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Counter-Regulation of Bifunctional Adipocyte Regulators Promotes Adipocyte Beiging
Charbel Saad
*, Nikhil Hajirnis, Seray Er, Sashank Reddy
Department of Plastic and Reconstructive Surgery, Johns Hopkins University, Baltimore, MD
Background: Obesity, a global epidemic affecting over 890 million individuals, is characterized by excessive white adipose tissue (WAT) accumulation and impaired energy expenditure. Beiging of WAT, through induction of thermogenic brown-like adipocytes, represents a promising strategy to reverse metabolic dysfunction. Prior studies have shown that silencing individual transcriptional repressors can derepress thermogenic genes and initiate beiging in white adipocytes. This study investigated targeted silencing of these regulators to unlock adipocyte plasticity and promote metabolic reprogramming.
Methods: We defined these targets as Bifunctional Adipogenic Regulators (BARs) based on their dual role in adipocyte differentiation and maintenance of mature white fat identity. BARs were silenced in differentiated 3T3-L1 adipocytes using lipid nanoparticle (LNP)-formulated siRNA. Molecular analyses included qPCR to assess gene expression changes. In vivo, AAV8-shRNA was used to target these regulators in murine inguinal adipose tissue.
Results: Double-dose siRNA treatment achieved up to 97% knockdown of target genes, while single-dose protocols yielded approximately 70% reduction. This intervention led to a 2- to 3-fold increase in uncoupling protein 1 (UCP1) expression, which increased further to 4- to 6-fold with mRNA co-administration. Dual BAR knockdown resulted in repression of white adipocyte markers and marked activation of the thermogenic program, including a 77.8-fold increase in UCP1 expression. In vivo, AAV8-shRNA delivery successfully targeted adipose tissue in mice.
Conclusions: These findings identify transcriptional repression as a major barrier to adipocyte beiging and support these factors as promising targets for RNA-based obesity therapies. Combinatorial strategies involving targeted knockdown and activation of thermogenic pathways enhanced reprogramming potential. This work provides a foundation for precision metabolic reprogramming strategies for obesity.
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