Clinical and Translational Medicine | DNA-mediated UCP1 overexpression in adipose tissue: A promising anti-obesity gene therapy

This study successfully developed a fat-specific gene therapy strategy by constructing a UCP1 overexpression plasmid driven by human fat-specific promoters, effectively promoting thermogenesis and energy expenditure in adipose tissue. It provides an innovative gene therapy approach for obesity and related metabolic disorders.

 

Literature Overview
This article titled 'DNA-mediated UCP1 overexpression in adipose tissue: A promising anti-obesity gene therapy' published in Clinical and Translational Medicine systematically explores a plasmid-mediated UCP1 overexpression strategy targeting adipose tissue to overcome limitations of existing anti-obesity therapies. The study comprehensively evaluated therapeutic effects in mouse models, including weight management, metabolic homeostasis improvement, and energy expenditure enhancement, while validating tissue-specific expression and biological activity through both in vitro and in vivo experiments.

Background Knowledge
Obesity has become a global health challenge, closely associated with cardiovascular diseases, diabetes, and certain cancers. Although GLP-1 receptor agonists demonstrate weight-control potential, their gastrointestinal side effects and non-specific fat mass reduction limit clinical applications. UCP1-mediated adipose thermogenesis represents a critical mechanism for regulating body weight and temperature homeostasis, yet clinical translation remains limited by the lack of effective tissue-specific gene delivery systems. By replacing plasmid promoters with fat-specific promoters, this study developed a gene therapy tool targeting adipose tissue, offering new solutions for obesity gene therapy. Additionally, the approach employs nanomaterial-encapsulated plasmid delivery to enhance in vivo stability and targeting efficiency, overcoming leakage expression issues in non-target tissues. Through systematic in vitro and in vivo experiments, the study evaluated plasmid specificity in adipocytes, thermogenic activation capacity, and therapeutic effects on obese mouse models, providing experimental foundations for future gene therapy research.

 

 

Research Methods and Experiments
The research team utilized pcDNA3.1(+) plasmids as the backbone, replacing CMV promoters with mouse or human adipose-specific aP2 promoters (mADP or hADP) to construct fat-specific UCP1 expression plasmids. Plasmids were encapsulated in nanomaterials and injected into mice for evaluation of tissue-specific expression, thermogenic capacity, and metabolic impacts in adipose tissue. In vitro validation used 3T3-L1 cells, NIH/3T3 cells, mouse primary adipocytes, and human adipose-derived stem cells (hADSCs), while in vivo experiments employed normal chow diet (NCD) and high-fat diet (HFD)-induced obesity models. Comprehensive assessments of plasmid expression, energy expenditure, weight changes, and metabolic homeostasis regulation were conducted through immunohistochemistry, Western blotting, thermal imaging, metabolic cage monitoring, glucose tolerance tests, and insulin tolerance tests.

Key Conclusions and Perspectives

• The hADP promoter-modified plasmid achieved adipocyte-specific UCP1 overexpression, whereas mADP modification showed no significant effect, suggesting superior functional activity of human promoters in mouse models.
• In vitro experiments demonstrated that hADP-UCP1 OE plasmids significantly reduced lipid droplet accumulation, enhanced energy expenditure, and improved glucose uptake capacity in adipocytes.
• In vivo studies revealed that hADP-Ucp1 OE plasmid treatment significantly reduced body weight and adipose tissue mass in HFD-induced obese mice while improving glucose homeostasis and insulin sensitivity.
• hADP-Ucp1 OE plasmid therapy markedly increased basal and maximal oxygen consumption rates (OCR), indicating enhanced thermogenic function in adipose tissue.
• Plasmid treatment showed no apparent toxicity or side effects in mice, with no abnormalities detected through biochemical blood analysis, organ pathology, or immunohistochemical evaluation, suggesting excellent biocompatibility.

Research Significance and Prospects
This study presents a novel, safe, and efficient adipose-tissue-targeted gene therapy strategy, offering potential clinical interventions for obesity and related metabolic diseases. Future work should focus on optimizing plasmid delivery systems to enhance expression efficiency and stability, while evaluating efficacy and safety in non-human primates. Additionally, exploring applications in other metabolic disorders like diabetes may expand its clinical utility.

 

 

Conclusion
This study successfully developed a plasmid-based gene therapy using hADP promoter-driven UCP1 overexpression, which effectively induced adipose thermogenesis, reduced body weight, and improved metabolic homeostasis in mouse models with excellent safety profiles. Compared to traditional plasmid systems, this strategy demonstrates stronger adipose-specific targeting, avoiding off-target expression. It provides a new direction for treating obesity and related metabolic disorders, establishing experimental foundations for future clinical translation and development of non-viral gene therapies applicable to human obesity management.

 

Ze‐Wei Zhao, Longyun Hu, Bigui Song, Jin Li, and Zhonghan Yang. DNA‐mediated UCP1 overexpression in adipose tissue: A promising anti‐obesity gene therapy. Clinical and Translational Medicine.