Berberine as a multi-target therapeutic agent for obesity: from pharmacological mechanisms to clinical evidence.

Obesity, clinically defined by pathological adipose tissue accumulation disrupting metabolic homeostasis, has reached pandemic proportions. The World Obesity Atlas 2024 reports over 1.5 billion projected cases by 2035, highlighting its growing threat among pediatric and adult populations globally. While newly approved pharmacotherapies such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) show efficacy, their clinical utility remains constrained by dose-dependent gastrointestinal complications, underscoring the urgent need for safer alternatives. This therapeutic gap has revitalized interest in natural bioactive compounds, particularly berberine (BBR)-a benzodioxoloquinolizine alkaloid derived from Coptis chinensis and related medicinal plants. Preclinical and clinical studies demonstrate BBR's multimodal anti-obesity mechanisms: (i) adenosine monophosphate-activated protein kinase (AMPK) activation enhancing lipolysis and β-oxidation, (ii) peroxisome proliferator-activated receptor γ (PPAR-γ) suppression inhibiting adipogenesis, (iii) gut microbiota modulation improving metabolic endotoxemia, and (iv) uncoupling protein 1 (UCP1) upregulation promoting adipose browning. Notably, BBR metabolites demonstrate pharmacological activity comparable to or exceeding that of the parent compound. However, BBR's translational applications face biopharmaceutical challenges, including poor intestinal absorption (< 1% bioavailability) due to P-glycoprotein efflux and first-pass metabolism. This comprehensive review critically evaluates recent advances in BBR's anti-obesity pharmacology through three lenses: (1) preclinical and clinical evidence from randomized controlled trials, (2) molecular mechanisms underlying metabolic regulation, and (3) innovative strategies for pharmacokinetic optimization. Given its multi-target efficacy and botanical safety profile, BBR represents a cost-effective adjuvant for obesity management, particularly in resource-limited settings. Future research should prioritize standardized clinical protocols and pharmacogenomic studies to optimize therapeutic outcomes.