Department of Pharmacology and Physiology, Center for Neuroscience Research, Saint Louis University School of Medicine, St. Louis, Missouri.
Am J Physiol Regul Integr Comp Physiol. 2020 Jun 1;318(6):R1027-R1035. doi: 10.1152/ajpregu.00023.2020. Epub 2020 Apr 15.
There are examples of physiological conditions under which thirst is inappropriately exaggerated, and the mechanisms for these paradoxical ingestive behaviors remain unknown. We are interested in thirst mechanisms across the female life cycle and have identified a novel mechanism through which ingestive behavior may be activated. We discovered a previously unrecognized endogenous hypothalamic peptide, phoenixin (PNX), identified physiologically relevant actions of the peptide in brain and pituitary gland to control reproductive hormone secretion in female rodents, and in the process identified the previously orphaned G protein-coupled receptor Gpr173 to be a potential receptor for the peptide. Labeled PNX binding distribution in brain parallels areas known to be important in ingestive behaviors as well in areas where gonadal steroids feedback to control estrous cyclicity (Stein LM, Tullock CW, Mathews SK, Garcia-Galiano D, Elias CF, Samson WK, Yosten GLC, 311: R489-R496, 2016). We have demonstrated upregulation of Gpr173 during puberty, fluctuations across the estrous cycle, and, importantly, upregulation during the last third of gestation. It is during this hypervolemic, hyponatremic state that both vasopressin secretion and thirst are inappropriately elevated in humans. Here, we show that central administration of PNX stimulated water drinking in both males and females under ad libitum conditions, increased water drinking after overnight fluid deprivation, and increased both water and 1.5% NaCl ingestion under fed and hydrated conditions. Importantly, losartan pretreatment blocked the effect of PNX on water drinking, and knockdown of Gpr173 by use of short interfering RNA constructs significantly attenuated water drinking in response to overnight fluid deprivation. These actions, together with the stimulatory action of PNX on vasopressin secretion, suggest that this recently discovered neuropeptide may impact the recruitment of critically important neural circuits through which ingestive behaviors and endocrine mechanisms that maintain fluid and electrolyte homeostasis are regulated.
有些生理状况会导致口渴被不适当地夸大，而这些矛盾性摄食行为的机制仍不清楚。我们对女性生命周期中的口渴机制感兴趣，并发现了一种新的机制，通过这种机制，摄食行为可能会被激活。我们发现了一种以前未被识别的内源性下丘脑肽——凤凰素（PNX），该肽在大脑和垂体中具有控制雌性啮齿动物生殖激素分泌的生理相关作用，在此过程中，我们还鉴定出了以前被认为是孤儿的 G 蛋白偶联受体 Gpr173 是该肽的潜在受体。标记的 PNX 结合分布与已知在摄食行为中重要的脑区以及控制发情周期的性腺类固醇反馈的脑区相吻合（Stein LM、Tullock CW、Mathews SK、Garcia-Galiano D、Elias CF、Samson WK、Yosten GLC，311：R489-R496，2016）。我们已经证明 Gpr173 在青春期上调，在发情周期中波动，重要的是，在妊娠的最后三分之一期间上调。正是在这种高血容量、低钠血症状态下，人类的血管加压素分泌和口渴都会不适当地增加。在这里，我们发现在自由摄取条件下，PNX 中枢给药会刺激雄性和雌性动物饮水，在经历一夜的液体剥夺后，会增加水的摄取量，在进食和水合状态下，会增加水和 1.5%NaCl 的摄取量。重要的是，洛沙坦预处理阻断了 PNX 对饮水的影响，并且使用短干扰 RNA 构建体敲低 Gpr173 会显著减弱对一夜液体剥夺的水摄取反应。这些作用，以及 PNX 对血管加压素分泌的刺激作用，表明这种新发现的神经肽可能会影响关键的神经回路的招募，通过这些回路，摄食行为和维持液体和电解质平衡的内分泌机制得以调节。
