miR-494 Deletion Improves Glucose Metabolism Independently of Obesity in Mice.

Abstract

The browning of white adipose tissue (WAT) enhances thermogenesis and represents a promising approach for combating obesity and metabolic disorders. miRNA-494 (miR-494) acts as a suppressor of browning in cultured adipocytes via regulation of peroxisome proliferator-activated receptor γ coactivator 1α, and its inhibition is expected to promote browning and thereby improve obesity and metabolic disorders. To assess its in vivo role and therapeutic potential, we generated miR-494-knockout (KO) mice using CRISPR/Cas9. KO mice showed increased browning of WAT and resistance to high-fat diet-induced obesity. Notably, they also exhibited improved glucose tolerance, even under normal chow feeding conditions without weight loss. Ex vivo analysis revealed enhanced β-adrenergic-stimulated oxidative phosphorylation directly induced by miR-494 deletion. Metabolomic and Seahorse analyses further suggested accelerated glucose metabolism independent of insulin secretion or sensitivity. Analysis of human adipose tissue transcriptomic data supported the association between low miR-494 expression and better glucose tolerance without weight differences. These findings suggest that suppression of miR-494 improves glucose metabolism through both insulin-dependent and insulin-independent mechanisms, independently of changes in body weight. Targeting miR-494 could represent a potential therapeutic strategy for obesity and various forms of diabetes. Browning of white adipose tissue enhances energy expenditure and may improve metabolic health; however, it remains unclear whether inhibition of its suppressor, miRNA-494 (miR-494), can exert therapeutic effects in vivo. We investigated whether genetic deletion of miR-494 expression in vivo promotes adipocyte browning, exerts antiobesity effects, and improves glucose tolerance. miR-494-knockout mice showed resistance to high-fat diet-induced obesity and improved glucose tolerance, even under normal chow feeding conditions. miR-494 inhibition may offer a therapeutic strategy for improving glycemic control through both insulin-dependent and insulin-independent mechanisms, independently of changes in body weight.