Objective To investigate the alleviating effects of soy isoflavones (SIF) on chronic inflammation in obese mice induced by a high-fat diet and elucidate the molecular mechanisms Methods Thirty C57BL/6 mice were randomly divided into control group, model group, 10 mg/kg SIF group, 20 mg/kg SIF group, and rosiglitazone group (positive control). All groups except the control group were fed a high-fat diet for 12 weeks. Body weight, epididymal adipose tissue weight, serum levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C), as well as inflammatory factor in adipose tissue, were measured. Transcriptome sequencing and GO/KEGG enrichment analysis were performed on epididymal adipose tissues from the model group and the 20 mg/kg SIF group. Immunohistochemical staining was used to detect the positive rate of CD86 in epididymal adipose tissue, and Western blot was employed to assess the protein expression of iNOS, CD86, and PPARγ in epididymal adipose tissue. RAW264.7 macrophages were cultured in vitro and divided into control group, model group, 10 μmol/L SIF, 30 μmol/L SIF, and 30 μmol/L SIF + PPARγ inhibitor GW9662 (10 μmol/L)groups. Except for the control group, M1 polarization was induced by LPS in all groups. The proportion of M1-polarized cells was detected by flow cytometry, and the expression levels of iNOS, CD86, and PPARγ were assessed by Western blot. Inflammatory factors levels in RAW264.7 macrophages were measured by ELISA. Molecular docking and surface plasmon resonance (SPR) assays were performed to validate the interaction between SIF and PPARγ. Results Compared with the model group, SIF intervention reduced body weight, epididymal adipose tissue weight, serum levels of TC, TG, and LDL-C, and inflammatory factors levels in epididymal adipose tissue. Transcriptome sequencing revealed that after SIF intervention, GO terms related to inflammatory response and M1 macrophage polarization,as well as the PPARγ signaling pathway, were significantly enriched in epididymal adipose tissue. Immunohistochemical results showed that SIF reduced the positive rate of CD86 in epididymal adipose tissue. SIF downregulated the expression of iNOS and CD86, while upregulating PPARγ expression in epididymal adipose tissue. In vitro experiments demonstrated that SIF reduced the proportion of LPS-induced M1-polarized RAW264.7 cells, downregulated the protein expression of iNOS and CD86, and decreased the levels of TNF-α, IL-1β, and IL-6. These effects were reversed by GW9662. Molecular docking indicated a favorable binding affinity between SIF and PPARγ, and SPR assays further confirmed their direct interaction (Kd value of 1.2 μmol/L). Conclusion SIF can inhibit M1 polarization of tissue macrophages in adipose tissue, thereby alleviating obesity-related chronic inflammation. The mechanism is associated with direct binding to and activation of PPARγ.
Key words
obesity /
soy isoflavones /
chronic inflammation /
macrophages /
PPARγ /
mouse
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