ESPE Abstracts

Background: Body fat distribution is associated with obesity-related disorders. Promoting subcutaneous fat proliferative expansion can reduce visceral fat ectopic deposition and the risk of obesity-related insulin resistance, hepatic steatosis, and cardiometabolic diseases. Argonaute 2 (Ago2) was found to mediate RNA silencing in the liver to regulate obesity-related energy metabolism, while its role in fat adipose tissue storing excess energy has not been addressed.

Methods: Adipose tissue-specific Ago2 knockout (AKO) mice were fed with high-fat diet (HDF) for 16 weeks and body fat distribution, glucolipid metabolic parameters, liver lipid deposition, and adipose tissue inflammatory infiltration were examined. Altered miRNAs of the inguinal white adipose tissue (iWAT) were identified by high-throughput miRNA sequencing and analyzing their target genes combined with proteomics. miRNA mimics were transfected into stromal vascular fraction (SVF) cells from iWAT to explore their impact on adipogenic differentiation.

Results: Adipose tissue-specific Ago2 deficiency in obese mice improved their body fat distribution characterized by increased subcutaneous fat and decreased visceral fat, ameliorated obesity-related insulin resistance, hepatic steatosis, and white adipose tissue metabolic inflammation. The depletion of Ago2 in iWAT increased the expression of the adipocyte differentiation regulator PPARγ and fat synthase Fasn and Srebp1c. Moreover, miRNA sequencing showed reduced expression of miR-335-3p, miR-103-3p, miR-365-3p, miR-107-3p, and miR-708-5p and proteomics analysis revealed enhanced BCAA catabolic pathway in iWAT of AKO mice. Ago2-dependent miRNAs and downstream target genes were predicted by Targetscan using altered miRNAs and proteins screened by KEGG enrichment analysis. In vitro, overexpression of miR-335-3p inhibited Bckdhb-mediated BCAA catabolism and the differentiation of SVF cells into mature adipocytes.

Conclusion: These findings indicate that Ago2-dependent miRNA production may determine fat distribution through the regulation of BCAA catabolism and adipogenesis.