣椒素模拟，这表明突触效应是由热敏感的TRPV1通道介导的。此外，升温通过激活ATP敏感性钾（KATP）通道抑制食欲素神经元，该效应由解偶联蛋白2（UCP2）调节，因为UCP2抑制剂京尼平消除了这种反应。这些特性是下丘脑外侧食欲素神经元所特有的，因为相邻的促黑素细胞激素神经元在生理温度范围内对升温无反应。有趣的是，用西式饮食喂养1周或11周的大鼠，食欲素神经元对升温的突触和KATP反应受损。总之，本研究揭示了食欲素神经元温度感受的几种机制及其被西式饮食减弱的情况。西式饮食引起的暴饮暴食可能部分归因于食欲素温度感受受损，因为餐后产热可能通过抑制食欲素神经元促进饱腹感和嗜睡。
