Baicalein alleviates hepatic lipid metabolism disorders via the PPARα-FGF21-adiponectin axis: Regulating crosstalk between the liver and adipose tissue.

ETHNOPHARMACOLOGICAL RELEVANCE: Ban-xia-xie-xin-tang (BXXXT) is a classic traditional Chinese medicine formula used for treating gastrointestinal and metabolic disorders. It has demonstrated definite ameliorative effects on blood glucose and lipid dysregulation. However, the molecular mechanisms underlying the actions of its active components remain to be elucidated.

AIM OF THE STUDY: The global rise in obesity has escalated the prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) and type 2 diabetes mellitus (T2DM), driven by lipid metabolism disorders and aberrant inter-organ crosstalk, particularly between liver and adipose tissue. This study aimed to identify baicalein as a novel natural peroxisome proliferator-activated receptor-α (PPARα) agonist. We further sought to elucidate its mechanism in alleviating MAFLD-associated lipid disorders by activating the fibroblast growth factor 21 (FGF21)-adiponectin axis.

MATERIALS AND

METHODS

Active components of BXXXT targeting PPARα were screened using molecular docking and validated by surface plasmon resonance (SPR). The therapeutic effects of baicalein were evaluated in high-fat diet (HFD)-induced obese mice through metabolic phenotyping, histopathology, and biomarker analysis. Mechanistically, a hepatocyte-adipocyte transwell co-culture model was established to investigate the intercellular communication mediated by the PPARα-FGF21-adiponectin axis.

RESULTS

The active component of BXXXT, baicalein, was identified as a high-affinity PPARα ligand. In vivo, baicalein treatment significantly reduced hepatic steatosis, body weight, and insulin resistance in HFD-fed mice. It promoted energy expenditure and fatty acid oxidation while inhibiting hepatic lipid synthesis. Crucially, baicalein upregulated hepatic FGF21 expression and increased circulating adiponectin levels. In the co-culture system, baicalein stimulated FGF21 secretion from hepatocytes, which subsequently triggered adiponectin release from adipocytes. This feedback loop suppressed lipid synthesis and enhanced fatty acid oxidation in hepatocytes.

CONCLUSIONS

By bridging traditional pharmacology with molecular endocrinology, this study demonstrates that baicalein restores liver-adipose crosstalk via the PPARα-FGF21-adiponectin axis. These findings position baicalein as a promising therapeutic candidate for managing metabolic disorders.