DNA-mediated UCP1 overexpression in adipose tissue: A promising anti-obesity gene therapy

IF 6.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Ze-Wei Zhao, Longyun Hu, Bigui Song, Qian Wu, Jiejing Lin, Qingqing Liu, Siqi Liu, Jin Li, Molin Wang, Jin Li, Zhonghan Yang
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引用次数: 0

Abstract

Background

Obesity has emerged as a global health challenge. Although GLP-1 receptor agonists are showing considerable promise in weight loss, their clinical utility is partly limited by gastrointestinal adverse reactions and non-fat weight loss side effects. UCP1-mediated adipose thermogenesis is a critical process for body temperature maintenance and weight management. However, the lack of effective and specific adipose thermogenesis therapies has restricted its clinical application. We aimed to explore the potential of inducing adipose-specific UCP1 overexpression via modified plasmids as an innovative therapeutic approach for obesity.

Methods

We replaced the cytomegalovirus (CMV) promoter in the plasmids with two types of adipose-specific promoters: mouse adiponectin (mADP) promoter and human adiponectin (hADP) promoter, to selectively overexpress UCP1 in adipocytes. The expression level of UCP1, weight loss, metabolic homeostasis and adipose thermogenesis effects were evaluated by immunohistochemistry, western blot, weight measurements, thermography, and comprehensive lab animal monitoring system.

Results

The experiments demonstrated that the mADP promoter-modified plasmids failed to drive UCP1 overexpression. In contrast, the hADP promoter-modified Ucp1 overexpression (hADP-Ucp1 OE) plasmids achieved robust adipose-specific UCP1 protein expression both in vitro and in vivo. In vitro experiments revealed that delivery of the hADP promoter-modified UCP1 overexpression (hADP-UCP1 OE) plasmids reduced lipid droplet size and enhanced energy consumption in human adipocytes. In obese mice, administration of the hADP-Ucp1 OE plasmids resulted in significant weight loss and improved metabolic homeostasis.

Conclusions

These findings highlight the therapeutic potential of hADP-UCP1 OE plasmids in obesity management.

Key points

  • The hADP promoter-modified plasmids selectively overexpress protein in adipose tissue.
  • Overexpression of UCP1 driven by hADP promoter induces thermogenesis in mouse and human adipocytes in vitro.
  • The hADP-Ucp1 OE treatment promotes thermogenesis and energy expenditure in mice.
  • The hADP-Ucp1 OE treatment restrains the development of obesity and glucose intolerance in mice.

Abstract Image

脂肪组织中dna介导的UCP1过表达:一种有前景的抗肥胖基因疗法。
背景:肥胖已经成为一个全球性的健康挑战。尽管GLP-1受体激动剂在减肥方面显示出相当大的前景,但其临床应用在一定程度上受到胃肠道不良反应和非脂肪减肥副作用的限制。ucp1介导的脂肪产热是体温维持和体重管理的关键过程。然而,缺乏有效和特异性的脂肪产热疗法限制了其临床应用。我们旨在探索通过修饰质粒诱导脂肪特异性UCP1过表达的潜力,作为一种创新的肥胖治疗方法。方法:用小鼠脂联素(mADP)启动子和人脂联素(hADP)启动子两种脂肪特异性启动子替代质粒中的巨细胞病毒(CMV)启动子,在脂肪细胞中选择性过表达UCP1。通过免疫组织化学、western blot、体重测量、热像仪和综合实验动物监测系统评估UCP1的表达水平、体重减轻、代谢稳态和脂肪产热效应。结果:实验表明,mADP启动子修饰的质粒不能驱动UCP1过表达。相比之下,hADP启动子修饰的Ucp1过表达(hADP-Ucp1 OE)质粒在体外和体内均实现了脂肪特异性Ucp1蛋白的强劲表达。体外实验表明,传递hADP启动子修饰的UCP1过表达(hADP-UCP1 OE)质粒可减少人脂肪细胞的脂滴大小并增加能量消耗。在肥胖小鼠中,给予hADP-Ucp1 OE质粒可显著减轻体重并改善代谢稳态。结论:这些发现强调了hADP-UCP1 OE质粒在肥胖管理中的治疗潜力。重点:hADP启动子修饰的质粒在脂肪组织中选择性过表达蛋白质。hADP启动子驱动的UCP1过表达在体外诱导小鼠和人脂肪细胞产热。hADP-Ucp1 OE处理促进小鼠产热和能量消耗。hADP-Ucp1 OE治疗抑制小鼠肥胖和葡萄糖耐受不良的发展。
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来源期刊
CiteScore
15.90
自引率
1.90%
发文量
450
审稿时长
4 weeks
期刊介绍: Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.
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