Mechanistic insights into GLP-1 receptor agonist-induced weight loss through ceRNA network analysis.

Background: GLP-1 receptor agonists (GLP-1RA) have been extensively utilized in the management of body weight in individuals with obesity. Circular RNA (circRNA), a class of covalently closed RNA molecules, has garnered increasing attention for its potential role in the pathogenesis of obesity. However, the specific mechanisms through which circRNA contributes to GLP-1RA-induced weight loss remains elusive.

Methods: High-throughput sequencing analyzed epididymal adipose tissue from obese mice under high-fat, and GLP-1RA intervention (600 μg/kg/d). The functions of differentially expressed (DE) genes were enriched and analyzed. The circRNA-miRNA-mRNA interaction network was constructed in Cytoscape, and KEGG pathway gene enrichment was validated via western blotting.

Results: A total of 644 DEcircRNAs, 186 DEmiRNAs, and 3474 DEmRNAs were identified. Based on ceRNA score calculations, network diagrams were constructed. Gene Ontology (GO) analysis revealed that DERNAs were linked to lipid and fatty acid metabolism. DE genes within ceRNA pairs were enriched in lipid metabolism pathways, especially the PI3K-Akt and AMPK signaling pathways. GLP-1RA induced the phosphorylation of AKT and AMPK, which subsequently led to a reduction of SREBP-1, ACC, and FAS.

Conclusion: GLP-1RA might activate PI3K-Akt and AMPK signaling pathways to combat obesity through the ceRNA network of circRNAs.