Metabolomic and microarray analyses of adipose tissue of dapagliflozin-treated mice, and effects of 3-hydroxybutyrate on induction of adiponectin in adipocytes

Sodium/glucose cotransporter 2 (SGLT2) inhibitor improves systemic glucose metabolism. To clarify the effect of dapagliflozin, we performed gene expression microarray and metabolomic analyses of murine adipose tissue. Three groups of mice were used; non-diabetic control KK mice (KK), diabetic KKAy mice (KKAy), and KKAy mice treated with dapagliflozin (KKAy + Dapa). Plasma glucose levels were significantly reduced in KKAy + Dapa compared with KKAy. Food consumption was larger in KKAy + Dapa than KKAy, and there were no significant differences in body and adipose tissue weight among the groups. Metabolomic analysis showed higher levels of many intermediate metabolites of the glycolytic pathway and TCA cycle in KKAy than KK, albeit insignificantly. Dapagliflozin partially improved accumulation of glycolytic intermediate metabolites, but not intermediate metabolites of the TCA cycle, compared with KKAy. Interestingly, dapagliflozin increased plasma and adipose 3-hydroxybutyric acid (3-HBA) levels. Microarray analysis showed that adipocytokines were downregulated in KKAy compared with KK mice, and upregulated by dapagliflozin. In vitro, 3-HBA induced beta-hydroxybutyrylation of histone H3 at lysine 9 and upregulation of adiponectin in 3T3-L1 adipocytes independent of their acetylation or methylation. Our results suggest that 3-HBA seems to provide protection through epigenetic modifications of adiponectin gene in adipocytes.