Dapagliflozin, a Sodium-Glucose Co-Transporter 2 Inhibitor, Acutely Reduces Energy Expenditure in BAT via Neural Signals in Mice

Abstract

Selective sodium glucose cotransporter-2 inhibitor (SGLT2i) treatment promotes urinary glucose excretion, thereby reducing blood glucose as well as body weight. However, only limited body weight reductions are achieved with SGLT2i treatment. Hyperphagia is reportedly one of the causes of this limited weight loss. However, the effects of SGLT2i treatment on systemic energy expenditure have not been fully elucidated. Herein, we investigated the acute effects of dapagliflozin, a SGLT2i, on systemic energy expenditure in mice. Eighteen hours after dapagliflozin treatment oxygen consumption and brown adipose tissue (BAT) expression of ucp1, a thermogenesis-related gene, were significantly decreased as compared to those after vehicle treatment. In addition, dapagliflozin significantly suppressed norepinephrine (NE) turnover in BAT and c-fos expression in the rostral raphe pallidus nucleus (rRPa) which contains the sympathetic premotor neurons responsible for thermogenesis. These findings indicate that the dapagliflozin-mediated acute decrease in energy expenditure involves a reduction in BAT thermogenesis via decreased sympathetic nerve activity from the rRPa. Furthermore, common hepatic branch vagotomy abolished the reductions in ucp1 expression and NE contents in BAT and c-fos expression in the rRPa. In addition, alterations in hepatic carbohydrate metabolism, such as decreases in glycogen contents and upregulation of phosphoenolpyruvate carboxykinase, manifested prior to the suppression of BAT thermogenesis, e.g. 6 hours after dapagliflozin treatment. Collectively, these results suggest that SGLT2i treatment acutely suppresses energy expenditure in BAT via regulation of an inter-organ neural network consisting of the common hepatic vagal branch and sympathetic nerves.

Effects of Dapagliflozin on Body Composition and Liver Tests in Patients with Nonalcoholic Steatohepatitis Associated with Type 2 Diabetes Mellitus: A Prospective, Open-label, Uncontrolled Study

“… 15 Dapagliflozin was also reported to reduce some of the complications associated with NASH in rodent models. 16 , 17 Therefore, in the present study, we evaluated the effects of dapagliflozin for the treatment of NASH in patients with T2DM. Eligible patients were administered dapagliflozin for 24 weeks, and its therapeutic effects were evaluated by measuring serum biochemistry parameters and performing body composition tests.…”

High released lactate by epicardial fat from coronary artery disease patients is reduced by dapagliflozin treatment

“…Thus, the role of this gene on mitochondrial biogenesis or uncoupled respiration [26] might explain the reduction of oxygen consumption [39]. This effect, lower oxygen consumption, and energy expenditure was also described in mice models after acute administration of dapagliflozin [40]. However, we cannot discard a possible switching from fatty acid to glucose oxidation with a gain in oxygen efficiency for ATP synthesis and low oxygen consumption.…”

Effect of dapagliflozin, a sodium‐glucose co‐transporter‐2 inhibitor, on gluconeogenesis in proximal renal tubules

“…The primary aim of SGLT2 inhibitor treatment is to prevent kidney glucose reabsorption; however, the role of kidneys in glucose metabolism requires attention, just as the liver indirectly alters glucose output. A previous study showed a significantly higher level of hepatic PEPCK in mice administered dapagliflozin compared to untreated mice . However, in that study, changes in renal PEPCK expression by dapagliflozin administration were not examined.…”

“…A previous study showed a significantly higher level of hepatic PEPCK in mice administered dapagliflozin compared to untreated mice. 27 However, in that study, changes in renal PEPCK expression by dapagliflozin administration were not examined. We evaluated the effect of dapagliflozin on two key gluconeogenesis enzymes, PEPCK and G6Pase, in the renal cortex.…”