Mercaptoacetate and fatty acids exert direct and antagonistic effects on nodose neurons via GPR40 fatty acid receptors.
β-mercaptoacetate (MA) is a drug known to block mitochondrial oxidation of medium- and long-chain fatty acids (FAs) and to stimulate feeding. Because MA-induced feeding is vagally dependent, it has been assumed that the feeding response is mediated by MA's antimetabolic action at a peripheral, vagally innervated site. However, MA's site of action has not yet been identified. Therefore, we used fluorescent calcium measurements in isolated neurons from rat nodose ganglia to determine whether MA has direct effects on vagal sensory neurons. We found that MA alone did not alter cytosolic calcium concentrations in nodose neurons. However, MA (60 μM to 6 mM) significantly decreased calcium responses to both linoleic acid (LA; 10 μM) and caprylic acid (C8; 10 μM) in all neurons responsive to LA and C8. GW9508 (40 μM), an agonist of the FA receptor, G protein-coupled receptor 40 (GPR40), also increased calcium levels almost exclusively in FA-responsive neurons. MA significantly inhibited this response to GW9508. MA did not inhibit calcium responses to serotonin, high K(+), or capsaicin, which do not utilize GPRs, or to CCK, which acts on a different GPR. GPR40 was detected in nodose ganglia by RT-PCR. Results suggest that FAs directly activate vagal sensory neurons via GPR40 and that MA antagonizes this effect. Thus, we propose that MA's nonmetabolic actions on GPR40 membrane receptors, expressed by multiple peripheral tissues in addition to the vagus nerve, may contribute to or mediate MA-induced stimulation of feeding.
Program in Neuroscience, Washington State University, Pullman, Washington.
Rebecca A
RA
Darling
Program in Neuroscience, Washington State University, Pullman, Washington.
Huan
H
Zhao
Program in Neuroscience, Washington State University, Pullman, Washington.
Dallas
D
Kinch
Program in Neuroscience, Washington State University, Pullman, Washington.
Ai-Jun
AJ
Li
Program in Neuroscience, Washington State University, Pullman, Washington.
Steven M
SM
Simasko
Program in Neuroscience, Washington State University, Pullman, Washington sjr@vetmed.wsu.edu.
Sue
S
Ritter
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002210:Caprylates / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D005227:Fatty Acids / Q000494:pharmacology*; D019787:Linoleic Acid / Q000494:pharmacology; D008297:Male; D009620:Nodose Ganglion / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism; D013864:Thioglycolates / Q000494:pharmacology*; D013997:Time Factors
D002210:Caprylates; D005227:Fatty Acids; C473035:G-protein-coupled receptor 40, rat; D043562:Receptors, G-Protein-Coupled; D013864:Thioglycolates; C017487:2-mercaptoacetate; D019787:Linoleic Acid; C031492:octanoic acid; D002118:Calcium
G-protein coupled receptor 40; calcium imaging; fatty acids; nodose ganglion; β-mercaptoacetate