Leptin inhibition of the hypothalamic-pituitary-adrenal axis in response to stress
Leptin inhibition of the hypothalamic-pituitary-adrenal axis in response to stress
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DOI：
10.1210/en.138.9.3859
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发表时间：
1997-09-01
期刊：
影响因子：
4.8
通讯作者：
Flier, JS
中科院分区：
文献类型：
--
作者：
Heiman, ML;Ahima, RS;Flier, JS
瘦素是一种新发现的蛋白质激素，由脂肪组织合成和分泌。成熟激素的缺乏是 ob lob 小鼠肥胖表型的原因。 ob lob 小鼠的下丘脑-垂体-肾上腺轴 (HPAA) 被激活，长期给予 ob/ob 小鼠瘦素会降低血浆皮质酮水平，表明脂肪激素能够抑制 HPAA。本研究的目的是确定瘦素是否会急性反馈抑制正常小鼠和大鼠的 HPAA。雄性C57BL小鼠腹腔注射100μl盐水和2或4μg/g BW小鼠瘦素（溶于盐水载体），4小时后，通过将后肢绑在一起或无压力，使它们承受2小时的约束应力。通过 ACTH 和皮质酮显着升高（P < 0.05）来测量，善意的腿部约束刺激了 HPAA。用重组小鼠瘦素进行预处理可阻断应激介导的两种血浆激素的刺激。为了确定这种抑制是否是通过抑制 CRH 在下丘脑水平发挥的，我们研究了瘦素对灌注含有葡萄糖 (5.5 mM) 的 Krebs-Ringer 缓冲液的离体大鼠下丘脑的作用。通过将缓冲液的葡萄糖浓度降低至 1.1 mM 来刺激 CRH 分泌。 CRH 在 2 小时内释放激增（基础综合释放量为 14.4 +/- 1.6 pg/2 小时，n = 5，增加至 34.7 +/- 3.1 pg/2 小时，n = 14）。这种反应被小鼠瘦素以剂量依赖性方式黑色化（1 nM、3 nM 和 30 nM 的综合刺激 CRH 分泌分别为 30.6 +/- 2.5 pg/2 h，n = 5；20.5 +/- 3.6 pg/2 h，n = 7；15.3 +/- 4.3 pg/2 h，n = 3）。瘦素不改变大鼠原代培养的垂体细胞分泌ACTH。这些数据表明，瘦素可以直接或通过另一种下丘脑神经肽（例如神经肽-Y）间接抑制下丘脑 CRH 释放。瘦素功能失调、瘦素水平不足或瘦素抵抗都应导致部分开环，从而解释伴随并导致许多肥胖表型的糖皮质激素水平升高。瘦素抑制 CRH 释放的能力可能是其抑制 HPAA 响应压力激活的能力的解释。
Leptin is a newly identified protein hormone that is synthesized and secreted by adipose tissue. Absence of the mature hormone is responsible for the obese phenotype of ob lob mice. The hypothalamic-pituitary-adrenal axis (HPAA) is activated in ob lob mice, and chronic administration of leptin to ob/ob mice decreases plasma corticosterone levels, suggesting that the adipose hormone is capable of inhibiting the HPAA. The aim of this study was to determine whether leptin feeds back acutely to inhibit the HPAA of normal mice and rats. Male C57BL mice were injected ip with 100 mu l saline and 2 or 4 mu g/g BW mouse leptin in saline vehicle, and 4 h later they were subjected to 2 h of restraint stress by taping the hind limbs together or no stress. Kind leg restraint stimulated the HPAA as measured by significant (P < 0.05) elevation of both ACTH and corticosterone. Pretreatment with recombinant mouse leptin blocked the stress-mediated stimulation of both plasma hormones. To determine whether this inhibition was exerted at the hypothalamic level through inhibition of CRH, we studied leptin action on isolated rat hypothalami perifused with Krebs-Ringer buffer containing glucose (5.5 mM). CRH secretion was stimulated by decreasing the glucose concentration of the buffer to 1.1 mM. A surge of CRH was released over a 2-h period (basal integrated release was 14.4 +/- 1.6 pg/2 h, n = 5 and increased to 34.7 +/- 3.1 pg/2 h, n = 14). This response was blacked by mouse leptin in a dose-dependent manner (integrated stimulated CRH secretion was 30.6 +/- 2.5 pg/2 h, n = 5; 20.5 +/- 3.6 pg/2 h, n = 7; 15.3 +/- 4.3 pg/2 h, n = 3 for 1 nM, 3 nM and 30 nM, respectively). Leptin did not alter secretion of ACTH from rat primary cultured pituitary cells. These data demonstrate that leptin can inhibit hypothalamic CRH release, either directly or indirectly through another hypothalamic neuropeptide such as neuropeptide-Y. Dysfunctional leptin, insufficient leptin levels, or leptin resistance should each result in a partial open loop, thereby accounting for elevated glucocorticoid levels that accompany and contribute to many obese phenotypes. Leptin's ability to inhibit CRH release is the likely explanation for its ability to inhibit activation of the HPAA in response to stress.