Abstract
OBJECTIVE: Obesity is increasingly recognized as an immunometabolic disorder driven by dysregulated crosstalk between visceral adipose tissue and the liver, particularly along the liver-omentum axis, which promotes insulin resistance and hepatic steatosis. Although Chaihu-Wendan Decoction (CHWD) is effective for metabolic disorders, its molecular mechanisms of action on this inflammatory axis remains unclear. This study aimed to investigate the therapeutic mechanisms of CHWD in high-fat diet (HFD)-induced obesity model, specifically focusing on insulin signaling and immune microenvironment remodeling in the liver-omentum axis. METHOD: C57BL/6J mice were fed a HFD to induce obesity and treated with CHWD. Metabolic phenotypes were assessed via biochemical and histological analyses. The molecular mechanisms were explored by evaluating the PTEN/PI3K/AKT/mTOR pathway and omental macrophage profiles using Western blot, ELISA, and immunohistochemistry. RESULTS: CHWD treatment significantly ameliorated HFD-induced body weight gain, dyslipidemia, and hepatic steatosis. Mechanistically, CHWD acted as a regulator of PTEN-associated signaling, which triggered a dual-regulation of PTEN/AKT/mTOR signaling, i.e., robust reactivation of upstream insulin signaling (INSR/IRS1/PI3K/AKT) coupled with the paradoxical suppression of downstream mTOR phosphorylation. This "uncoupling" process restored insulin sensitivity without promoting lipogenesis. Concurrently, CHWD remodeled the omental immune microenvironment by restoring omentin-1 secretion and promoting macrophage phenotype switching, characterized by maintenance of a CD68(+) macrophage population accompanied by suppression of iNOS-mediated cytotoxic effector functions. CONCLUSION: CHWD alleviates HFD-induced obesity and metabolic inflammation by coordinately targeting the PTEN/AKT/mTOR axis and reprogramming omental immunity. These findings provide the primary evidence supporting that CHWD modulates the liver-omentum axis via distinct signaling and immune mechanisms, offering a novel therapeutic strategy for metabolic syndrome.