title: Disallowance of Acot7 in β-Cells Is Required for Normal Glucose Tolerance and Insulin Secretion.
abstract: 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.
authors: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, U.K.
authors: Aida
authors: A
authors: Martinez-Sanchez
authors: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, U.K.
authors: Timothy J
authors: TJ
authors: Pullen
authors: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, U.K.
authors: Pauline
authors: P
authors: Chabosseau
authors: Babraham Institute, Babraham, Cambridge, U.K.
authors: Qifeng
authors: Q
authors: Zhang
authors: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, U.K.
authors: Elizabeth
authors: E
authors: Haythorne
authors: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, U.K.
authors: Matthew C
authors: MC
authors: Cane
authors: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, U.K.
authors: Marie-Sophie
authors: MS
authors: Nguyen-Tu
authors: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, U.K.
authors: Sophie R
authors: SR
authors: Sayers
authors: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, U.K. g.rutter@imperial.ac.uk.
authors: Guy A
authors: GA
authors: Rutter
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D002999:Clone Cells; D015536:Down-Regulation; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009928:Organ Specificity; D010170:Palmitoyl-CoA Hydrolase / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012727:Sex Characteristics; D046509:Tissue Culture Techniques; D015854:Up-Regulation
chemical_list: D005230:Fatty Acids, Nonesterified; D007328:Insulin; D011994:Recombinant Proteins; C521939:Acot7 protein, mouse; D010170:Palmitoyl-CoA Hydrolase; D005947:Glucose