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

This study constructs a human adipose-specific promoter-driven UCP1 overexpression plasmid, achieving adipose tissue-specific gene therapy that effectively promotes thermogenesis and energy expenditure in adipose tissue. It provides an innovative gene therapy approach for treating 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 gene therapy strategy targeting adipose tissue through plasmid-mediated UCP1 overexpression to overcome limitations of existing anti-obesity therapies. The study comprehensively evaluates therapeutic effects in mouse models, including weight management, metabolic homeostasis improvement, and energy expenditure enhancement, 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 restrict clinical applications. UCP1-mediated thermogenesis in adipose tissue represents a critical mechanism for regulating body weight and maintaining thermal homeostasis, but current effective adipose-specific gene delivery systems remain limited for clinical translation. By replacing plasmid promoters with adipose-specific promoters, this study develops a gene therapy tool targeting adipose tissue, offering new solutions for obesity gene therapy. Additionally, this approach encapsulates plasmids with nanomaterials to enhance in vivo stability and targeting efficiency, overcoming leakage expression issues in traditional plasmid systems. Through systematic in vitro and in vivo experiments, the study evaluates plasmid specificity, thermogenic activation capacity, and therapeutic effects on obese mouse models, providing experimental foundations for subsequent 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 adiponectin promoters (mADP or hADP) to construct plasmids specifically expressing UCP1 in adipose tissue. Plasmids were encapsulated with nanomaterials and injected into mice to evaluate expression specificity, thermogenic capacity, and metabolic impacts in adipose tissue. In vitro validation used 3T3-L1, NIH/3T3, 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 obese mouse models. Comprehensive assessments of plasmid expression, energy expenditure, weight changes, and metabolic homeostasis regulation were conducted using immunohistochemistry, Western blotting, thermal imaging, metabolic cage monitoring, glucose tolerance, and insulin tolerance tests.

Key Conclusions and Perspectives

• hADP promoter-modified plasmids achieve adipocyte-specific UCP1 overexpression, whereas mADP modifications show no significant effect, suggesting superior functional activity of human promoters in mouse models.
• In vitro experiments demonstrate hADP-UCP1 OE plasmids significantly reduce lipid droplet accumulation, enhance energy expenditure, and improve glucose uptake capacity in adipocytes.
• In vivo studies reveal hADP-Ucp1 OE plasmid treatment significantly reduces body weight, adipose tissue mass, and improves glucose homeostasis and insulin sensitivity in HFD-induced obese mice.
• hADP-Ucp1 OE plasmid therapy increases basal and maximal oxygen consumption rates (OCR), confirming enhanced thermogenic function in adipose tissue.
• Plasmid treatment shows no detectable toxicity or side effects in mice, with normal biochemical profiles, organ histopathology, and immunohistochemical analyses indicating excellent biocompatibility.

Research Significance and Prospects
This study presents a novel, safe, and efficient adipose-targeted gene therapy strategy, offering potential clinical interventions for obesity and related metabolic diseases. Future research should optimize plasmid delivery systems to improve expression efficiency and stability, evaluate efficacy and safety in non-human primates, and explore applications in other metabolic disorders like diabetes to expand clinical utility.

 

 

Conclusion
This study successfully develops a plasmid-based gene therapy strategy utilizing hADP promoter-driven UCP1 overexpression. The approach effectively induces adipose thermogenesis, reduces body weight, improves metabolic homeostasis, and demonstrates excellent safety in mouse models. Compared to traditional plasmid systems, this strategy offers stronger adipose specificity by avoiding off-target tissue expression, establishing a new direction for treating obesity and related metabolic disorders. The research provides experimental foundations for future clinical translation, potentially enabling non-viral gene therapy approaches for 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.