title: 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.
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Chiba
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
authors.forename: Sohei
authors.initials: S
authors.lastname: Tsukita
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Munakata
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Shirai
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
authors.forename: Shinjiro
authors.initials: S
authors.lastname: Kodama
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Asai
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sugisawa
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Uno
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
authors.forename: Shojiro
authors.initials: S
authors.lastname: Sawada
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
authors.forename: Junta
authors.initials: J
authors.lastname: Imai
authors.affiliation: Department of Integrative Physiology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.|Japan Agency for Medical Research and Development (AMED), CREST, Sendai, 980-8575, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Katagiri
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D050260:Carbohydrate Metabolism / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D005960:Glucosides / Q000494:pharmacology*; D006003:Glycogen / Q000378:metabolism; D007473:Ion Channels / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D066267:Midbrain Raphe Nuclei / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000096:biosynthesis; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D009435:Synaptic Transmission / Q000187:drug effects*; D022722:Thermogenesis / Q000187:drug effects*; D000071256:Uncoupling Protein 1; D014630:Vagus Nerve / Q000378:metabolism
chemical_list: D001559:Benzhydryl Compounds; D005960:Glucosides; D007473:Ion Channels; D024101:Mitochondrial Proteins; D016760:Proto-Oncogene Proteins c-fos; C490299:Slc5a2 protein, mouse; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C529054:dapagliflozin; D006003:Glycogen