Regulation of Hypothalamic Signaling by Tuberoinfundibular Peptide of 39 Residues Is Critical for the Response to Cold: A Novel Peptidergic Mechanism of Thermoregulation
Regulation of Hypothalamic Signaling by Tuberoinfundibular Peptide of 39 Residues Is Critical for the Response to Cold: A Novel Peptidergic Mechanism of Thermoregulation
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DOI：
10.1523/jneurosci.2619-11.2011
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发表时间：
2011-12-07
影响因子：
5.3
通讯作者：
Usdin, Ted B.
中科院分区：
文献类型：
--
作者：
Dimitrov, Eugene L.;Kim, Yoon Yi;Usdin, Ted B.
低温对哺乳动物的体内平衡至关重要。视前下丘脑内的回路调节温度，通过降低gaba能抑制控制棕色脂肪组织（BAT）产热和皮肤血管张力的前交感运动神经元来进行精细控制。下丘脑兴奋性神经元的体温调节作用尚不清楚。在这里，我们报告了有助于温度调节的视前谷氨酸能神经元的肽能调节。tuberininfundibular peptide of 39个残基（TIP39）是甲状旁腺激素2受体（PTH2R）的配体。肽和受体在视前下丘脑中均丰富。基于PTH2R和囊性谷氨酸转运蛋白2 （VGlut2）免疫标记动物逆行示色剂注射，含有PTH2R的谷氨酸能纤维突触前连接到从视前正中核（MnPO）投射到下丘脑背内侧的神经元。假性狂犬病毒的跨神经元逆行通路追踪揭示了MnPO VGlut2和PTH2R神经元与BAT之间的联系。注射TIP39的MnPO使体温升高2℃，持续数小时。由于PTH2R缺失突变或PTH2R拮抗剂的脑传递，缺乏TIP39信号的小鼠在冷暴露时产生的热量受损，但基础温度没有变化，对热环境的反应没有损伤。因此，TIP39似乎作用于存在于MnPO谷氨酸末端的PTH2Rs，以调节其对投射神经元的激活和随后的交感BAT激活。这种产热的兴奋性机制似乎在需要时被激活，在寒冷暴露期间，与体温的强直性抑制性gaba能控制相似。
Euthermia is critical for mammalian homeostasis. Circuits within the preoptic hypothalamus regulate temperature, with fine control exerted via descending GABAergic inhibition of presympathetic motor neurons that control brown adipose tissue (BAT) thermogenesis and cutaneous vascular tone. The thermoregulatory role of hypothalamic excitatory neurons is less clear. Here we report peptidergic regulation of preoptic glutamatergic neurons that contributes to temperature regulation. Tuberoinfundibular peptide of 39 residues (TIP39) is a ligand for the parathyroid hormone 2 receptor (PTH2R). Both peptide and receptor are abundant in the preoptic hypothalamus. Based on PTH2R and vesicular glutamate transporter 2 (VGlut2) immunolabeling in animals with retrograde tracer injection, PTH2R-containing glutamatergic fibers are presynaptic to neurons projecting from the median preoptic nucleus (MnPO) to the dorsomedial hypothalamus. Transneuronal retrograde pathway tracing with pseudorabies virus revealed connectivity between MnPO VGlut2 and PTH2R neurons and BAT. MnPO injection of TIP39 increased body temperature by 2 degrees C for several hours. Mice lacking TIP39 signaling, either because of PTH2R-null mutation or brain delivery of a PTH2R antagonist had impaired heat production upon cold exposure, but no change in basal temperature and no impairment in response to a hot environment. Thus, TIP39 appears to act on PTH2Rs present on MnPO glutamatergic terminals to regulate their activation of projection neurons and subsequent sympathetic BAT activation. This excitatory mechanism of heat production appears to be activated on demand, during cold exposure, and parallels the tonic inhibitory GABAergic control of body temperature.