成熟促肾上腺皮质激素释放激素神经元中糖皮质激素和矿物质皮质激素受体之间的功能冗余可防止肥胖。

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Obesity Pub Date : 2024-09-24 DOI:10.1002/oby.24116
Yu Liu, Dongfa Lin, Syeda Sadia Najam, Shangyuan Huang, Muyi Song, Chaweewan Sirakawin, Catherine Zhao, Haixia Jiang, Witold Konopka, Stephan Herzig, Ilya A. Vinnikov
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引用次数: 0

摘要

目的:我们旨在研究糖皮质激素受体(GRs)和矿物质皮质激素受体(MRs)在能量平衡调控中的作用:我们使用了三种同时在前脑神经元、室旁核或促肾上腺皮质激素释放激素(CRH)神经元中缺失 GRs 和 MRs 的小鼠模型,并将它们与野生型对照组或分离的基因敲除组进行了比较。除了体重、食物摄入量、能量消耗、胰岛素敏感性、脂肪/瘦肉分布和血浆皮质酮水平外,我们还对CRH神经元进行了转录组学分析,并评估了它们对黑色皮质素能刺激的反应:结果:与全球双基因敲除模型相似,在成熟的CRH神经元中特异性地缺失GRs和MRs会导致肥胖。重要的是,后者伴有胰岛素抵抗,但血浆皮质酮水平并未升高。对这些神经元进行的转录组分析表明,突触后信号转导过程中涉及的几个基因出现了上调,其中包括编码富脯氨酸酪氨酸激酶 2 的 Ptk2b 基因。两种核受体的敲除都会导致CRH神经元中Ptk2b的上调,从而导致它们对黑皮质激素刺激的反应性降低:我们的数据证明了 GRs 和 MRs 在 CRH 神经元中维持能量平衡和预防肥胖的功能冗余。同时靶向这两种受体可能是对抗肥胖的一种前所未有的方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Functional redundancy between glucocorticoid and mineralocorticoid receptors in mature corticotropin-releasing hormone neurons protects from obesity

Objective

Here, we aimed to investigate the role of glucocorticoid and mineralocorticoid receptors (GRs and MRs, respectively) in the regulation of energy homeostasis.

Methods

We used three mouse models with simultaneous deletion of GRs and MRs in either forebrain neurons, the paraventricular nucleus, or corticotropin-releasing hormone (CRH) neurons and compared them with wild-type controls or isolated knockout groups. In addition to body weight, food intake, energy expenditure, insulin sensitivity, fat/lean mass distribution, and plasma corticosterone levels, we also performed transcriptomic analysis of CRH neurons and assessed their response to melanocortinergic stimulation.

Results

Similar to global double-knockout models, deletion of GRs and MRs specifically in mature CRH neurons resulted in obesity. Importantly, the latter was accompanied by insulin resistance, but not increased plasma corticosterone levels. Transcriptomic analysis of these neurons revealed upregulation of several genes involved in postsynaptic signal transduction, including the Ptk2b gene, which encodes proline-rich tyrosine kinase 2. Knockout of both nuclear receptors leads to upregulation of Ptk2b in CRH neurons, which results in their diminished responsiveness to melanocortinergic stimulation.

Conclusions

Our data demonstrate the functional redundancy of GRs and MRs in CRH neurons to maintain energy homeostasis and prevent obesity. Simultaneous targeting of both receptors might represent an unprecedented approach to counteract obesity.

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来源期刊
Obesity
Obesity 医学-内分泌学与代谢
CiteScore
11.70
自引率
1.40%
发文量
261
审稿时长
2-4 weeks
期刊介绍: Obesity is the official journal of The Obesity Society and is the premier source of information for increasing knowledge, fostering translational research from basic to population science, and promoting better treatment for people with obesity. Obesity publishes important peer-reviewed research and cutting-edge reviews, commentaries, and public health and medical developments.
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