Effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on weight loss is partly mediated by liver-brain-adipose neurocircuitry.

Abstract

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.

• Authors: Yoshikazu Sawada, Yoshihiko Izumida, Yoshinori Takeuchi, Yuichi Aita, Nobuhiro Wada, EnXu Li, Yuki Murayama, Xianying Piao, Akito Shikama, Yukari Masuda, Makiko Nishi-Tatsumi, Midori Kubota, Motohiro Sekiya, Takashi Matsuzaka, Yoshimi Nakagawa, Yoko Sugano, Hitoshi Iwasaki, Kazuto Kobayashi, Shigeru Yatoh, Hiroaki Suzuki, Hiroaki Yagyu, Yasushi Kawakami, Takashi Kadowaki, Hitoshi Shimano, Naoya Yahagi
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 493 Issue 1 Pg. 40-45 (11 04 2017) ISSN: 1090-2104 [Electronic] United States
• PMID: 28928093 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Anti-Obesity Agents
• Benzhydryl Compounds
• Glucosides
• Slc5a2 protein, mouse
• Sodium-Glucose Transporter 2
• Sodium-Glucose Transporter 2 Inhibitors
• 6-((4-ethylphenyl)methyl)-3',4',5',6'-tetrahydro-6'-(hydroxymethyl)spiro(isobenzofuran-1(3H),2'-(2H)pyran)-3',4',5'-triol

Topics

• Adipose Tissue (drug effects, innervation, physiology)
• Animals
• Anti-Obesity Agents (administration & dosage)
• Benzhydryl Compounds (administration & dosage)
• Brain (drug effects, physiology)
• Glucosides (administration & dosage)
• Liver (drug effects, innervation, physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Sodium-Glucose Transporter 2 (metabolism)
• Sodium-Glucose Transporter 2 Inhibitors
• Vagotomy
• Vagus Nerve (drug effects, physiology, surgery)
• Weight Loss (physiology)