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

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

 

Literature Overview
The article "DNA-mediated UCP1 overexpression in adipose tissue: A promising anti-obesity gene therapy" published in Clinical and Translational Medicine systematically explores a gene therapy strategy targeting adipose tissue through plasmid-mediated UCP1 overexpression to overcome limitations of existing anti-obesity treatments. The study comprehensively evaluated therapeutic effects in mouse models, including weight management, metabolic homeostasis improvement, and enhanced energy expenditure, while verifying 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 potential in weight control, their gastrointestinal side effects and non-adipose tissue weight reduction effects limit clinical applications. UCP1-mediated thermogenesis in adipose tissue represents a critical mechanism for regulating body weight and temperature maintenance; however, the lack of effective tissue-specific gene delivery systems has hindered clinical translation. By replacing the CMV promoter in plasmids with adipose-specific promoters, this study constructs a gene therapy tool targeting adipose tissue, offering a novel solution for obesity gene therapy. Furthermore, the approach encapsulates plasmids with nanomaterials to enhance in vivo stability and targeting specificity, overcoming leakage expression issues in non-target tissues observed in traditional plasmid systems. Through in vitro and in vivo experiments, the study systematically evaluates plasmid specificity in adipocytes, thermogenic activation capacity, and therapeutic effects in obese mouse models, providing experimental evidence for future gene therapy research.

 

 

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

Key Conclusions and Perspectives

• Plasmids modified with the hADP promoter achieved adipocyte-specific UCP1 overexpression, whereas mADP-modified plasmids showed no significant effects, indicating superior functional activity of human promoters in mouse models.
• In vitro experiments demonstrated that the hADP-UCP1 OE plasmid 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, adipose tissue mass, and improved glucose homeostasis and insulin sensitivity in high-fat diet-induced obese mice.
• Plasmid treatment significantly increased basal and maximal oxygen consumption rates (OCR) in mice, confirming enhanced thermogenic function in adipose tissue.
• Plasmid therapy exhibited no apparent toxicity or side effects in mice, with no abnormalities detected in biochemical blood tests, organ histopathology, or immunohistochemical analysis, suggesting excellent biocompatibility.

Research Significance and Prospects
This study introduces a novel, safe, and efficient adipose tissue-targeting gene therapy strategy, offering potential clinical interventions for obesity and related metabolic diseases. Future research should focus on optimizing the plasmid delivery system to improve expression efficiency and stability, while evaluating efficacy and safety in non-human primates. Additionally, exploring this strategy for other metabolic disorders (e.g., diabetes) may expand its clinical applicability.

 

 

Conclusion
This study successfully developed a plasmid-based gene therapy driven by the hADP promoter for UCP1 overexpression. The approach effectively induced thermogenesis in adipose tissue, reduced body weight, improved metabolic homeostasis, and demonstrated excellent safety profiles in mouse models. Compared to traditional plasmid systems, this strategy exhibits stronger adipose tissue specificity, avoiding off-target expression. It provides a new direction for gene therapy targeting obesity and related metabolic disorders, laying 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.