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

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 Raphaël Roduit 1 , Christopher Nolan 1 , Cristina Alarcon 2 , Patrick Moore 2 , Annie Barbeau 1 , Viviane Delghingaro-Augusto 1 , Ewa Przybykowski 1 , Johane Morin 1 , Frédéric Massé 1 , Bernard Massie 3 , Neil Ruderman 4 , Christopher Rhodes 2 5 , Vincent Poitout 2 6 and Marc Prentki 1 1 Molecular Nutrition Unit, Department of Nutrition, University of Montreal and the Centre Hospitalier de l’Université de Montréal, Montreal, Quebec, Canada 2 Pacific Northwest Research Institute, University of Washington, Seattle, Washington 3 Institut de Recherches en Biotechnologie, Montreal, Quebec, Canada 4 Diabetes Unit, Section of Endocrinology and Departments of Medicine, Physiology, and Biochemistry, Boston Medical Center, Boston, Massachusetts 5 Department of Pharmacology, University of Washington, Seattle, Washington 6 Department of Medicine, University of Washington, Seattle, Washington Address correspondence and reprint requests to Marc Prentki, CR-CHUM, Pavillon de Sève 4 e , 1560 Sherbrooke East, Montreal, QC, H2L 4M1, Canada. E-mail: marc.prentki{at}umontreal.ca Abstract 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 β-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 pro