Oral Supplementation of Indole-3-acetic Acid Alleviates High-Fat-Induced Obesity by Activating the Gpha2-Mediated...

Obesity is a major global public health challenge. Indole-3-acetic acid (IAA), a gut microbiota-derived tryptophan metabolite, exhibits antiobesogenic potential. In this study, we found that in high-fat-diet-induced obese mice, oral IAA supplementation dose dependently attenuated body weight gain, adiposity, hepatic steatosis, and dyslipidemia while improving insulin sensitivity. Notably, intraperitoneal administration of IAA (50 mg/kg/day) paradoxically exacerbated weight gain. Metagenomic sequencing showed that oral IAA selectively enriched beneficial genera (Ileibacterium, Anaerotignum, and Clostridium) and significantly increased short-chain fatty acid (SCFA) production, particularly acetate and butyrate. In vitro experiments in Saccharomyces cerevisiae further confirmed that IAA directly suppresses de novo fatty acid biosynthesis and triacylglycerol assembly. Mechanistically, IAA upregulated hepatic Gpha2 expression, thereby activating the TSH-THR-PGC-1α-PPARγ signaling cascade and concomitantly repressing key lipogenic genes (Fasn, Acaca, and Srebp-1c). Collectively, these findings position IAA as a promising microbiota-derived metabolite with substantial preventive and therapeutic potential for obesity and related metabolic disorders.