Dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, acutely reduces energy expenditure in brown adipose tissue via neural signals in mice

Yumiko Chiba, Tetsuya Yamada, Hideki Katagiri

Research output: Contribution to journalReview articlepeer-review

1 Citation (Scopus)

Abstract

Selective sodium glucose transporter-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 administration. Hyperphagia is reportedly one of the causes of this limited weight loss. However, the eŠects of SGLT2i on systemic energy expenditure have not been fully elucidated. We investigated the acute eŠects of dapagliflozin, an SGLT2i, on systemic energy expenditure in mice. Eighteen hours after dapagliflozin administration, oxygen consumption and brown adipose tissue (BAT) expression of ucp1, a thermogenesis-related gene, were signiˆcantly decreased as compared with those after vehicle administration. In addition, dapagliflozin signiˆcantly 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 ˆndings 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, 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, occurred prior to the suppression of BAT thermogenesis, e.g., 6 h after dapagliflozin treatment. Collectively, these results suggest that SGLT2i acutely suppresses energy expenditure in BAT via regulation of an interorgan neural network consisting of the common hepatic vagal branch and sympathetic nerves.

Original languageEnglish
Pages (from-to)945-954
Number of pages10
JournalYakugaku Zasshi
Volume138
Issue number7
DOIs
Publication statusPublished - 2018
Externally publishedYes

Keywords

  • Brown adipose tissue
  • Energy expenditure
  • Sodium glucose transporter-2 inhibitor
  • Sympathetic nerve

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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