Activation of FFA1 mediates GLP-1 secretion in mice. Evidence for allosterism at FFA1

FFA1 (GPR40) and GPR120 are G-protein-coupled receptors activated by long-chain fatty acids. FFA1 is expressed in pancreatic β-cells, where it regulates glucose-dependent insulin secretion, and GPR120 has been implicated in mediating GLP-1 secretion. We show here that FFA1 co-localizes with GLP-1 in enteroendocrine cells and plays a critical role in glucose management by mediating GLP-1 secretion in vivo. Corn oil induces GLP-1 secretion in wild type mice and in GPR120−/− mice, but not in FFA1−/− mice. α-Linolenic acid, an endogenous ligand of FFA1, induces GLP-1 secretion in GLUTag cells and in primary fetal mouse intestinal cells. Synthetic partial FFA1 agonists do not stimulate GLP-1 secretion in mice, but partial and full agonists combined function cooperatively to enhance receptor activation and GLP-1 secretion both in vitro and in vivo. We conclude that allosterism at FFA1 can contribute to postprandial glucose management by stimulating insulin secretion via an extrapancreatic mechanism of action, and that GPR120 in GLP-1 secretion requires further investigation.

► FFA1 agonists induce GLP-1 secretion from enteroendocrine cells in vivo.
► FFA1, but not GPR120, is required for corn oil induced GLP-1 secretion in mice.
► Full and partial FFA1 agonists induce insulin and GLP-1 secretion synergistically.
► Allosteric FFA1 activation has implications for the design of novel T2D therapies.