Gut microbiota modified by Mulberry leaf water extract improves T2DM through browning of WAT/BAT activation mediated by SCFAs-AMPK/SIRT1/PGC-1α signaling pathway

Aug 18, 2025Journal of ethnopharmacology

Mulberry leaf extract changes gut bacteria to improve type 2 diabetes by activating fat burning through short-chain fatty acids and energy-regulating signals

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Abstract

Fecal microbiota transplantation from mulberry leaf-treated mice significantly improved glucose and lipid metabolism in diabetic mice.

Mulberry leaf water extract (MLE) is associated with enhanced levels of short-chain fatty acids (SCFAs) in the gut.
Both fecal microbiota transplantation (FMT) from MLE-treated donors and direct SCFAs supplementation showed metabolic benefits.
Improvements included better glucose and lipid homeostasis, reduced hepatic steatosis and inflammation, and restored gut microbiota balance.
Increased activity in brown adipose tissue (BAT) and elevated energy expenditure were observed following treatments.
Protein expression of key regulatory proteins involved in metabolism was upregulated in adipose tissues after FMT-MLE and SCFAs treatments.

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ETHNOPHARMACOLOGICAL RELEVANCE: Mulberry leaf (Morus alba L.), traditionally recorded in "Compendium of Materia Medica" for diabetes treatment. Mulberry leaf water extract (MLE) has also been shown in modern studies to improve blood glucose levels while restoring gut microbiota homeostasis and increasing short-chain fatty acids (SCFAs) levels. However, the causal relationship between MLE-promoted SCFAs elevation and improvements in glucose/lipid metabolism as well as the exact mechanism, remain unclear.

AIM OF THE STUDY: This study aimed to clarify the causal relationship between MLE-promoted SCFAs elevation and improvements in glucose/lipid metabolism as well as the exact mechanism.

MATERIALS AND METHODS: db/db mice received antibiotic-induced microbiota depletion to generate pseudo-germ-free model, followed by parallel interventions: fecal microbiota transplantation (FMT) from MLE (4 g crude drug/kg)-treated or untreated donors, and direct SCFAs supplementation. Glucose and lipid metabolism in brown adipose tissue (BAT) and inguinal white adipose tissue (IWAT), and hepatic steatosis/inflammation were evaluated through biochemical assays, qRT-PCR and histology. Protein expressions in adipose tissues were assessed by Western blotting and immunohistochemistry. Gut microbiota composition was analyzed by 16S rRNA sequencing and fecal SCFAs levels were detected by targeted metabolomics.

RESULTS: Both FMT-MLE and SCFAs treatments demonstrated marked metabolic benefits, including enhanced glucose/lipid homeostasis, improved lipid metabolism, alleviated hepatic steatosis and inflammation, restored microbial balance, and elevated SCFAs concentrations. Mechanistically, mice treated with FMT-MLE and SCFAs showed increased BAT activity and exhibited increased energy expenditure, and browning of WAT. Additionally, FMT-MLE and SCFAs upregulated the protein expression of phosphorylated-AMP-activated protein kinase (p-AMPK), p-AMPK/adenosine monophosphate-activated protein kinase (AMPK), sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) in BAT and IWAT.

CONCLUSION: MLE-modulated gut microbiota ameliorates T2DM via SCFAs-activated AMPK/SIRT1/PGC-1α signaling , promoting WAT browning and BAT activation.

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Gut microbiota modified by Mulberry leaf water extract improves T2DM through browning of WAT/BAT activation mediated by SCFAs-AMPK/SIRT1/PGC-1α signaling pathway

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