title: Conjugated linoleic acids mediate insulin release through islet G protein-coupled receptor FFA1/GPR40.
abstract: Among dietary components, conjugated linoleic acids (CLAs) have attracted considerable attention as weight loss supplements in the Western world because they reduce fat stores and increase muscle mass. However, a number of adverse effects are also ascribed to the intake of CLAs such as aggravation of insulin resistance and the risk of developing diabetes. However, the mechanisms accounting for the effects of CLAs on glucose homeostasis are incompletely understood. Herein we provide evidence that CLAs specifically activate the cell surface receptor FFA1, an emerging therapeutic target to treat type 2 diabetes. Using different recombinant cellular systems engineered to stably express FFA1 and a set of diverse functional assays including the novel, label-free non-invasive dynamic mass redistribution technology (Corning® Epic® biosensor), both CLA isomers cis-9, trans-11-CLA and trans-10, cis-12-CLA were found to activate FFA1 in vitro at concentrations sufficient to also account for FFA1 activation in vivo. Each CLA isomer markedly increased glucose-stimulated insulin secretion in insulin-producing INS-1E cells that endogenously express FFA1 and in primary pancreatic β-cells of wild type but not FFA1-/- knock-out mice. Our findings establish a clear mechanistic link between CLAs and insulin production and identify the cell surface receptor FFA1 as a molecular target for CLAs, explaining their acute stimulatory effects on insulin secretion in vivo. CLAs are also revealed as insulinotropic components in widely used nutraceuticals, a finding with significant implication for development of FFA1 modulators to treat type 2 diabetes.
authors.affiliation: Institute of Pharmaceutical Biology, University of Bonn, Nussallee 6, D-53115 Bonn, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schmidt
authors.forename: Kathrin
authors.initials: K
authors.lastname: Liebscher
authors.forename: Nicole
authors.initials: N
authors.lastname: Merten
authors.forename: Manuel
authors.initials: M
authors.lastname: Grundmann
authors.forename: Manfred
authors.initials: M
authors.lastname: Mielenz
authors.forename: Helga
authors.initials: H
authors.lastname: Sauerwein
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Christiansen
authors.forename: Maria E
authors.initials: ME
authors.lastname: Due-Hansen
authors.forename: Trond
authors.initials: T
authors.lastname: Ulven
authors.forename: Susanne
authors.initials: S
authors.lastname: Ullrich
authors.forename: Jesús
authors.initials: J
authors.lastname: Gomeza
authors.forename: Christel
authors.initials: C
authors.lastname: Drewke
authors.forename: Evi
authors.initials: E
authors.lastname: Kostenis
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D044243:Linoleic Acids, Conjugated / Q000494:pharmacology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C473034:FFAR1 protein, human; D007328:Insulin; D044243:Linoleic Acids, Conjugated; D043562:Receptors, G-Protein-Coupled; D002118:Calcium