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.
Highlights
The number of obese patients is tremendously increasing at an alarming rate in the industrialized nations and in developing countries
There were no significant differences in plasma insulin levels between sodium glucose cotransporter-2 inhibitor (SGLT2i)- and control-mice (Fig 1D)
It was previously reported that SGLT2i treatment induced hyperphagia but did not affect oxygen consumption in ad libitum fed rats [6,18]
Summary
The number of obese patients is tremendously increasing at an alarming rate in the industrialized nations and in developing countries. The sodium glucose cotransporter-2 inhibitors (SGLT2is) were recently developed as a novel class of drugs for T2D [1]. Weight loss degrees after SGLT2i treatment appear to be much less than those predicted from the excreted glucose amounts in both human and animal studies [4,5]. Body weight loss in SGLT2i-PF rats decreased by only -13.2% and did not further decrease despite ongoing substantial glucose excretion [6]. These findings prompted us to hypothesize that SGLT2i suppresses systemic energy expenditure. We examined whether SGLT2i treatment suppresses energy expenditure and, if so, to identify the mechanism(s) involved using an experimental model of food deprivation for 24h after dapagliflozin administration
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