Prenatal programming by testosterone of hypothalamic metabolic control neurones in the ewe.
Prenatal programming by testosterone of hypothalamic metabolic control neurones in the ewe.
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DOI：
10.1111/j.1365-2826.2011.02126.x
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发表时间：
2011-05
影响因子：
3.2
通讯作者：
Lehman MN
中科院分区：
文献类型：
--
作者：
Sheppard KM;Padmanabhan V;Coolen LM;Lehman MN
母羊在产前接受睾酮（T）治疗后，除了生殖功能障碍外，还会出现代谢缺陷，包括胰岛素抵抗，这些功能障碍共同模仿多囊卵巢综合征（PCOS），这是一种常见的女性内分泌疾病。我们假设与产前T过量相关的代谢缺陷涉及弓状核（ARC）神经元的改变，这些神经元含有刺鼠相关肽（AgRP）或阿黑皮素原（POMC）。这些神经元在母羊的特征表明，免疫反应性AgRP和POMC神经元存在于单独的人群中的ARC，AgRP和POMC神经元共表达神经肽Y或可卡因和安非他明调节的转录，分别，和每个人口具有高度的共定位与雄激素受体。产前T暴露对成年母羊AgRP和POMC神经元数量的影响的研究表明，与对照组相比，产前T过量显著增加AgRP神经元数量，但POMC神经元数量不增加;这种增加仅限于ARC的中间部分，通过用双氢睾酮（一种非芳香化雄激素）进行产前治疗来模拟，并且通过产前T与抗雄激素的共同治疗来阻断，流感。在视前区、室旁核、下丘脑外侧核和背内侧核的AgRP纤维免疫反应密度也增加。因此，母羊在胎儿期暴露于雄激素显示AgRP免疫反应神经元的数量和纤维免疫反应的密度在其投射区的变化，提示永久性产前规划的代谢回路，这可能反过来，有助于胰岛素抵抗和肥胖的风险增加，在这个模型的PCOS。
Ewes treated prenatally with testosterone (T) develop metabolic deficits, including insulin resistance, in addition to reproductive dysfunctions that collectively mimic polycystic ovarian syndrome (PCOS), a common endocrine disease in women. We hypothesised that metabolic deficits associated with prenatal T excess involve alterations in arcuate nucleus (ARC) neurones that contain either agouti-related peptide (AgRP) or proopiomelanocortin (POMC). Characterization of these neurones in the ewe showed that immunoreactive AgRP and POMC neurones were present in separate populations in the ARC, that AgRP and POMC neurones co-expressed either neuropeptide Y or cocaine- and amphetamine-regulated transcript, respectively, and that each population had a high degree of colocalization with androgen receptors. Examination of the effect of prenatal T exposure on the number of AgRP and POMC neurones in adult ewes showed that prenatal T excess significantly increased the number of AgRP but, not POMC neurones compared to controls; this increase was restricted to the middle division of the ARC, was mimicked by prenatal treatment with dihydrotestosterone, a non-aromatizable androgen, and was blocked by co-treatment of prenatal T with the anti-androgen, flutamide. The density of AgRP fibre immunoreactivity in the preoptic area, paraventricular nucleus, lateral hypothalamus and dorsomedial hypothalamic nucleus was also increased by prenatal T exposure. Thus, ewes that were exposed to androgens during foetal life showed alterations in the number of AgRP-immunoreactive neurones and the density of fibre immunoreactivity in their projection areas, suggestive of permanent prenatal programming of metabolic circuitry that may, in turn, contribute to insulin resistance and increased risk of obesity in this model of PCOS.
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