SGLT2 Inhibitor-Induced Sympathoexcitation in White Adipose Tissue: A Novel Mechanism for Beiging

• Main Authors: Jennifer R. Matthews, Lakshini Y. Herat, Aaron L. Magno, Shelley Gorman, Markus P. Schlaich, Vance B. Matthews
• Format: Article
• Language: English
• Published: MDPI AG 2020-11-01
• Series: Biomedicines
• Subjects: sympathetic nervous system; sodium glucose cotransporter 2 inhibition; Dapagliflozin; beiging; adipose tissue; hypertension
• Online Access: https://www.mdpi.com/2227-9059/8/11/514

Recent preclinical data show that sodium glucose cotransporter 2 (SGLT2) inhibitors are able to reduce weight gain and induce beiging in white adipose tissue (WAT). We have previously shown that in neurogenic hypertensive Schlager (BPH/2J) mice, treatment with the SGLT2 inhibitor, Dapagliflozin, reduced blood pressure and prevented weight gain. Here we show that chemical sympathetic denervation achieved by systemic administration of 6-hydroxy-dopamine (6-OHDA) reduces body weight and the heightened sympathetic nervous system (SNS) innervation in WAT. Furthermore, we demonstrate that 2 weeks of Dapagliflozin treatment increases SNS innervation in WAT of hypertensive mice. This increase is accompanied by a non-significant elevation in mRNA levels of the <i>Ucp1</i> and <i>Pgc-1α</i> genes, which are markers of beiging. No significant difference in the mRNA levels of the inflammatory mediators <i>Il-6</i> and <i>Tnf-α</i> were detected in WAT of Dapagliflozin treated mice. These findings suggest that SGLT-2 inhibitor-associated prevention of weight gain may be mediated, at least in part, by inducing the beiging of WAT.