GPR119 regulates genetic markers of fatty acid oxidation in cultured skeletal muscle myotubes.
Gene knockout and agonist studies indicate that activation of the G protein-coupled receptor, GPR119, protects against diet-induced obesity and insulin resistance. It is not known if GPR119 activation in skeletal muscle mediates these effects. To address this uncertainty, we measured GPR119 expression in skeletal muscle and determined the effects of PSN632408, a GPR119 agonist, on the expression of genes and proteins required for fatty acid and glucose oxidation in cultured myotubes. GPR119 expression was readily detected in rat skeletal muscle and mRNAs were induced by 12 weeks of high-fat feeding. Treatment of cultured mouse C₂C₁₂ myotubes with 5 μM PSN632408 or 0.5 mM palmitate reduced expression of mRNAs encoding fatty acid oxidation genes to similar extents. More so, treatment with PSN632408 decreased AMPKα (Thr172 phosphorylation) activity in the absence of palmitate and ACC (Ser79 phosphorylation) activity in the presence of palmitate. In human primary myotubes PSN632408 decreased expression of PDK4 and AMPKα2 mRNA in myotubes derived from obese donors. These data suggest GPR119 activation in skeletal muscle may impair fatty acid and glucose oxidation.
Biomedical and Lifestyle Diseases Unit, School of Biomedical and Health Sciences, Victoria University, Melbourne 8001, Australia. lauren.cornall@live.vu.edu.au
L M
LM
Cornall
M L
ML
Mathai
D H
DH
Hryciw
A C
AC
Simcocks
P E
PE
O'Brien
J M
JM
Wentworth
A J
AJ
McAinch
D000147:Acids, Heterocyclic / Q000494:pharmacology; D000328:Adult; D000818:Animals; D015992:Body Mass Index; D002478:Cells, Cultured; D002999:Clone Cells; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005819:Genetic Markers; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009767:Obesity, Morbid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010069:Oxadiazoles / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
D000147:Acids, Heterocyclic; D005230:Fatty Acids, Nonesterified; C519854:GPR119 protein, human; C532423:GPR119 protein, rat; D005819:Genetic Markers; C516207:Gpr119 protein, mouse; D010069:Oxadiazoles; C534146:PSN 632408; D043562:Receptors, G-Protein-Coupled; D005947:Glucose