title: Mercaptoacetate blocks fatty acid-induced GLP-1 secretion in male rats by directly antagonizing GPR40 fatty acid receptors.
abstract: Mercaptoacetate (MA) is an orexigenic agent reported to block fatty acid (FA) oxidation. Recently, however, we reported evidence from isolated nodose ganglion neurons that MA antagonizes the G protein-coupled long- and medium-chain FA receptor GPR40. GPR40 mediates FA-induced secretion of the satietogenic incretin peptide glucagon-like peptide 1 (GLP-1), by enteroendocrine L cells, as well as FA-induced enhancement of glucose-stimulated insulin secretion. Our results in cultured nodose neurons suggest that MA would also block GPR40 in enteroendocrine cells controlling GLP-1 secretion. If so, this would suggest an alternative mechanism by which MA increases food intake. We tested the hypothesis that MA blocks FA-induced GLP-1 secretion in vitro using cultured STC-1 cells (a murine enteroendocrine cell line) and in vivo in adult male rats. In vitro, MA blocked the increase in both cytosolic Ca(2+)and GLP-1 release stimulated by FAs and also reduced (but less effectively) the response of STC-1 cells to grifolic acid, a partial agonist of the GPR120 FA receptor. In vivo, MA reduced GLP-1 secretion following olive oil gavage while also increasing glucose and decreasing insulin levels. The carnitine palmatoyltransferase 1 antagonist etomoxir did not alter these responses. Results indicate that MA's actions, including its orexigenic effect, are mediated by GPR40 (and possibly GPR120) receptor antagonism and not by blockade of fat oxidation, as previously believed. Analysis of MA's interaction with GPR40 may facilitate understanding of the multiple functions of this receptor and the manner in which FAs participate in the control of hunger and satiety.
authors.affiliation: Programs in Neuroscience, Washington State University, Pullman, Washington aijunli@vetmed.wsu.edu.
authors.forename: Ai-Jun
authors.identifier: http://orcid.org/0000-0003-3585-886X
authors.initials: AJ
authors.lastname: Li
authors.affiliation: Programs in Neuroscience, Washington State University, Pullman, Washington.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Programs in Neuroscience, Washington State University, Pullman, Washington.
authors.forename: Thu T
authors.initials: TT
authors.lastname: Dinh
authors.affiliation: Programs in Neuroscience, Washington State University, Pullman, Washington.
authors.forename: Steve M
authors.initials: SM
authors.lastname: Simasko
authors.affiliation: Programs in Neuroscience, Washington State University, Pullman, Washington.
authors.forename: Sue
authors.initials: S
authors.lastname: Ritter
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D001069:Appetite Regulation / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D019858:Enteroendocrine Cells / Q000187:drug effects* / Q000378:metabolism; D005227:Fatty Acids / Q000008:administration & dosage* / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D008297:Male; D000069463:Olive Oil / Q000008:administration & dosage* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013864:Thioglycolates / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D001067:Appetite Depressants; D001786:Blood Glucose; D005227:Fatty Acids; C533284:Ffar4 protein, rat; C473035:G-protein-coupled receptor 40, rat; D007328:Insulin; D000069463:Olive Oil; D043562:Receptors, G-Protein-Coupled; D013864:Thioglycolates; C017487:2-mercaptoacetate; D052216:Glucagon-Like Peptide 1
keywords: G protein-coupled receptor 120; G protein-coupled receptor 40; fatty acids; glucagon-like peptide-1; mercaptoacetate