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Biochem Biophys Res Commun. 2017 Nov 4;493(1):40-45. doi: 10.1016/j.bbrc.2017.09.081. Epub 2017 Sep 18.

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

Author information

1
Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan; Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan.
2
Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan; Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, 113-8655, Japan.
3
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan.
4
Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, 113-8655, Japan.
5
Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan; Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan; Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, 113-8655, Japan. Electronic address: nyahagi-tky@umin.ac.jp.

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.

KEYWORDS:

Diabetes; Glycogen depletion signal; Liver-brain-adipose neurocircuitry; Obesity; SGLT2 inhibitor

PMID:
28928093
DOI:
10.1016/j.bbrc.2017.09.081
[Indexed for MEDLINE]

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