Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA.
Max-Planck-Institute for Metabolism Research, 50931 Cologne, Germany ; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50674 Cologne, Germany.
Mol Metab. 2014 Dec 10;4(2):83-92. doi: 10.1016/j.molmet.2014.12.001. eCollection 2015 Feb.
Obesity is often accompanied by hyperactivity of the neuroendocrine stress axis and has been linked to an increased risk of psychiatric disorders. Insulin is reciprocally regulated with the stress hormone corticosterone (CORT), raising the possibility that insulin normally provides inhibitory tone to the hypothalamus-adrenal-pituitary (HPA) axis. Here we examined whether disrupting signaling via the insulin receptor (InsR) in hypothalamic subpopulations impacts the neuroendocrine response to acute psychological stress.
We used Nkx2.1-Cre, Sim1-Cre and Agrp-Cre transgenic driver lines to generate conditional knockouts of InsR signaling throughout the hypothalamus, paraventricular nucleus of the hypothalamus (PVH) and in neurons expressing Agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus (ARH), respectively. We used a combination of molecular, behavioral and neuroendocrine criteria to evaluate the consequences on HPA axis responsiveness.
Endpoints related to body weight and glucose homeostasis were not altered in any of the conditional mutant lines. Consistent with observations in the neuronal Insr knockout mice (NIRKO), baseline levels of serum CORT were similar to controls in all three lines. In male mice with broad disruptions of InsR signals in Nkx2.1-expressing regions of the hypothalamus (IR(Nkx2.1) KO), we observed elevated arginine vasopressin (AVP) levels at baseline and heightened neuroendocrine responses to restraint stress. IR(Nkx2.1) KO males also exhibited increased anxiety-like behaviors in open field, marble burying, and stress-induced hyperthermia testing paradigms. HPA axis responsivity was not altered in IR(Sim1) KO males, in which InsR was disrupted in the PVH. In contrast to observations in the IR(Nkx2.1) KO males, disrupting InsR signals in ARH neurons expressing Agrp (IR(Agrp) KO) led to reduced AVP release in the median eminence (ME).
We find that central InsR signals modulate HPA responsivity to restraint stress. InsR signaling in AgRP/NPY neurons appears to promote AVP release, while signaling in other hypothalamic neuron(s) likely acts in an opposing fashion. Alterations in InsR signals in neurons that integrate metabolic and psychiatric information could contribute to the high co-morbidity of obesity and mental disorders.
肥胖常伴有神经内分泌应激轴的过度活跃，并与精神疾病风险增加有关。胰岛素与应激激素皮质酮（CORT）呈反向调节，这表明胰岛素通常对下丘脑-垂体-肾上腺（HPA）轴提供抑制性调谐。在这里，我们研究了破坏下丘脑亚群中胰岛素受体（InsR）的信号传导是否会影响急性心理应激对神经内分泌的反应。
我们使用 Nkx2.1-Cre、Sim1-Cre 和 Agrp-Cre 转基因驱动线，分别在整个下丘脑、下丘脑室旁核（PVH）中和表达 AgRP 的神经元中产生条件性敲除 InsR 信号，从而产生条件性敲除 InsR 信号。我们使用分子、行为和神经内分泌标准的组合来评估对 HPA 轴反应性的影响。
在任何一种条件性突变系中，与体重和葡萄糖稳态相关的终点均未改变。与神经元 Insr 敲除小鼠（NIRKO）的观察结果一致，所有三种系的基础血清 CORT 水平与对照相似。在广泛破坏下丘脑 Nkx2.1 表达区域的 InsR 信号的雄性小鼠（IR（Nkx2.1）KO）中，我们观察到基础水平的血管加压素（AVP）水平升高，并且对束缚应激的神经内分泌反应增强。IR（Nkx2.1）KO 雄性小鼠在旷场、埋珠和应激诱导性体温升高测试模型中也表现出焦虑样行为增加。在 PVH 中破坏 InsR 的雄性 IR（Sim1）KO 中，HPA 轴反应性没有改变。与 IR（Nkx2.1）KO 雄性小鼠的观察结果相反，破坏表达 Agrp 的 ARH 神经元中的 InsR 信号（IR（Agrp）KO）导致中脑下垂体释放的 AVP 减少。
我们发现中枢 InsR 信号调节束缚应激对 HPA 的反应性。AgRP/NPY 神经元中的 InsR 信号似乎促进 AVP 释放，而其他下丘脑神经元中的信号可能以相反的方式起作用。整合代谢和精神信息的神经元中 InsR 信号的改变可能导致肥胖症和精神障碍的高共病率。
