Gm15441 improves adipogenesis and insulin sensitivity by TXNIP regulation in white adipose tissue

Abstract

Gm15441, a long non-coding RNA antisense to thioredoxin interacting protein (TXNIP) mRNA, exhibits undefined roles in adipogenesis and insulin resistance. This study aimed to explore its functions and mechanisms in white adipose tissue (WAT). Gm15441 expression was assessed in 3T3-L1 cells and WAT of insulin-resistant mice. Stable Gm15441 overexpression and knockdown 3T3-L1 cell models were established, followed by differentiation induction and analysis of lipid accumulation and differentiation markers. A subcutaneous adipose-specific Gm15441 overexpression mouse model was fed high-fat diets (HFD) and evaluated for metabolic parameters, adipogenesis, and insulin signaling. Subcellular localization in vitro was determined via fluorescence in situ hybridization, while transcriptome sequencing, TXNIP expression analysis, and RNA-RNA pull-down assays were performed. Results showed that Gm15441 expression increased during cell differentiation and decreased in insulin-resistant WAT. Gm15441 overexpression promoted adipogenesis in vitro, while knockdown suppressed it. In HFD-fed mice, adipose-specific Gm15441 overexpression enhanced adipogenesis, reduced blood glucose, and improved insulin sensitivity. Although PPARγ expression increased with cell differentiation, Gm15441 probes did not pull down PPARγ mRNA. Conversely, TXNIP protein levels decreased in Gm15441-overexpressing cells without corresponding changes in mRNA levels, but Gm15441 probes successfully pulled down TXNIP mRNA. These results suggested that Gm15441 may promote adipogenesis and enhance insulin sensitivity by inhibiting TXNIP expression.