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

Oral IAA supplementation dose-dependently attenuated body weight gain, adiposity, hepatic steatosis, and dyslipidemia while improving insulin sensitivity in high-fat-diet-induced obese mice.

• The model used was high-fat-diet (HFD)-induced obese mice.
• Effects on body weight gain, adiposity, hepatic steatosis, and dyslipidemia were dose-dependent with oral administration.
• Insulin sensitivity was improved alongside the reduction in obesity-related parameters.
• The route of administration was critical to the outcome, as oral supplementation produced antiobesogenic effects.

Intraperitoneal administration of IAA at 50 mg/kg/day paradoxically exacerbated weight gain in HFD-induced obese mice.

• The dose used for intraperitoneal (IP) administration was 50 mg/kg/day.
• This finding contrasted sharply with the beneficial effects observed with oral IAA supplementation.
• The paradoxical weight-gain effect with IP administration highlights the importance of the gut-mediated route for IAA's antiobesogenic activity.
• This route-dependent difference suggests that IAA's benefits are contingent on intestinal metabolism or microbiota interactions.

Oral IAA selectively enriched beneficial gut microbial genera and significantly increased short-chain fatty acid (SCFA) production, particularly acetate and butyrate.

• Metagenomic sequencing was used to assess gut microbiota composition.
• The beneficial genera enriched by oral IAA included Ileibacterium, Anaerotignum, and Clostridium.
• SCFA production was significantly increased, with acetate and butyrate specifically highlighted.
• The selective enrichment of these genera suggests a prebiotic-like role for oral IAA in reshaping the gut microbiome.

IAA directly suppresses de novo fatty acid biosynthesis and triacylglycerol assembly, as confirmed in vitro in Saccharomyces cerevisiae.

• In vitro experiments were conducted using Saccharomyces cerevisiae as the model organism.
• IAA was shown to directly inhibit de novo fatty acid biosynthesis.
• IAA also suppressed triacylglycerol assembly in this yeast model.
• These findings confirm a direct biochemical effect of IAA on lipid metabolism independent of mammalian host factors.

IAA upregulated hepatic Gpha2 expression, thereby activating the TSH-THR-PGC-1α-PPARγ signaling cascade and concomitantly repressing key lipogenic genes.

• The mechanistic pathway identified was Gpha2 → TSH (thyroid-stimulating hormone) → THR (thyroid hormone receptor) → PGC-1α → PPARγ.
• Key lipogenic genes repressed downstream of this cascade included Fasn (fatty acid synthase), Acaca (acetyl-CoA carboxylase alpha), and Srebp-1c (sterol regulatory element-binding protein 1c).
• Gpha2 (glycoprotein hormone alpha 2 subunit) was identified as a hepatic mediator of IAA's antilipogenic effects.
• This represents a microbiota-metabolite-to-nuclear-receptor signaling axis linking gut IAA production to hepatic lipid metabolism.

IAA is a gut microbiota-derived tryptophan metabolite with antiobesogenic potential that is positioned as a promising microbiota-derived metabolite for obesity and related metabolic disorders.

• IAA (indole-3-acetic acid) is produced from tryptophan by gut microbiota.
• The study collectively identifies IAA as having 'substantial preventive and therapeutic potential for obesity and related metabolic disorders.'
• The antiobesogenic effects were demonstrated through multiple mechanisms: microbiome modulation, direct lipid biosynthesis inhibition, and hepatic signaling pathway activation.
• Obesity is described as 'a major global public health challenge,' framing the clinical relevance of these findings.