Mulberry leaf extracts and quercetin glycosides promote glycogen accumulation in astrocytes

OBJECTIVE: The astrocyte-neuron lactate shuttle is the mechanism by which astrocytic lactate is transferred to neurons to maintain brain function and is modulated by astrocytic glycogen content. The aims of this study were to determine whether mulberry leaf extracts promote astrocytic glycogen accumulation and to explore the active compounds of mulberry leaf extracts. MATERIALS AND METHODS: Glycogen content was determined in human-induced pluripotent stem cell-derived astrocytes treated with mulberry leaf extracts or their active compounds. To determine the involvement of active compounds in glycogen synthesis and degradation, human-induced pluripotent stem cell-derived astrocytes were treated with glucose-free medium containing 13C-glucose, and the amounts of 12C- and 13C-glucose in glycogen were quantified. RESULTS: Mulberry leaf extracts promoted astrocytic glycogen accumulation. Iminosugars in mulberry leaf extracts did not significantly increase the glycogen content of astrocytes. In contrast, several quercetin glycosides exhibited some of the activities of the mulberry leaf extracts. Quercetin aglycone, the basic backbone structure without glycosides, increased astrocytic glycogen content. Additionally, quercetin aglycone increased both 12C- and 13C-glucose contents, meaning it promoted glycogen synthesis and inhibited glycogen breakdown. CONCLUSIONS: In this study, quercetin glycosides were identified as active compounds present in mulberry leaf extracts. The principal compound responsible for the activity was identified as quercetin aglycone. Mulberry leaf extracts and quercetin analogs may induce astrocyte-neuron lactate shuttling by promoting the accumulation of glycogen in astrocytes.

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