雄激素受体对AgRP神经元的作用并不是围青春期雄激素化小鼠生殖和代谢障碍的主要原因。

IF 3.3 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM
Romy I. Kerbus, Caroline Decourt, Megan A. Inglis, Rebecca E. Campbell, Greg M. Anderson
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引用次数: 0

摘要

产前或围青春期发育过程中循环雄激素水平过高是导致多囊卵巢综合征(PCOS)的一个重要原因,而大脑是一个关键靶点。被诊断出患有多囊卵巢综合征的妇女中,约有一半人同时患有代谢综合征,其共同特征包括肥胖、胰岛素抵抗和高胰岛素血症。尽管大量临床和临床前证据证实了雄激素与多囊卵巢综合征的生殖和代谢特征之间的关系,但雄激素导致这种失调的机制尚不清楚。在围青春期双氢睾酮(DHT)小鼠模型中,神经元特异性雄激素受体敲除可减轻一些类似多囊卵巢综合征的特征,但介导这些效应的特定神经元群尚未确定。一个候选群是表达激动相关肽(AgRP)的神经元,它们对生殖和代谢功能都很重要。我们使用了一种特征明确的围青春期雄激素化小鼠模型和 Cre-loxP 转基因小鼠,研究从 AgRP 神经元中特异性地删除雄激素受体是否能缓解诱导的生殖和代谢失调。在对照组小鼠中,66%的AgRP神经元共同表达雄激素受体,但只有在
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Androgen receptor actions on AgRP neurons are not a major cause of reproductive and metabolic impairments in peripubertally androgenized mice

Androgen receptor actions on AgRP neurons are not a major cause of reproductive and metabolic impairments in peripubertally androgenized mice

Androgen receptor actions on AgRP neurons are not a major cause of reproductive and metabolic impairments in peripubertally androgenized mice

Excess levels of circulating androgens during prenatal or peripubertal development are an important cause of polycystic ovary syndrome (PCOS), with the brain being a key target. Approximately half of the women diagnosed with PCOS also experience metabolic syndrome; common features including obesity, insulin resistance and hyperinsulinemia. Although a large amount of clinical and preclinical evidence has confirmed this relationship between androgens and the reproductive and metabolic features of PCOS, the mechanisms by which androgens cause this dysregulation are unknown. Neuron-specific androgen receptor knockout alleviates some PCOS-like features in a peripubertal dihydrotestosterone (DHT) mouse model, but the specific neuronal populations mediating these effects are undefined. A candidate population is the agouti-related peptide (AgRP)-expressing neurons, which are important for both reproductive and metabolic function. We used a well-characterised peripubertal androgenized mouse model and Cre-loxP transgenics to investigate whether deleting androgen receptors specifically from AgRP neurons can alleviate the induced reproductive and metabolic dysregulation. Androgen receptors were co-expressed in 66% of AgRP neurons in control mice, but only in <2% of AgRP neurons in knockout mice. The number of AgRP neurons was not altered by the treatments. Only 20% of androgen receptor knockout mice showed rescue of DHT-induced androgen-induced anovulation and acyclicity. Furthermore, androgen receptor knockout did not rescue metabolic dysfunction (body weight, adiposity or glucose and insulin tolerance). While we cannot rule out developmental compensation in our model, these results suggest peripubertal androgen excess does not markedly influence Agrp expression and does not dysregulate reproductive and metabolic function through direct actions of androgens onto AgRP neurons.

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来源期刊
Journal of Neuroendocrinology
Journal of Neuroendocrinology 医学-内分泌学与代谢
CiteScore
6.40
自引率
6.20%
发文量
137
审稿时长
4-8 weeks
期刊介绍: Journal of Neuroendocrinology provides the principal international focus for the newest ideas in classical neuroendocrinology and its expanding interface with the regulation of behavioural, cognitive, developmental, degenerative and metabolic processes. Through the rapid publication of original manuscripts and provocative review articles, it provides essential reading for basic scientists and clinicians researching in this rapidly expanding field. In determining content, the primary considerations are excellence, relevance and novelty. While Journal of Neuroendocrinology reflects the broad scientific and clinical interests of the BSN membership, the editorial team, led by Professor Julian Mercer, ensures that the journal’s ethos, authorship, content and purpose are those expected of a leading international publication.
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