Du Yuhang, He Changhao, An Yongcheng, Zhao Yige, Zhang Huilin, Shan Ziyi, Yang Yang, Wang Menglu, Xie Jiamei, Huang Yan, Fu Wanxin, Yuan Yueying, Zhao Baosheng
Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.
J Ethnopharmacol. 2025 Aug 16;353(Pt B):120408. doi: 10.1016/j.jep.2025.120408.
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.
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.
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.
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.
MLE-modulated gut microbiota ameliorates T2DM via SCFAs-activated AMPK/SIRT1/PGC-1α signaling , promoting WAT browning and BAT activation.
桑叶（桑科植物桑），传统上在《本草纲目》中有治疗糖尿病的记载。现代研究也表明，桑叶水提取物（MLE）可改善血糖水平，同时恢复肠道微生物群稳态并提高短链脂肪酸（SCFAs）水平。然而，MLE促进SCFAs升高与改善葡萄糖/脂质代谢之间的因果关系以及确切机制仍不清楚。
本研究旨在阐明MLE促进SCFAs升高与改善葡萄糖/脂质代谢之间的因果关系以及确切机制。
给db/db小鼠使用抗生素诱导微生物群耗竭以建立伪无菌模型，随后进行平行干预：来自MLE（4 g生药/kg）处理或未处理供体的粪便微生物群移植（FMT），以及直接补充SCFAs。通过生化分析、qRT-PCR和组织学评估棕色脂肪组织（BAT）和腹股沟白色脂肪组织（IWAT）中的葡萄糖和脂质代谢，以及肝脏脂肪变性/炎症。通过蛋白质印迹和免疫组织化学评估脂肪组织中的蛋白质表达。通过16S rRNA测序分析肠道微生物群组成，并通过靶向代谢组学检测粪便SCFAs水平。
FMT-MLE和SCFAs处理均显示出显著的代谢益处，包括增强葡萄糖/脂质稳态、改善脂质代谢、减轻肝脏脂肪变性和炎症、恢复微生物平衡以及提高SCFAs浓度。从机制上讲，接受FMT-MLE和SCFAs处理的小鼠显示BAT活性增加，能量消耗增加，白色脂肪组织褐变。此外，FMT-MLE和SCFAs上调了BAT和IWAT中磷酸化-AMP活化蛋白激酶（p-AMPK）、p-AMPK/腺苷单磷酸活化蛋白激酶（AMPK）、沉默调节蛋白1（SIRT1）和过氧化物酶体增殖物激活受体γ辅激活因子1α（PGC-1α）的蛋白质表达。
MLE调节的肠道微生物群通过SCFAs激活的AMPK/SIRT1/PGC-1α信号通路改善2型糖尿病，促进白色脂肪组织褐变和BAT激活。
