Enrichment of Akkermansia muciniphila by red ginseng promotes GDF15 secretion and suppresses obesity in mice.

BACKGROUND

Obesity is a growing global health burden with rising incidence. Red ginseng (RGS), a traditional processed ginseng product, shows potential for improving metabolic parameters, though its anti-obesity mechanism remains incompletely understood.

PURPOSE: This study investigated the therapeutic effects of short-term RGS administration on obesity and sought to elucidate the underlying mechanism.

METHODS

A high-fat diet (HFD)-induced obese mouse model was used to assess short-term RGS effects. Antibiotic treatment and fecal microbiota transplantation were performed to evaluate gut microbiota involvement. 16S rRNA sequencing and metagenomic analysis identified key bacterial species, and mass spectrometry-based proteomics identified A. muciniphila-derived proteins. The growth differentiation factor 15 (GDF15)-GFRAL axis was interrogated using Gfral‒/‒ mice.

RESULTS

Short-term RGS treatment suppressed appetite, reduced body weight, and elevated circulating GDF15 in diet-induced obese (DIO) mice. RGS enriched A. muciniphila, and its depletion abrogated RGS-mediated weight loss and appetite suppression. The A. muciniphila-derived protein Amuc_1631 was identified as a key effector promoting GDF15 secretion. Mechanistically, RGS upregulated colonic Gdf15 transcription via the PERK-eIF2α-ATF4-CHOP axis and activated the brainstem GDF15-GFRAL pathway. The RGS 50% ethanol eluate (RGS/50) fraction was identified as the potential active component responsible for A. muciniphila enrichment and GDF15 elevation.

CONCLUSIONS

This study identifies a gut microbiota-dependent mechanism underlying the anti-obesity effects of RGS, centered on A. muciniphila enrichment and its derived protein Amuc_1631, which promotes GDF15 secretion to suppress food intake via the GDF15-GFRAL axis.