In vivo and in vitro validation of GATA-3 suppression for correcting impaired adipogenesis, restoring insulin sensitivity, and lowering risk of T2D

Abstract Purpose Impaired adipogenesis is associated with development of insulin resistance and increased risk of type 2 diabetes (T2D). GATA Binding Protein 3 (GATA3) is implicated in impaired adipogenesis and the onset of insulin resistance. Therefore, we hypothesize that inhibition of GATA3 could promote adipogenesis, restore healthy fat distribution, and enhance insulin signaling. Methods BALB/c mice were treated with GATA3 inhibitor (DNAzyme hgd40) over a period of two weeks. Liposomes loaded with DNAzyme, pioglitazone, or vehicle controls were administered subcutaneously every two days, at the right thigh. At the end of the study, adipose tissues were collected and weighed from the site of injection, the opposite side, and the omental tissues. Anti-oxidant enzyme (SOD and catalase) activities were assessed in animals’ sera, and gene expression was measured using well-established protocols. Primary human preadipocytes were treated with DNAzyme hgd40. Cell proliferation, adipogenic capacity, gene expression, and insulin signaling were measured following well-established protocols. Results In vivo GATA3 inhibition promoted adipogenesis at the site of injection and reduced MCP-1 expression. GATA3 inhibition also reduced omental tissue size and PPARγ expression. Additionally, in vitro GATA3 inhibition induced adipogenesis of primary human preadipocytes, and enhanced insulin signaling through reduced expression of p70S6K. Conclusions These findings suggest that modulating GATA3 expression offers a potential therapeutic benefit by correcting impaired adipogenesis, promoting healthy fat distribution, restoring insulin sensitivity and lowering the risk of T2D.