Effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on weight loss is partly mediated by liver-brain-adipose neurocircuitry
2017
Abstract Sodium-glucose
cotransporter2 (SGLT2) inhibitors have both anti-diabetic and anti-obesity effects. However, the
precise mechanismof the anti-obesity effect remains unclear. We previously demonstrated that the
glycogen depletionsignal triggers
lipolysisin 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 obesemice 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 phosphorylationby protein kinase A (PKA) in
white adipose tissuecompared with the sham group. As PKA pathway is known to act as an effector of the liver-brain-adipose axis and activate
triglyceride lipasesin adipocytes, these results indicated that SGLT2 inhibition triggered
glycogen depletionsignal 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.
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