Combination of Citrus aurantifolia Fruit Rind and Theobroma cacao Seed Extracts Stimulates Glucagon-Like Peptide-1 Secretion by Activating hTAS2Rs and the Phospholipase C-Mediated Signaling Pathway in NCI-H716 Cells.

LN19183 is a proprietary blend containing Citrus aurantifolia fruit rind and Theobroma cacao seed extracts in a 2:1 ratio. Recently, LN19183 was found to improve serum glucagon-like peptide-1 (GLP-1) levels after 16 weeks of intake in overweight adults. However, its specific mechanisms remain unknown. Therefore, the present study evaluated whether LN19183 acts through the bitter taste receptor-phospholipase C (PLC)-calcium signaling pathway in the human enteroendocrine L-cell line NCI-H716. The results showed that LN19183 dose-dependently increased relative GLP-1 secretion and reached statistical significance at 50 µg/mL (P<0.05). At the same dose, LN19183 selectively amplified the mRNA expression of bitter taste receptors (hTAS2R3, hTAS2R45, and most strongly, hTAS2R46) and concurrently increased the mRNA expression of α-gustducin. In addition, LN19183 upregulated the mRNA expression of proglucagon and prohormone convertase 1/3. To determine its mechanisms, cells were treated with U73122 (a PLC inhibitor) and 2-aminoethoxydiphenyl borate (an inositol 1,4,5-trisphosphate receptor inhibitor). These treatments inhibited the mRNA expression of proglucagon and secretion of GLP-1. Collectively, these findings indicate that LN19183 activates hTAS2R46-α-gustducin-PLC signaling to stimulate the biosynthesis and secretion of GLP-1. These data provide a molecular rationale for the increase in GLP-1 observed in previous animal and human studies of LN19183, thereby positioning this botanical as a promising adjunct for the prevention or comanagement of obesity and related metabolic diseases.