Activation of temperature-sensitive TRPV1-like receptors in ARC POMC neurons reduces food intake.
Activation of temperature-sensitive TRPV1-like receptors in ARC POMC neurons reduces food intake.
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DOI：
10.1371/journal.pbio.2004399
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发表时间：
2018-04
期刊：
影响因子：
9.8
通讯作者：
Jo YH
中科院分区：
文献类型：
--
作者：
Jeong JH;Lee DK;Liu SM;Chua SC Jr;Schwartz GJ;Jo YH
下丘脑弓状核（ARC）中的前阿黑皮素（POMC）神经元对许多激素和神经信号作出反应，导致食物摄入量的变化。在这里，我们表明，ARC POMC神经元表达辣椒素敏感的瞬时受体电位香草酸受体1（TRPV 1）样受体。为了显示TRPV 1样受体在ARC POMC神经元中的表达，我们使用单细胞逆转录聚合酶链反应（RT-PCR），免疫组织化学，电生理学，TRPV 1敲除（KO）和TRPV 1-Cre敲入小鼠。在生理范围内，温度的小幅升高足以使ARC POMC神经元去活化。这种去极化被TRPV 1受体拮抗剂和Trpv 1基因敲低阻断。辣椒素诱导的激活减少食物摄入，这被黑皮质素受体拮抗剂所消除。为了选择性地刺激ARC中表达TRPV 1样受体的ARC POMC神经元，我们产生了携带Cre依赖性通道视紫红质-2（ChR 2）增强的黄色荧光蛋白（eYFP）表达盒的腺相关病毒血清型5（AAV 5），该表达盒在两个神经元POMC增强子（nPE）的控制下。TRPV 1样受体表达POMC神经元的光遗传刺激减少食物摄入。下丘脑温度迅速升高，在跑步机跑步期间达到约39 °C。这种升高与食物摄入量减少有关。Trpv 1基因的敲除只在ARC POMC神经元阻断摄食抑制下丘脑温度升高产生的。综上所述，我们的研究结果确定了一个黑皮质素能回路，该回路将下丘脑温度的急性升高与食物摄入的急性减少联系起来。剧烈运动会严重降低食欲和随后的食物摄入量。由于运动伴随着体温的升高，我们假设运动期间体温的升高在减少食物摄入方面起着作用。下丘脑神经元是神经回路的主要组成部分，其响应于激素和神经信号来控制进食。在下丘脑神经元中，下丘脑弓状核中表达阿黑皮素原（POMC）的神经元在控制食物摄入方面很重要。在这项研究中，我们发现这些POMC表达神经元表达TRPV 1样的温度感受器，这些温度感受器在小鼠生理范围内的温度升高时被激活。我们还表明，运动期间体温的升高是通过这些POMC表达神经元激活TRPV 1样受体直接感知的。因此，这项研究为能量平衡的细胞机制提供了一个新的视角：体温通过下丘脑弓状核POMC表达神经元中的TRPV 1样受体减少食物摄入。
Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC) respond to numerous hormonal and neural signals, resulting in changes in food intake. Here, we demonstrate that ARC POMC neurons express capsaicin-sensitive transient receptor potential vanilloid 1 receptor (TRPV1)-like receptors. To show expression of TRPV1-like receptors in ARC POMC neurons, we use single-cell reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, electrophysiology, TRPV1 knock-out (KO), and TRPV1-Cre knock-in mice. A small elevation of temperature in the physiological range is enough to depolarize ARC POMC neurons. This depolarization is blocked by the TRPV1 receptor antagonist and by Trpv1 gene knockdown. Capsaicin-induced activation reduces food intake that is abolished by a melanocortin receptor antagonist. To selectively stimulate TRPV1-like receptor-expressing ARC POMC neurons in the ARC, we generate an adeno-associated virus serotype 5 (AAV5) carrying a Cre-dependent channelrhodopsin-2 (ChR2)–enhanced yellow fluorescent protein (eYFP) expression cassette under the control of the two neuronal POMC enhancers (nPEs). Optogenetic stimulation of TRPV1-like receptor-expressing POMC neurons decreases food intake. Hypothalamic temperature is rapidly elevated and reaches to approximately 39 °C during treadmill running. This elevation is associated with a reduction in food intake. Knockdown of the Trpv1 gene exclusively in ARC POMC neurons blocks the feeding inhibition produced by increased hypothalamic temperature. Taken together, our findings identify a melanocortinergic circuit that links acute elevations in hypothalamic temperature with acute reductions in food intake. Intense exercise acutely decreases appetite and subsequent food intake. As exercise is accompanied by increased body temperature, we hypothesized that a rise in body temperature during exercise plays a role in reducing food intake. The hypothalamic neurons are major components of the neural circuits that control feeding in response to hormones and neural signals. Among hypothalamic neurons, those that express proopiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus are important in controlling food intake. In this study, we found that these POMC-expressing neurons express TRPV1-like thermoreceptors that are activated by an increase in temperature within the physiological range in mice. We also showed that an increase in body temperature during exercise is directly sensed by these POMC-expressing neurons through activation of the TRPV1-like receptors. Hence, this study provides a novel perspective on the cellular mechanisms underlying energy balance: body temperature reduces food intake via TRPV1-like receptors in POMC-expressing neurons in the arcuate nucleus of the hypothalamus.
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DOI：
10.1523/jneurosci.6451-10.2011
发表时间：
2011-03-30
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Cavanaugh DJ;Chesler AT;Jackson AC;Sigal YM;Yamanaka H;Grant R;O'Donnell D;Nicoll RA;Shah NM;Julius D;Basbaum AI
通讯作者：
Basbaum AI
影响因子：
4.9
作者：
Hibi, M.;Oishi, S.;Matsushita, M.;Yoneshiro, T.;Yamaguchi, T.;Usui, C.;Yasunaga, K.;Katsuragi, Y.;Kubota, K.;Tanaka, S.;Saito, M.
通讯作者：
Saito, M.
影响因子：
7.7
作者：
Henry FE;Sugino K;Tozer A;Branco T;Sternson SM
通讯作者：
Sternson SM
影响因子：
3.5
作者：
Anderson EJ;Çakir I;Carrington SJ;Cone RD;Ghamari-Langroudi M;Gillyard T;Gimenez LE;Litt MJ
通讯作者：
Litt MJ
影响因子：
16.2
作者：
Elias, CF;Aschkenasi, C;Elmquist, JK
通讯作者：
Elmquist, JK