Wilson Mark E, Fisher Jeffrey, Brown Juliet
Division of Psychobiology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, United States.
Physiol Behav. 2005 Mar 16;84(3):449-58. doi: 10.1016/j.physbeh.2005.01.013.
The fat derived protein leptin has its anorexic action through a number of neuropeptides including an upregulation of corticotropin releasing hormone (CRH) expression in the hypothalamus. However, the influence of leptin on these neuropeptides may be different during stress. The present study used ovariectomized female rhesus monkeys (n=8) to further define the effect of leptin on HPA responsivity. To accomplish this, we assessed the effects of constant leptin infusion on cortisol and ACTH secretion in both a predictable and unpredictable situation as well as in response to dexamethasone suppression-CRH stimulation test. We hypothesized that leptin would attenuate the increase in cortisol and ACTH to a novel, unpredictable situation and would enhance glucocorticoid negative feedback and diminish the response to CRH. Animals were assessed under control placebo conditions and during a 28 day infusion with recombinant human leptin (6 microg/kg/day, SC). Within each treatment condition, HPA responsivity was assessed during no estradiol replacement and acute estradiol replacement that produced serum concentrations of approximately 40 pg/ml. However, the results indicated that neither estradiol alone or in combination with leptin had any consistent effect on the outcome measures. Compared to the control condition, leptin had no effect on the cortisol diurnal rhythm; however, evening but not morning plasma ACTH concentrations were significantly lower during leptin infusion. In contrast, the response in plasma cortisol and ACTH to an unpredictable situation was significantly attenuated by chronic leptin infusion. Furthermore, leptin enhanced glucocorticoid negative feedback and blunted CRH-induced increase in both cortisol and ACTH. Taken together, these data suggest that in the female monkey, leptin has little effect on basal cortisol. However, when the HPA axis is activated, leptin attenuates the neuroendocrine response by enhancing glucocorticoid negative feedback. These data underscore the potential importance of leptin in maintaining homeostasis through its diverse interaction with the HPA axis.
脂肪衍生蛋白瘦素通过多种神经肽发挥其厌食作用，包括上调下丘脑促肾上腺皮质激素释放激素（CRH）的表达。然而，在应激期间，瘦素对这些神经肽的影响可能有所不同。本研究使用去卵巢雌性恒河猴（n = 8）进一步明确瘦素对下丘脑-垂体-肾上腺（HPA）轴反应性的影响。为此，我们评估了在可预测和不可预测情况下持续输注瘦素对皮质醇和促肾上腺皮质激素（ACTH）分泌的影响，以及对地塞米松抑制-促肾上腺皮质激素释放激素刺激试验的反应。我们假设瘦素会减弱皮质醇和促肾上腺皮质激素对新的、不可预测情况的增加反应，并会增强糖皮质激素负反馈，减少对促肾上腺皮质激素释放激素的反应。在对照安慰剂条件下以及在28天输注重组人瘦素（6微克/千克/天，皮下注射）期间对动物进行评估。在每种治疗条件下，在不进行雌二醇替代和急性雌二醇替代（产生血清浓度约为40皮克/毫升）期间评估HPA轴反应性。然而，结果表明，单独的雌二醇或与瘦素联合使用对结果指标均无任何一致的影响。与对照条件相比，瘦素对皮质醇昼夜节律无影响；然而，在输注瘦素期间，夜间而非早晨的血浆促肾上腺皮质激素浓度显著降低。相反，慢性输注瘦素可显著减弱血浆皮质醇和促肾上腺皮质激素对不可预测情况的反应。此外，瘦素增强了糖皮质激素负反馈，并减弱了促肾上腺皮质激素释放激素诱导的皮质醇和促肾上腺皮质激素的增加。综上所述，这些数据表明，在雌性猴子中，瘦素对基础皮质醇影响不大。然而，当HPA轴被激活时，瘦素通过增强糖皮质激素负反馈来减弱神经内分泌反应。这些数据强调了瘦素通过与HPA轴的多种相互作用在维持体内平衡方面的潜在重要性。
