Betulin Activates Hepatic PPARα-FGF21 Signaling to Combat Obesity

Area of Science:

• Metabolic disorders
• Obesity research
• Natural product pharmacology

Background:

• Betulin, a pentacyclic triterpenoid, shows promise for metabolic disorders.
• Its precise mechanisms of action, particularly in obesity, are not fully understood.

Purpose of the Study:

• To investigate the metabolic effects of betulin in a high-fat diet-induced obesity mouse model.
• To elucidate the molecular pathways mediating betulin's action, focusing on hepatic gene expression and signaling.

Main Methods:

• Dietary supplementation with betulin in mice fed a high-fat diet.
• Hepatic transcriptomics to analyze gene expression changes.
• Molecular dynamics simulations and experimental validation to confirm molecular interactions.

Main Results:

• Betulin supplementation reduced body weight gain, improved glucose tolerance, and decreased liver lipid accumulation.
• Hepatic transcriptomics identified the peroxisome proliferator-activated receptor-α (PPARα) pathway and fibroblast growth factor 21 (FGF21) as key targets.
• Betulin was confirmed to act as a PPARα agonist, inducing FGF21 expression both in vivo and in vitro.

Conclusions:

• Betulin acts as a PPARα agonist, leading to increased FGF21 expression and conferring metabolic benefits.
• This study elucidates a novel hepatokine-dependent pathway for betulin's anti-obesity and anti-metabolic disorder effects.