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Published on: May 16, 2025
Tks4-Targeted Gene Therapy Inhibited White Adipocyte Hypertrophy in Mice
Meng Tian1, Jingwen Deng1, Yuzhu Hong1
1Key Laboratory of Molecular Epigenetics, Ministry of Education, Institute of Genetics and Cytology, Northeast Normal University, Changchun, Jilin, China.
Abstract:
Obesity is one of the most prevalent public health issues worldwide, which substantially increases the risk of many metabolic disorders. Anti-obesity medications and bariatric surgery are clinical treatments for obesity, but suffer from certain limitations. Gene therapy with effective and safe targets provides a novel approach for obesity intervention. Tks4 has been shown to play an essential role in preadipocyte to adipocyte differentiation. However, it is still elusive if it could be a drug target against obesity in vivo. Here, we found the expression levels of Tks4 correlate with adipocyte development and hypertrophy in mice. By generating a Tks4 KO mouse model, we showed Tks4 deletion significantly restricted adipocyte hypertrophy and reduced blood glucose and lipid levels. We further used an adeno-associated viral (AAV) vector to mediate sustained Tks4 silencing. For a single administration, the adipocyte hypertrophy at the injection site was significantly reduced in a dosage-dependent manner. The TAG biosynthesis defect was also verified by lipidomics analysis of the infected WAT, though an elevation of TAG in blood was also detected. These data support the potential of Tks4 gene therapy to treat obesity.
Insights
Targeting Tks4 shows promise for obesity treatment. Gene therapy using Tks4 silencing effectively reduced adipocyte hypertrophy and improved metabolic markers in mice, supporting its therapeutic potential.
Area of Science:
- Biochemistry
- Genetics
- Metabolic Disorders
Background:
- Obesity is a global health concern, increasing metabolic disorder risk.
- Current obesity treatments (medications, surgery) have limitations.
- Gene therapy offers a novel obesity intervention approach.
Purpose of the Study:
- Investigate Tks4 as a potential in vivo drug target for obesity.
- Evaluate the role of Tks4 in adipocyte development and hypertrophy.
- Assess the efficacy of Tks4 gene therapy for obesity treatment.
Main Methods:
- Generated Tks4 knockout (KO) mouse models.
- Utilized adeno-associated virus (AAV) for Tks4 gene silencing.
- Performed lipidomics analysis on white adipose tissue (WAT).
Main Results:
- Tks4 expression correlated with adipocyte development and hypertrophy in mice.
- Tks4 deletion restricted adipocyte hypertrophy and lowered blood glucose/lipid levels.
- AAV-mediated Tks4 silencing reduced adipocyte hypertrophy dose-dependently and induced TAG biosynthesis defects.
Conclusions:
- Tks4 plays a crucial role in adipocyte hypertrophy.
- Sustained Tks4 gene silencing via AAV is effective in reducing obesity indicators.
- Tks4 gene therapy presents a viable strategy for obesity intervention.
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