KLF3 impacts insulin sensitivity and glucose uptake in skeletal muscle.

ABSTRACT

Skeletal muscle is one of the predominant sites involved in glucose disposal, accounting for ∼80% of postprandial glucose uptake, and plays a critical role in maintaining glycemic homeostasis. Dysregulation of energy metabolism in skeletal muscle is involved in developing insulin resistance and type 2 diabetes (T2D). Transcriptomic responses of skeletal muscle to exercise found that the expression of Klf3 was increased in T2D Goto-Kakizaki (GK) rats and decreased after exercise with improved hyperglycemia and insulin resistance, implying that Klf3 might be associated with insulin sensitivity and glucose metabolism. We also found that knockdown of Klf3 promoted basal and insulin-stimulated glucose uptake in L6 myotubes, whereas overexpression of Klf3 resulted in the opposite. Through pairwise comparisons of L6 myotubes transcriptome, we identified 2,256 and 1,988 differentially expressed genes in Klf3 knockdown and overexpression groups, respectively. In insulin signaling, the expression of Slc2a4, Akt2, Insr, and Sorbs1 was significantly increased by Klf3 knockdown and decreased with Klf3 overexpression; Ptprf and Fasn were markedly downregulated in Klf3 reduced group and upregulated in Klf3 overexpressed group. Moreover, downregulation of Klf3 promoted the expression of glucose transporter 4 (GLUT4) and protein kinase B (AKT) proteins, as well as the translocation of GLUT4 to the cell membrane in the basal situation, and enhanced insulin sensitivity, characterized by increased insulin-stimulated GLUT4 translocation and AKT, TBC1 domain family member 1 (TBC1D1) and TBC1 domain family member 4 (TBC1D4) phosphorylation, whereas overexpression of Klf3 showed contrary results. These results suggest that Klf3 affects glucose uptake and insulin sensitivity via insulin signal transduction and intracellular metabolism, offering a novel potential treatment strategy for T2D.NEW & NOTEWORTHY The knockdown of Klf3 increased glucose uptake and improved insulin sensitivity in L6 myotubes, whereas its overexpression had the opposite effect. To explore the underlying mechanisms, we evaluated the transcriptional profiles of L6 myotubes after Klf3 knockdown and overexpression and revealed that metabolism and insulin-related pathways were significantly impacted. Klf3 also influenced the expression or modification of glucose transporter 4 (GLUT4), protein kinase B (AKT), TBC1 domain family member 1 (TBC1D1), and TBC1 domain family member 4 (TBC1D4) in the insulin signaling pathway, affecting insulin sensitivity and glucose uptake.