Table_1_The Raphe Pallidus and the Hypothalamic-Pituitary-Thyroid Axis Gate Seasonal Changes in Thermoregulation in the Hibernating Arctic Ground Squirrel (Urocitellus parryii).DOCX

Thermoregulation is necessary to maintain energy homeostasis. The novel discovery of brown adipose tissue (BAT) in humans has increased research interests in better understanding BAT thermogenesis to restore energy balance in metabolic disorders. The hibernating Arctic ground squirrel (AGS) offers a novel approach to investigate BAT thermogenesis. AGS seasonally increase their BAT mass to increase the ability to generate heat during interbout arousals. The mechanisms promoting the seasonal changes in BAT thermogenesis are not well understood. BAT thermogenesis is regulated by the raphe pallidus (rPA) and by thyroid hormones produced by the hypothalamic–pituitary–thyroid (HPT) axis. Here, we investigate if the HPT axis and the rPA undergo seasonal changes to modulate BAT thermogenesis in hibernation. We used histological analysis and tandem mass spectrometry to assess activation of the HPT axis and immunohistochemistry to measure neuronal activation. We found an increase in HPT axis activation in fall and in response to pharmacologically induced torpor when adenosine A1 receptor agonist was administered in winter. By contrast, the rPA neuronal activation was lower in winter in response to pharmacologically induced torpor. Activation of the rPA was also lower in winter compared to the other seasons. Our results suggest that thermogenic capacity develops during fall as the HPT axis is activated to reach maximum capacity in winter seen by increased free thyroid hormones in response to cooling. However, thermogenesis is inhibited during torpor as sympathetic premotor neuronal activation is lower in winter, until arousal when inhibition of thermogenesis is relieved. These findings describe seasonal modulation of thermoregulation that conserves energy through attenuated sympathetic drive, but retains heat generating capacity through activation of the HPT axis.

体温调节对于维持能量稳态至关重要。人类体内棕色脂肪组织（brown adipose tissue, BAT）的全新发现，使得学界对解析BAT产热功能以改善代谢紊乱患者能量平衡的研究兴趣显著提升。冬眠北极地松鼠（Arctic ground squirrel, AGS）为研究BAT产热提供了全新模型：该物种会季节性增加BAT质量，以增强蛰伏间期觉醒时的产热能力。目前，调控BAT产热季节性变化的分子机制仍未被充分阐明。BAT产热受苍白中缝核（raphe pallidus, rPA）以及下丘脑-垂体-甲状腺轴（hypothalamic–pituitary–thyroid axis, HPT轴）分泌的甲状腺激素共同调控。本研究旨在探究HPT轴与rPA是否会发生季节性变化，进而调控冬眠过程中的BAT产热功能。我们采用组织学分析与串联质谱法评估HPT轴的激活状态，并通过免疫组织化学技术检测神经元激活情况。研究发现，在秋季以及冬季给予腺苷A1受体激动剂以药物诱导蛰伏时，HPT轴的激活水平均显著升高。与之相反，在药物诱导蛰伏的冬季个体中，rPA神经元激活水平显著降低；且与其他季节相比，冬季的rPA神经元激活水平同样更低。本研究结果表明，产热能力会在秋季逐步发育，伴随HPT轴激活，在冬季达到峰值——这一现象可通过冷却刺激下游离甲状腺激素水平升高得到验证。然而，蛰伏期间产热过程会被抑制，表现为冬季交感前运动神经元激活水平降低，直至觉醒时该抑制才会解除。本研究揭示了体温调节的季节性调控机制：通过减弱交感神经驱动以节约能量，同时通过激活HPT轴保留产热能力。