SUN-684 Anti-Obesity Effects of HSYA through Inducing Lac-Phe and Inhibiting GIP

Abstract Disclosure: W. Hu: None. K. Yan: None. X. Lyu: None. X. Guo: None. Z. Zhou: None. Y. Zhao: None. L. Wang: None. H. Yang: None. H. Zhu: None. H. Pan: None. Q. Yang: None. F. Gong: None. Hydroxysafflor yellow A (HSYA), the primary bioactive compound in safflower (Carthamus tinctorius), has been shown in our previous studies to reduce feeding efficiency and prevent diet-induced obesity (DIO) by inhibiting glucose-dependent insulinotropic polypeptide (GIP) production. To investigate the underlying mechanisms of HSYA-inhibited GIP production, we performed metabolomics analysis of cecal contents from HSYA and vehicle-treated DIO mice. N-lactoyl-phenylalanine (Lac-Phe) emerged as one of the most significantly upregulated metabolites in HSYA-treated mice compared to controls. To determine the source of Lac-Phe production, we co-administered HSYA with antibiotics in DIO mice to deplete the gut microbiome. Antibiotics treatment did not reduce the elevated Lac-Phe levels in HSYA-treated mice, indicating that the gut microbiome is not the primary source of Lac-Phe production. We then investigated whether Lac-Phe could be generated by the small intestine. RT-PCR and immunohistochemistry analysis of the small intestine revealed that carnosine dipeptidase II (CNDP2), the sole synthetase of Lac-Phe, was upregulated by HSYA. Furthermore, treating Caco-2 cells with HSYA increased CNDP2 expression and Lac-Phe production, while CNDP2 knockdown abolished the HSYA-induced Lac-Phe elevation. These results suggest that HSYA increases Lac-Phe synthesis in the intestinal epithelial cells. To explore whether Lac-Phe is involved in GIP suppression by HSYA, we treated enteroendocrine STC-1 cells with Lac-Phe and found that GIP expression and production were significantly reduced. These findings suggest that HSYA exerts its anti-obesity effects by inducing Lac-Phe production in intestinal epithelial cells, which in turn reduces GIP secretion in intestinal enteroendocrine cells, dually leading to suppressed food efficiency and weight loss in DIO mice. Presentation: Sunday, July 13, 2025