PDF(Pubmed)
Abstract：
Introduction: Obesity is a major risk factor associated with multiple pathological conditions including diabetes and cardiovascular disease. Endothelial dysfunction is an early predictor of obesity. However, little is known regarding how early endothelial changes trigger obesity. In the present work we report a novel endothelial-mediated mechanism essential for regulation of metabolic homeostasis, driven by c-Myc. Methods: We used conditional knockout (EC-Myc KO) and overexpression (EC-Myc OE) mouse models to investigate the endothelial-specific role of c-Myc in metabolic homeostasis during aging and high-fat diet exposure. Body weight and metabolic parameters were collected over time and tissue samples collected at endpoint for biochemical, pathology and RNA-sequencing analysis. Animals exposed to high-fat diet were also evaluated for cardiac dysfunction. Results: In the present study we demonstrate that EC-Myc KO triggers endothelial dysfunction, which precedes progressive increase in body weight during aging, under normal dietary conditions. At endpoint, EC-Myc KO animals showed significant increase in white adipose tissue mass relative to control littermates, which was associated with sex-specific changes in whole body metabolism and increase in systemic leptin. Overexpression of endothelial c-Myc attenuated diet-induced obesity and visceral fat accumulation and prevented the development of glucose intolerance and cardiac dysfunction. Transcriptome analysis of skeletal muscle suggests that the protective effects promoted by endothelial c-Myc overexpression are associated with the expression of genes known to increase weight loss, energy expenditure and glucose tolerance. Conclusion: Our results show a novel important role for endothelial c-Myc in regulating metabolic homeostasis and suggests its potential targeting in preventing obesity and associated complications such as diabetes type-2 and cardiovascular dysfunction.
摘要：
简介：肥胖是与包括糖尿病和心血管疾病在内的多种病理状况相关的主要危险因素。内皮功能障碍是肥胖的早期预测因子。然而,关于早期内皮变化如何引发肥胖，人们知之甚少。在目前的工作中，我们报道了一种新的内皮介导的机制，对调节代谢稳态至关重要，由c-Myc驱动。方法：我们使用条件敲除（EC-MycKO）和过表达（EC-MycOE）小鼠模型来研究衰老和高脂饮食暴露期间c-Myc在代谢稳态中的内皮特异性作用。随着时间的推移收集体重和代谢参数，并在终点收集组织样本进行生化检查，病理学和RNA测序分析。还评估了暴露于高脂肪饮食的动物的心脏功能障碍。结果：在本研究中，我们证明EC-MycKO引发内皮功能障碍，在衰老过程中体重逐渐增加之前，在正常饮食条件下。在端点，与对照同窝动物相比，EC-MycKO动物的白色脂肪组织质量显着增加，这与全身代谢的性别特异性变化和全身瘦素的增加有关。内皮c-Myc的过表达减轻了饮食诱导的肥胖和内脏脂肪积累，并预防了葡萄糖不耐受和心脏功能障碍的发展。骨骼肌的转录组分析表明，内皮c-Myc过表达促进的保护作用与已知增加体重减轻的基因表达有关。能量消耗和葡萄糖耐量。结论：我们的结果显示内皮c-Myc在调节代谢稳态方面具有新的重要作用，并提示其在预防肥胖和相关并发症如2型糖尿病和心血管功能障碍方面具有潜在的靶向作用。
