Fatty acid composition in 2-monoacylglycerol modulates GLP-1 secretion

Glucagon-like peptide-1 (GLP-1) is an intestinal hormone secreted by L cells that regulates blood glucose levels by stimulating insulin secretion, regulating appetite, and β-cell growth. In this study, we screened eight 2-monoacylglycerols (2-MAGs) in STC-1 cells and identified 2-palmitoylglycerol (2-PG) as the most potent bioactive enhancer of GLP-1 secretion. Its activity was significantly greater than 2-oleoylglycerol (2-OG), which was previously reported to induce GLP-1 secretion. Pharmacological inhibition studies have indicated that GLP-1 secretion induced by 2-PG is attenuated by G protein-coupled receptor 119 (GPR119) and G protein-coupled receptor 40 (GPR40) antagonists. This is the first evidence indicating that GPR40 can be activated by 2-PG. Furthermore, to examine their physiological relevance, we evaluated the effect of two types of oils with similar fatty acid composition but different sn-2 fatty acid composition within triacylglycerols (TAGs) on GLP-1 secretion in mice. Mice administered oil enriched with palmitate at sn-2 exhibited significantly elevated total GLP-1 levels in portal vein 30 min after oil administration, compared to those administered oil enriched with oleate at sn-2 and palmitate at sn-1/sn-3. These findings suggest that both the specific fatty acid species of 2-MAGs and the positional distribution of fatty acids within TAGs critically influence GLP-1 secretion. This study highlights that 2-PG is a promising component for modulating GLP-1 secretion, which offers new insights into the development of nutritional therapeutic strategies for metabolic regulation.