Pacak K, McCarty R, Palkovits M, Cizza G, Kopin I J, Goldstein D S, Chrousos G P
Clinical Neuroscience Branch, National Institute of Neurological Disorders and Stroke, National Institute of Mental Health, Bethesda, Maryland 20892, USA.
Endocrinology. 1995 Oct;136(10):4360-7. doi: 10.1210/endo.136.10.7664655.
The Zucker rat is an animal model of autosomal recessive obesity characterized by excessive hypothalamic-pituitary-adrenal (HPA) axis and parasympathetic activities and deficient sympathetic outflow. Alterations in norepinephrine (NE) release, reuptake, and metabolism in the hypothalamic paraventricular nucleus (PVN) could also contribute to dysregulation of the HPA axis in obese Zucker rats via effects on corticotropin-releasing hormone neurons or could be secondary to some other primary defect. The present study assessed whether the obese phenotype defect. The present study assessed whether the obese phenotype (fa/fa) compared to the lean phenotype (Fa/?) of this strain was also associated with alterations in basal and immobilization (IMMO) stress-induced noradrenergic activation in the PVN, using in vivo microdialysis. To evaluate concurrent activity of the peripheral sympathetic nervous system and the HPA axis, we also measured plasma concentrations of catecholamines, ACTH, and corticosterone. IMMO-induced increases in PVN NE levels were significantly lower in obese Zucker rats, as were elevations in plasma concentrations of dihydroxyphenylglycol and epinephrine. Basal and IMMO-stimulated plasma ACTH concentrations were similar in obese and lean rats. Basal plasma corticosterone concentrations were also similar in obese and lean rats; however, IMMO-stimulated corticosterone levels were significantly greater in obese than in lean animals. Basal plasma free corticosterone levels, measured by ultrafiltration, were significantly higher in obese than in lean rats, confirming the state of chronic hypercorticosteronism in these animals. These findings indicate that obese Zucker rats have diminished central noradrenergic and peripheral sympathetic nervous system responses to IMMO stress along with a chronically hyperactive HPA axis. We suggest that defective regulation of PVN NE reflects and contributes to the development and/or maintenance of obesity in Zucker rats via central hypoactivity of the sympathetic system. The hypercorticosteronism of these animals, apparently sustained by some nonadrenergic stimulatory input, might participate in the suppression of the sympathetic system.
Zucker大鼠是常染色体隐性肥胖的动物模型，其特征为下丘脑 - 垂体 - 肾上腺（HPA）轴过度活跃和副交感神经活动以及交感神经输出不足。下丘脑室旁核（PVN）中去甲肾上腺素（NE）释放、再摄取和代谢的改变，也可能通过对促肾上腺皮质激素释放激素神经元的影响，导致肥胖Zucker大鼠的HPA轴失调，或者可能是某些其他原发性缺陷的继发结果。本研究评估了该品系肥胖表型（fa/fa）与瘦型表型（Fa/?）相比，是否也与PVN中基础和固定（IMMO）应激诱导的去甲肾上腺素能激活改变有关，采用体内微透析法。为了评估外周交感神经系统和HPA轴的同时活动，我们还测量了血浆中儿茶酚胺、促肾上腺皮质激素（ACTH）和皮质酮的浓度。肥胖Zucker大鼠中，IMMO诱导的PVN中NE水平升高显著低于正常大鼠，血浆中二羟苯乙二醇和肾上腺素浓度的升高情况也是如此。肥胖和瘦大鼠的基础及IMMO刺激后的血浆ACTH浓度相似。肥胖和瘦大鼠的基础血浆皮质酮浓度也相似；然而，IMMO刺激后，肥胖大鼠的皮质酮水平显著高于瘦大鼠。通过超滤测量的基础血浆游离皮质酮水平，肥胖大鼠显著高于瘦大鼠，证实了这些动物存在慢性高皮质酮血症状态。这些发现表明，肥胖Zucker大鼠对IMMO应激的中枢去甲肾上腺素能和外周交感神经系统反应减弱，同时伴有HPA轴长期过度活跃。我们认为，PVN中NE调节缺陷反映并促成了Zucker大鼠肥胖的发生和/或维持，其机制是交感神经系统中枢活性降低。这些动物的高皮质酮血症显然由一些非肾上腺素能刺激输入维持，可能参与了对交感神经系统的抑制。
