TY - JOUR
T1 - Effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on weight loss is partly mediated by liver-brain-adipose neurocircuitry
AU - Sawada, Yoshikazu
AU - Izumida, Yoshihiko
AU - Takeuchi, Yoshinori
AU - Aita, Yuichi
AU - Wada, Nobuhiro
AU - Li, En Xu
AU - Murayama, Yuki
AU - Piao, Xianying
AU - Shikama, Akito
AU - Masuda, Yukari
AU - Nishi-Tatsumi, Makiko
AU - Kubota, Midori
AU - Sekiya, Motohiro
AU - Matsuzaka, Takashi
AU - Nakagawa, Yoshimi
AU - Sugano, Yoko
AU - Iwasaki, Hitoshi
AU - Kobayashi, Kazuto
AU - Yatoh, Shigeru
AU - Suzuki, Hiroaki
AU - Yagyu, Hiroaki
AU - Kawakami, Yasushi
AU - Kadowaki, Takashi
AU - Shimano, Hitoshi
AU - Yahagi, Naoya
N1 - Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/11/4
Y1 - 2017/11/4
N2 - Sodium-glucose cotransporter 2 (SGLT2) inhibitors have both anti-diabetic and anti-obesity effects. However, the precise mechanism of the anti-obesity effect remains unclear. We previously demonstrated that the glycogen depletion signal triggers lipolysis in adipose tissue via liver-brain-adipose neurocircuitry. In this study, therefore, we investigated whether the anti-obesity mechanism of SGLT2 inhibitor is mediated by this mechanism. Diet-induced obese mice were subjected to hepatic vagotomy (HVx) or sham operation and loaded with high fat diet containing 0.015% tofogliflozin (TOFO), a highly selective SGLT2 inhibitor, for 3 weeks. TOFO-treated mice showed a decrease in fat mass and the effect of TOFO was attenuated in HVx group. Although both HVx and sham mice showed a similar level of reduction in hepatic glycogen by TOFO treatment, HVx mice exhibited an attenuated response in protein phosphorylation by protein kinase A (PKA) in white adipose tissue compared with the sham group. As PKA pathway is known to act as an effector of the liver-brain-adipose axis and activate triglyceride lipases in adipocytes, these results indicated that SGLT2 inhibition triggered glycogen depletion signal and actuated liver-brain-adipose axis, resulting in PKA activation in adipocytes. Taken together, it was concluded that the effect of SGLT2 inhibition on weight loss is in part mediated via the liver-brain-adipose neurocircuitry.
AB - Sodium-glucose cotransporter 2 (SGLT2) inhibitors have both anti-diabetic and anti-obesity effects. However, the precise mechanism of the anti-obesity effect remains unclear. We previously demonstrated that the glycogen depletion signal triggers lipolysis in adipose tissue via liver-brain-adipose neurocircuitry. In this study, therefore, we investigated whether the anti-obesity mechanism of SGLT2 inhibitor is mediated by this mechanism. Diet-induced obese mice were subjected to hepatic vagotomy (HVx) or sham operation and loaded with high fat diet containing 0.015% tofogliflozin (TOFO), a highly selective SGLT2 inhibitor, for 3 weeks. TOFO-treated mice showed a decrease in fat mass and the effect of TOFO was attenuated in HVx group. Although both HVx and sham mice showed a similar level of reduction in hepatic glycogen by TOFO treatment, HVx mice exhibited an attenuated response in protein phosphorylation by protein kinase A (PKA) in white adipose tissue compared with the sham group. As PKA pathway is known to act as an effector of the liver-brain-adipose axis and activate triglyceride lipases in adipocytes, these results indicated that SGLT2 inhibition triggered glycogen depletion signal and actuated liver-brain-adipose axis, resulting in PKA activation in adipocytes. Taken together, it was concluded that the effect of SGLT2 inhibition on weight loss is in part mediated via the liver-brain-adipose neurocircuitry.
KW - Diabetes
KW - Glycogen depletion signal
KW - Liver-brain-adipose neurocircuitry
KW - Obesity
KW - SGLT2 inhibitor
UR - http://www.scopus.com/inward/record.url?scp=85029584029&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2017.09.081
DO - 10.1016/j.bbrc.2017.09.081
M3 - 学術論文
C2 - 28928093
AN - SCOPUS:85029584029
SN - 0006-291X
VL - 493
SP - 40
EP - 45
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 1
ER -
