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IF 6 2区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Liver International Pub Date : 2025-03-13 DOI:10.1111/liv.70068

Rafael Calais Gaspar, Ana Paula Azevêdo Macêdo, Susana Castelo Branco Ramos Nakandakari, Vitor Rosetto Muñoz, Gabriela Ferreira Abud, Renan Fudoli Lins Vieira, Ivo Vieira de Sousa Neto, Isadora Carolina Betim Pavan, Luiz Guilherme Salvino da Silva, Fernando Moreira Simabuco, Adelino S. R. da Silva, Wilson Salgado Junior, Julio Sergio Marchini, Carla Barbosa Nonino, Dennys Esper Cintra, Eduardo Rochete Ropelle, Utpal B. Pajvani, Ellen Cristini de Freitas, José Rodrigo Pauli

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引用次数: 0

摘要

背景和目的 Notch1 蛋白在肝脏代谢中发挥着重要作用，这一点从它与肥胖者肝脏中胰岛素抵抗的相关性中可见一斑，因此它是一个引人关注的研究目标。因此，本研究旨在探讨有氧运动对肥胖小鼠肝组织中 Notch1 通路的影响及其在控制肝脏代谢中的作用。因此，我们利用瘦人和肥胖者的肝脏活检组织进行了一项横断面研究，并对高脂饮食小鼠进行了干预研究。肥胖训练小鼠组进行了为期 4 周的跑步训练。结果我们的研究结果表明，与瘦人相比，肥胖者的 NOTCH1 mRNA 水平升高。Notch1信号的有害影响通过Notch1外显的HepG2细胞系得到证实。肝脏 Notch1 信号水平较高的肥胖小鼠在接受为期 4 周的跑步机跑步训练后，Notch1 信号通路有所减少。该训练组的另一个优点是改善了胰岛素抵抗，并降低了丙酮酸不耐受性和葡萄糖生成酶。此外，我们还观察到这些保护性结果伴随着 mTORC1 通路活性的降低和肝脏中脂质的积累。药理抑制肥胖小鼠的 Notch1 会导致肝脏线粒体呼吸增加。结论我们得出结论，Notch1 信号可能是肥胖症的潜在治疗靶点，而有氧运动训练可抑制肝脏中的 Notch1 通路，有助于调节肥胖小鼠的肝糖和肝脂代谢。

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Notch1 Signalling Is Downregulated by Aerobic Exercise, Leading to Improvement of Hepatic Metabolism in Obese Mice

Background and Aims

Notch1 protein plays a significant role in hepatic metabolism, as evidenced by its correlation with insulin resistance in the livers of obese individuals, making it an intriguing research target. Therefore, this study aims to investigate the impact of aerobic exercise on Notch1 pathways in the hepatic tissue of obese mice and its role in controlling hepatic metabolism.

Methods

Therefore, we conducted a cross-sectional study utilising liver biopsies from lean and obese humans, as well as an intervention study involving mice subjected to a high-fat diet. The obese-trained mice group underwent a treadmill-running protocol for 4 weeks.

Results

Our findings revealed that obese individuals exhibited increased NOTCH1 mRNA levels compared to lean subjects. The detrimental effects of Notch1 signalling were confirmed by Notch1-overexpressed HepG2 cell lines. Obese mice with higher hepatic Notch1 signalling demonstrated a reduction in this pathway when subjected to a 4-week treadmill running. Another benefit noticed in this trained group was the amelioration of insulin resistance, as well as a reduction in pyruvate intolerance and gluconeogenic enzymes. Additionally, we observed that these protective findings were accompanied by a decrease in mTORC1 pathway activity and lipid accumulation in the liver. Pharmacological inhibition of Notch1 in obese mice led to an increase in mitochondrial respiration in the liver.

Conclusions

We conclude that Notch1 signalling may be a potentially useful therapeutic target in obesity, while aerobic exercise training suppresses the Notch1 pathway in the liver, contributing to the regulation of hepatic glucose and lipid metabolism in obese mice.

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来源期刊

Liver International 医学-胃肠肝病学

CiteScore

13.90

自引率

4.50%

发文量

348

审稿时长

2 months

期刊介绍： Liver International promotes all aspects of the science of hepatology from basic research to applied clinical studies. Providing an international forum for the publication of high-quality original research in hepatology, it is an essential resource for everyone working on normal and abnormal structure and function in the liver and its constituent cells, including clinicians and basic scientists involved in the multi-disciplinary field of hepatology. The journal welcomes articles from all fields of hepatology, which may be published as original articles, brief definitive reports, reviews, mini-reviews, images in hepatology and letters to the Editor.