title: Activation of FFA1 mediates GLP-1 secretion in mice. Evidence for allosterism at FFA1.
abstract: 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.
authors: Department of Metabolic Disorders, Amgen Inc., South San Francisco, CA 94080, USA.
authors: Yumei
authors: Y
authors: Xiong
authors: Gayathri
authors: G
authors: Swaminath
authors: Qiong
authors: Q
authors: Cao
authors: Li
authors: L
authors: Yang
authors: Qi
authors: Q
authors: Guo
authors: Heather
authors: H
authors: Salomonis
authors: Jenny
authors: J
authors: Lu
authors: Jonathan B
authors: JB
authors: Houze
authors: Paul J
authors: PJ
authors: Dransfield
authors: Yingcai
authors: Y
authors: Wang
authors: Jiwen Jim
authors: JJ
authors: Liu
authors: Simon
authors: S
authors: Wong
authors: Ralf
authors: R
authors: Schwandner
authors: Franziska
authors: F
authors: Steger
authors: Helene
authors: H
authors: Baribault
authors: Lily
authors: L
authors: Liu
authors: Suzanne
authors: S
authors: Coberly
authors: Lynn
authors: L
authors: Miao
authors: Jane
authors: J
authors: Zhang
authors: Daniel C-H
authors: DC
authors: Lin
authors: Margrit
authors: M
authors: Schwarz
mesh_terms: D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D003001:Cloning, Molecular; D006224:Cricetinae; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C498007:FFAR4 protein, mouse; C473036:Ffar1 protein, mouse; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D052216:Glucagon-Like Peptide 1