Abstract
Walnut septum, an underutilized agricultural by-product, exhibits anti-obesity potential. However, the in vivo hypolipidemic mechanisms of walnut septum polyphenols (WSP) remain unexplored. We investigated the effects of WSP on lipid metabolism in high-fat diet (HFD)-fed mice using integrated transcriptomic and gut microbiomic analyses. The results indicated that WSP inhibited lipid accumulation in HFD mice and ameliorated HFD-induced oxidative stress, inflammation, and gut barrier impairment. Further studies revealed that WSP positively regulated FoxO1 expression by suppressing the PI3K/AKT signaling pathway, which in turn inhibited hepatic lipid synthesis in HFD mice. Furthermore, WSP concurrently remodeled gut microbiota via selective enrichment of beneficial Akkermansia and depletion of inflammation-associated norank_f__Desulfovibrionaceae. This microbial shift correlated with enhanced intestinal barrier integrity, reduced endotoxemia, and a predicted upregulation of propanoate metabolism. This study provides the first evidence of the synergistic regulation of the PI3K/AKT/FoxO1 pathway and gut microbiota restructuring by WSP, establishing a scientific foundation for valorizing walnut-processing waste into nutraceuticals against obesity.
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Data availability
The sequences generated in this study are stored in the National Center for Biotechnology Information (NCBI) and the project numbers are PRJNA1234563 and PRJNA1235473.
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Acknowledgements
This study was supported by the Project of Yunnan Province Xing Dian Talent Support Program-Young Talent Special (XDYC-QNRC-2023-0405), Yunnan Province Food and Drug Homologous Resources Functional Food Innovation Team (A3032023057), Yunnan Province-City Integration Project (202302 AN360002), and Yunnan International Joint Laboratory of Green Health Food (China and Thailand) (202203AP140011).
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Yuexiu Pan: Methodology, investigation, data organization, writing—original draft. Lei Peng: Conceptualization and methodology. Xia Hu: Data organization. Jinlian Chen: Methodology. Min Su: Methodology. Jingjing Dai: Software, visualization. Jun Sheng: Investigation and resources. Zishan Hong: validation, writing—review and editing. Jing Xie: Conceptualization, guidance, writing—review and editing. Yang Tian: Supervision and funding acquisition.
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Pan, YX., Peng, L., Hu, X. et al. Integration of transcriptomics and gut microbiomics reveals walnut septum polyphenols alleviate HFD-induced lipid disorders. npj Sci Food (2026). https://doi.org/10.1038/s41538-026-00801-y
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DOI: https://doi.org/10.1038/s41538-026-00801-y
