Journal of ethnopharmacology · 2025
Fufang zhenzhu tiaozhi capsule alleviates hypothalamic endoplasmic reticulum stress and leptin resistance through autophagy modulation in DIO rats.
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Hua Tingyu, Wu Qiwen, Huang Zhang, Cai Jinyan
Аннотация
ETHNOPHARMACOLOGICAL RELEVANCE: Fufang Zhenzhu TiaoZhi (FTZ), a Chinese medicinal decoction, has continuously been used to treat glycolipid metabolic diseases (GLMD). Berberine (BBR) is the main active ingredient of FTZ. Our findings suggest the therapeutic effects of FTZ through hypothalamic regulation. Hypothalamic ER stress and leptin resistance may be implicated in this process.
AIM OF THE STUDY: To investigate whether FTZ and its active ingredient, BBR can effectively alleviate hypothalamic ER stress and leptin resistance by autophagy modulation in DIO rats.
METHODS: FTZ and BBR were orally administered at two different doses daily for 6 weeks. Glycolipid indicators, autophagy, ER stress, and leptin resistance markers were evaluated using biochemical assays, qPCR, Western blotting, and immunofluorescence. BV2 and GT1-7 cell models with autophagy modulators validated the findings.
RESULTS: FTZ and BBR significantly reduced body weight and fat percentage. Additionally, they improved the hypothalamic ER structure in DIO rats. They downregulated ER stress-related genes ATF6, eIF2α, GRP78, IRE1α, PERK, XBP1 and inhibited activation of the p-IRE1α/sXBP1 signaling pathway, while decreasing leptin resistance markers PTP1B, SOCS3 and increasing LepRb mRNA and p-STAT3 protein. They also enhanced autophagy by upregulating Beclin1 and Atg7 in the hypothalamus, with increased Atg7 expression in POMC neurons and decreased expression in AgRP neurons. In BV2 and GT1-7 cells, FTZ and BBR increased autophagy and modulated the p-IRE1α/sXBP1 and p-STAT3/SOCS3 pathways.
CONCLUSION: FTZ and BBR effectively alleviated glycolipid metabolic disorders in DIO rats, potentially through enhancing autophagy flux in hypothalamic POMC neurons, AgRP neurons, and microglial cells, inhibiting the p-IRE1α/sXBP1 signaling pathway to relieve hypothalamic ER stress, and regulating the p-STAT3/SOCS3 pathway to improve leptin sensitivity.
AIM OF THE STUDY: To investigate whether FTZ and its active ingredient, BBR can effectively alleviate hypothalamic ER stress and leptin resistance by autophagy modulation in DIO rats.
METHODS: FTZ and BBR were orally administered at two different doses daily for 6 weeks. Glycolipid indicators, autophagy, ER stress, and leptin resistance markers were evaluated using biochemical assays, qPCR, Western blotting, and immunofluorescence. BV2 and GT1-7 cell models with autophagy modulators validated the findings.
RESULTS: FTZ and BBR significantly reduced body weight and fat percentage. Additionally, they improved the hypothalamic ER structure in DIO rats. They downregulated ER stress-related genes ATF6, eIF2α, GRP78, IRE1α, PERK, XBP1 and inhibited activation of the p-IRE1α/sXBP1 signaling pathway, while decreasing leptin resistance markers PTP1B, SOCS3 and increasing LepRb mRNA and p-STAT3 protein. They also enhanced autophagy by upregulating Beclin1 and Atg7 in the hypothalamus, with increased Atg7 expression in POMC neurons and decreased expression in AgRP neurons. In BV2 and GT1-7 cells, FTZ and BBR increased autophagy and modulated the p-IRE1α/sXBP1 and p-STAT3/SOCS3 pathways.
CONCLUSION: FTZ and BBR effectively alleviated glycolipid metabolic disorders in DIO rats, potentially through enhancing autophagy flux in hypothalamic POMC neurons, AgRP neurons, and microglial cells, inhibiting the p-IRE1α/sXBP1 signaling pathway to relieve hypothalamic ER stress, and regulating the p-STAT3/SOCS3 pathway to improve leptin sensitivity.