Lyoniresinol Improves Insulin Sensitivity and Induces White-to-Beige Adipose Tissue Conversion in Obese Rats: Associated with JNK/PI3K/mTOR Pathway Modulation.

Background: Obesity contributes to multiple chronic diseases and remains a critical global health challenge. Objectives: This study evaluated the therapeutic effects of lyoniresinol on high-fat diet-induced obesity and its underlying molecular mechanisms. Methods: Network pharmacology was used to identify potential targets of lyoniresinol in obesity treatment, followed by validation using molecular docking. High-fat diet-induced obese rats received lyoniresinol (30 mg/kg/day) for six weeks. The primary efficacy endpoints were insulin sensitivity, assessed by the oral glucose tolerance test (OGTT), insulin tolerance test (ITT), fasting glucose, and fasting insulin, and adiposity measures, including body weight and regional fat mass. The key secondary endpoint was uncoupling protein 1 (UCP1) expression in adipose tissue, evaluated by Western blotting and immunohistochemistry. Mechanistic validation comprised analysis of the phosphorylation status of c-Jun N-terminal kinase (JNK), phosphatidylinositol 3-kinase (PI3K), and mammalian target of rapamycin (mTOR) by Western blotting. Exploratory assessments included serum lipid profiles, inflammatory cytokines, oxidative stress biomarkers, and histopathological examination. Results: Network pharmacology identified 50 shared targets between lyoniresinol and obesity. Molecular docking indicated favorable binding to JNK, PI3K, and mTOR. For the primary endpoints, lyoniresinol treatment was associated with reduced body weight gain, restored normoglycaemia, enhanced insulin sensitivity, and decreased regional adipose tissue mass. For the key secondary endpoint, UCP1 expression was upregulated, suggesting the browning of white adipose tissue. For the exploratory endpoints, lyoniresinol was associated with improved dyslipidaemia, reduced oxidative stress, suppressed pro-inflammatory cytokines and C-reactive protein (CRP), and attenuated adipocyte hypertrophy. For mechanistic validation, lyoniresinol treatment was associated with suppressed JNK phosphorylation and activation of PI3K/mTOR signaling in adipose tissue, suggesting potential involvement of the JNK/PI3K/mTOR pathway in these effects. Conclusions: Based on the primary efficacy endpoints, lyoniresinol was associated with improved insulin sensitivity and reduced adiposity in obese rats. The key secondary endpoint (UCP1 upregulation) and mechanistic validation (altered JNK/PI3K/mTOR phosphorylation) further support its association with the browning of white adipose tissue. These findings suggest that lyoniresinol may represent a multi-target candidate for further investigation in obesity-related metabolic disorders; however, the precise molecular mechanisms require additional validation.