A role for the malonyl-CoA/long-chain acyl-CoA pathway of lipid signaling in the regulation of insulin secretion in response to both fuel and nonfuel stimuli.
The malonyl-CoA/long-chain acyl-CoA (LC-CoA) model of glucose-induced insulin secretion (GIIS) predicts that malonyl-CoA derived from glucose metabolism inhibits fatty acid oxidation, thereby increasing the availability of LC-CoA for lipid signaling to cellular processes involved in exocytosis. For directly testing the model, INSr3 cell clones overexpressing malonyl-CoA decarboxylase in the cytosol (MCDc) in a tetracycline regulatable manner were generated, and INS(832/13) and rat islets were infected with MCDc-expressing adenoviruses. MCD activity was increased more than fivefold, and the malonyl-CoA content was markedly diminished. This was associated with enhanced fat oxidation at high glucose, a suppression of the glucose-induced increase in cellular free fatty acid (FFA) content, and reduced partitioning at elevated glucose of exogenous palmitate into lipid esterification products. MCDc overexpression, in the presence of exogenous FFAs but not in their absence, reduced GIIS in all beta-cell lines and in rat islets. It also markedly curtailed the stimulation of insulin secretion by other fuel and nonfuel secretagogues. In the absence of MCDc overexpression, the secretory responses to all types of secretagogues were amplified by the provision of exogenous fatty acids. In the presence of exogenous FFAs, the fatty acyl-CoA synthetase inhibitor triacsin C reduced secretion in response to glucose and nonfuel stimuli. The data show the existence of important links between the metabolic coupling factor malonyl-CoA, the partitioning of fatty acids, and the stimulation of insulin secretion to both fuel and nonfuel stimuli.
Roduit
Raphaël
R
Molecular Nutrition Unit, Department of Nutrition, University of Montreal and the Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
Nolan
Christopher
C
Alarcon
Cristina
C
Moore
Patrick
P
Barbeau
Annie
A
Delghingaro-Augusto
Viviane
V
Przybykowski
Ewa
E
Morin
Johane
J
Massé
Frédéric
F
Massie
Bernard
B
Ruderman
Neil
N
Rhodes
Christopher
C
Poitout
Vincent
V
Prentki
Marc
M
D000214:Acyl Coenzyme A / Q000502:physiology*; D000818:Animals; D002262:Carboxy-Lyases / Q000235:genetics / Q000378:metabolism; D002999:Clone Cells; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008055:Lipids / Q000502:physiology*; D008316:Malonyl Coenzyme A / Q000378:metabolism*; D008954:Models, Biological; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
D000214:Acyl Coenzyme A; D007328:Insulin; D008055:Lipids; D011994:Recombinant Proteins; D008316:Malonyl Coenzyme A; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase; D005947:Glucose