title: Free fatty acid receptor 1 (FFAR1/GPR40) signaling affects insulin secretion by enhancing mitochondrial respiration during palmitate exposure.
abstract: Fatty acids affect insulin secretion via metabolism and FFAR1-mediated signaling. Recent reports indicate that these two pathways act synergistically. Still it remains unclear how they interrelate. Taking into account the key role of mitochondria in insulin secretion, we attempted to dissect the metabolic and FFAR1-mediated effects of fatty acids on mitochondrial function. One-hour culture of MIN6 cells with palmitate significantly enhanced mitochondrial respiration. Antagonism or silencing of FFAR1 prevented the palmitate-induced rise in respiration. On the other hand, in the absence of extracellular palmitate FFAR1 agonists caused a modest increase in respiration. Using an agonist of the M3 muscarinic acetylcholine receptor and PKC inhibitor we found that in the presence of the fatty acid mitochondrial respiration is regulated via Gαq protein-coupled receptor signaling. The increase in respiration in palmitate-treated cells was largely due to increased glucose utilization and oxidation. However, glucose utilization was not dependent on FFAR1 signaling. Collectively, these results indicate that mitochondrial respiration in palmitate-treated cells is enhanced via combined action of intracellular metabolism of the fatty acid and the Gαq-coupled FFAR1 signaling. Long-term palmitate exposure reduced ATP-coupling efficiency of mitochondria and deteriorated insulin secretion. The presence of the FFAR1 antagonist during culture did not improve ATP-coupling efficiency, however, it resulted in enhanced mitochondrial respiration and improved insulin secretion after culture. Taken together, our study demonstrates that during palmitate exposure, integrated actions of fatty acid metabolism and fatty acid-induced FFAR1 signaling on mitochondrial respiration underlie the synergistic action of the two pathways on insulin secretion.
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala SE-75123, Sweden.
authors.forename: Hjalti
authors.initials: H
authors.lastname: Kristinsson
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala SE-75123, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Bergsten
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala SE-75123, Sweden. Electronic address: ernest.sargsyan@mcb.uu.se.
authors.forename: Ernest
authors.initials: E
authors.lastname: Sargsyan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects*; D019308:Palmitic Acid / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C473034:FFAR1 protein, human; C473036:Ffar1 protein, mouse; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D019308:Palmitic Acid
keywords: FFAR1; Fatty acid; GPR40; Insulin secretion; Mitochondrial respiration