Oral Supplementation of Indole-3-acetic Acid Alleviates High-Fat-Induced Obesity by Activating the Gpha2-Mediated Thyroid-Stimulating Hormone Pathway

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 (<i>Ileibacterium, Anaerotignum</i>, and <i>Clostridium</i>) and significantly increased short-chain fatty acid (SCFA) production, particularly acetate and butyrate. In vitro experiments in <i>Saccharomyces cerevisiae</i> 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.