Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.
Department of Physiological Sciences, State University of Londrina, Londrina, Brazil.
J Endocrinol. 2019 Aug;242(2):125-138. doi: 10.1530/JOE-19-0217.
Adrenalectomy (ADX) induces hypophagia and glucocorticoids counter-regulate the peripheral metabolic effects of insulin. This study evaluated the effects of ADX on ICV (lateral ventricle) injection of insulin-induced changes on food intake, mRNA expression of hypothalamic neuropeptides (insulin receptor (InsR), proopiomelanocortin, cocaine and amphetamine-regulated transcript (Cart), agouti-related protein, neuropeptide Y (Npy) in the arcuate nucleus of the hypothalamus (ARC), corticotrophin-releasing factor in the paraventricular nucleus of the hypothalamus) and hypothalamic protein content of insulin signaling-related molecules (insulin receptor substrate (IRS) 1, protein kinase B (AKT), extracellular-signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), protein tyrosine phosphatase-1B (PTP1B) and T cell protein tyrosine phosphatase (TCPTP)) Compared with sham animals, ADX increased the hypothalamic content of pJNK/JNK, PTP1B and TCPTP, as well as decreased mRNA expression of InsR, and corticosterone (B) treatment reversed these effects. Insulin central injection enhanced hypothalamic content of pAKT/AKT and Cart mRNA expression, decreased Npy mRNA expression and food intake only in sham rats, without effects in ADX and ADX + B rats. Insulin did not alter the hypothalamic phosphorylation of IRS1 and ERK1/2 in the three experimental groups. These data demonstrate that ADX reduces the expression of InsR and increases insulin counter-regulators in the hypothalamus, as well as ADX abolishes hypophagia, activation of hypothalamic AKT pathway and changes in Cart and Npy mRNA expression in the ARC induced by insulin. Thus, the higher levels of insulin counter-regulatory proteins and lower expression of InsR in the hypothalamus are likely to underlie impaired insulin-induced hypophagia and responses in the hypothalamus after ADX.
肾上腺切除术（ADX）可引起摄食量减少，而糖皮质激素则可拮抗胰岛素对周围代谢的作用。本研究评估了 ADX 对侧脑室（ICV）注射胰岛素诱导的摄食量变化、下丘脑神经肽（胰岛素受体（InsR）、促阿黑皮素原、可卡因和安非他命调节转录物（Cart）、刺鼠相关蛋白、神经肽 Y（Npy）在下丘脑弓状核中的 mRNA 表达、下丘脑室旁核中的促皮质素释放因子）和与胰岛素信号相关的分子（胰岛素受体底物（IRS）1、蛋白激酶 B（AKT）、细胞外信号调节激酶（ERK1/2）、c-Jun N 末端激酶（JNK）、蛋白酪氨酸磷酸酶-1B（PTP1B）和 T 细胞蛋白酪氨酸磷酸酶（TCPTP））的影响。与假手术动物相比，ADX 增加了下丘脑 pJNK/JNK、PTP1B 和 TCPTP 的含量，并降低了 InsR 的 mRNA 表达，而皮质酮（B）处理则逆转了这些效应。胰岛素中枢注射仅在假手术大鼠中增强了下丘脑 pAKT/AKT 和 Cart mRNA 表达，降低了 Npy mRNA 表达和摄食量，而在 ADX 和 ADX + B 大鼠中则没有这些作用。胰岛素没有改变三组实验动物下丘脑 IRS1 和 ERK1/2 的磷酸化。这些数据表明，ADX 降低了下丘脑 InsR 的表达，并增加了胰岛素的拮抗物，同时 ADX 消除了胰岛素引起的摄食量减少、下丘脑 AKT 通路的激活以及 ARC 中 Cart 和 Npy mRNA 表达的变化。因此，ADX 后，下丘脑内胰岛素拮抗蛋白水平升高和 InsR 表达降低，可能是胰岛素诱导摄食量减少和下丘脑反应受损的基础。
