NAT10-mediated N4-acetylcytidine modification in KLF9 mRNA promotes adipogenesis.
Summary
The study identifies an epitranscriptomic pathway in which NAT10 installs ac4C on KLF9 mRNA to stabilize it, thereby activating CEBPA/B–PPARG and promoting adipogenesis. Genetic knockdown of NAT10 in adipose tissue and pharmacologic inhibition with Remodelin reduced adipose expansion and weight gain in high-fat diet mice.
Key Findings
- NAT10 expression is upregulated in adipose tissue from obese humans and high-fat diet mice.
- NAT10 overexpression promotes, while silencing inhibits, adipogenesis in hADSCs and 3T3‑L1 cells.
- acRIP‑seq/RNA‑seq identified KLF9 as an ac4C-modified NAT10 target; NAT10 enhances KLF9 mRNA stability and activates the CEBPA/B–PPARG pathway.
- Adipose-targeted AAV shRNA against NAT10 reduced adipose expansion in mice.
- Remodelin, a NAT10 inhibitor, lowered body weight, adipocyte size, and adipose expansion in HFD mice by inhibiting KLF9 mRNA ac4C.
Clinical Implications
NAT10 inhibition (e.g., Remodelin) or downstream KLF9 targeting may represent novel anti-obesity strategies; ac4C/KLF9 signatures could serve as biomarkers to stratify or monitor therapy.
Why It Matters
This work uncovers a druggable epitranscriptomic mechanism of adipogenesis with in vivo efficacy, pointing to NAT10–ac4C–KLF9 as a therapeutic axis for obesity.
Limitations
- Preclinical models; human clinical safety and efficacy of NAT10 inhibition remain unknown.
- Potential off-target effects of Remodelin and chronic inhibition of RNA acetylation need evaluation.
Future Directions
Define safety/PK and metabolic efficacy of selective NAT10 inhibitors in large animals; develop adipose-targeted delivery; assess ac4C/KLF9 biomarkers in human obesity trials.
Study Information
- Study Type
- Basic/Mechanistic research
- Research Domain
- Pathophysiology/Treatment
- Evidence Level
- V - Preclinical mechanistic evidence from cell and animal models
- Study Design
- OTHER