Disruption of Ephb1 causes reduced hypothalamic CRH and TRH expression and obesity in mice

IF 4.2 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Obesity Pub Date : 2025-04-10 DOI:10.1002/oby.24275

Simin Xie, Tao Zhao, Chengchen Hu, Yongyong Meng, Jing Cui, Xiaohui Wu

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引用次数: 0

Abstract

Objective

Ephrin type-B receptor 1 (EphB1) is a receptor tyrosine kinase involved in axon guidance, synaptic plasticity, and tumorigenesis. However, the role of EphB1 in metabolic regulation and obesity remains poorly understood. This study aims to uncover the role of EphB1 in energy metabolism and provide insights into the underlying mechanisms by which EphB1 regulates obesity.

Methods

Two Ephb1 mutations identified from a forward genetic screen for obesity-related loci in mice were examined for their effects in gene expression, energy metabolism, and endocrine changes. The impacts of EphB1 on neuropeptide expression and signal transduction were evaluated in both hypothalamic tissues and primary cells. Potential downstream signals were modified in Ephb1 mutants to verify the interaction.

Results

Ephb1 mutants develop obesity in adolescence and develop impaired glucose tolerance during adulthood. EphB1 deficiency caused lower body temperature, blunted cold-induced thermogenesis, and decreased locomotor activity, but it did not alter food intake. EphB1 promotes cyclic AMP-responsive element-binding protein (CREB) phosphorylation via phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling in a cell-autonomous manner. EphB1 deficiency leads to reduced expression of corticotropin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH) in the brain. Intraventricular administration of either TRH or a CRH fragment suppressed obesity in Ephb1 mutants.

Conclusions

EphB1 regulates hypothalamic CRH and TRH expression and promotes energy expenditure in mice.

查看原文本刊更多论文

Ephb1的破坏导致小鼠下丘脑CRH和TRH表达减少和肥胖。

目的：Ephrin b型受体1 （EphB1）是一种参与轴突引导、突触可塑性和肿瘤发生的受体酪氨酸激酶。然而，EphB1在代谢调节和肥胖中的作用仍然知之甚少。本研究旨在揭示EphB1在能量代谢中的作用，并为EphB1调节肥胖的潜在机制提供见解。方法：从小鼠肥胖相关基因座的正向遗传筛选中鉴定出两个Ephb1突变，研究它们对基因表达、能量代谢和内分泌变化的影响。在下丘脑组织和原代细胞中观察EphB1对神经肽表达和信号转导的影响。在Ephb1突变体中修改潜在的下游信号以验证相互作用。结果：Ephb1突变体在青春期发生肥胖，并在成年期发生糖耐量受损。EphB1缺乏导致体温降低，冷致产热减弱，运动活动减少，但不改变食物摄入量。EphB1通过磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B （AKT）信号通路以细胞自主方式促进环amp响应元件结合蛋白（CREB）磷酸化。EphB1缺乏导致脑内促肾上腺皮质激素释放激素（CRH）和促甲状腺激素释放激素（TRH）表达减少。脑室内注射TRH或CRH片段可抑制Ephb1突变体的肥胖。结论：EphB1调节小鼠下丘脑CRH和TRH表达，促进能量消耗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

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.