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Encoding acyl-CoA thioesterase-7 (Acot7) is one of ∼60 genes expressed ubiquitously across tissues but relatively silenced, or disallowed, in pancreatic β-cells. The capacity of ACOT7 to hydrolyze long-chain acyl-CoA esters suggests potential roles in β-oxidation, lipid biosynthesis, signal transduction, or insulin exocytosis. We explored the physiological relevance of β-cell-specific Acot7 silencing by re-expressing ACOT7 in these cells. ACOT7 overexpression in clonal MIN6 and INS1(832/13) β-cells impaired insulin secretion in response to glucose plus fatty acids. Furthermore, in a panel of transgenic mouse lines, we demonstrate that overexpression of mitochondrial ACOT7 selectively in the adult β-cell reduces glucose tolerance dose dependently and impairs glucose-stimulated insulin secretion. By contrast, depolarization-induced secretion was unaffected, arguing against a direct action on the exocytotic machinery. Acyl-CoA levels, ATP/ADP increases, membrane depolarization, and Ca(2+) fluxes were all markedly reduced in transgenic mouse islets, whereas glucose-induced oxygen consumption was unchanged. Although glucose-induced increases in ATP/ADP ratio were similarly lowered after ACOT7 overexpression in INS1(832/13) cells, changes in mitochondrial membrane potential were unaffected, consistent with an action of Acot7 to increase cellular ATP consumption. Because Acot7 mRNA levels are increased in human islets in type 2 diabetes, inhibition of the enzyme might provide a novel therapeutic strategy.

Original publication

DOI

10.2337/db15-1240

Type

Journal article

Journal

Diabetes

Publication Date

05/2016

Volume

65

Pages

1268 - 1282

Keywords

Animals, Calcium Signaling, Cell Line, Tumor, Clone Cells, Down-Regulation, Fatty Acids, Nonesterified, Female, Gene Expression Regulation, Enzymologic, Glucose, Glucose Intolerance, Insulin, Insulin Secretion, Insulin-Secreting Cells, Islets of Langerhans, Male, Mice, Inbred C57BL, Mice, Transgenic, Organ Specificity, Palmitoyl-CoA Hydrolase, Rats, Recombinant Proteins, Sex Characteristics, Tissue Culture Techniques, Up-Regulation