N-Acetyltaurine induces an IRX2-GDF15 endocrine response that suppresses high-fat diet-induced energy intake.

N-acetyltaurine (NAT) is a taurine-derived metabolite that has recently been linked to feeding behavior and body-weight regulation. Although NAT has been shown to lower body weight through GFRAL-dependent signaling, the tissue source and upstream regulatory mechanism responsible for NAT-induced GDF15 production remain incompletely defined. Here we show that NAT administration suppressed food intake, limited early HFD-induced weight gain and adipose tissue expansion, and attenuated lipid accumulation in skeletal muscle and liver. These effects were accompanied by increased circulating GDF15. Genetic ablation of Gdf15 abolished the effects of NAT on food intake, body weight, adipose tissue mass, serum triglycerides, and ectopic lipid deposition, establishing GDF15 as an essential mediator of NAT-induced metabolic regulation. Tissue profiling identified the heart as a prominent NAT-responsive tissue for Gdf15 induction. In cardiomyocyte derived H9C2 cells, NAT increased Gdf15 expression together with induction of the transcription factor IRX2. IRX2 enhanced Gdf15 promoter activity, and IRX2 knockdown attenuated NAT-induced GDF15 expression. In a human serum cohort, circulating NAT and GDF15 levels are elevated and positively correlated in the serum of individuals with obesity, indicating the activation of this pathway as an adaptive response to excess nutrient load. These findings identify a GDF15-dependent endocrine mechanism linking NAT to food-intake regulation during HFD challenge and suggest a potential cardiac IRX2-GDF15 transcriptional response in NAT-induced GDF15 production. The association between circulating NAT and GDF15 in human obesity supports translational relevance, while further studies are needed to establish tissue-specific causality and long-term therapeutic potential.