title: FoxO1 Deacetylation Decreases Fatty Acid Oxidation in β-Cells and Sustains Insulin Secretion in Diabetes.
abstract: Pancreatic β-cell dysfunction contributes to onset and progression of type 2 diabetes. In this state β-cells become metabolically inflexible, losing the ability to select between carbohydrates and lipids as substrates for mitochondrial oxidation. These changes lead to β-cell dedifferentiation. We have proposed that FoxO proteins are activated through deacetylation-dependent nuclear translocation to forestall the progression of these abnormalities. However, how deacetylated FoxO exert their actions remains unclear. To address this question, we analyzed islet function in mice homozygous for knock-in alleles encoding deacetylated FoxO1 (6KR). Islets expressing 6KR mutant FoxO1 have enhanced insulin secretion in vivo and ex vivo and decreased fatty acid oxidation ex vivo Remarkably, the gene expression signature associated with FoxO1 deacetylation differs from wild type by only ∼2% of the >4000 genes regulated in response to re-feeding. But this narrow swath includes key genes required for β-cell identity, lipid metabolism, and mitochondrial fatty acid and solute transport. The data support the notion that deacetylated FoxO1 protects β-cell function by limiting mitochondrial lipid utilization and raise the possibility that inhibition of fatty acid oxidation in β-cells is beneficial to diabetes treatment.
authors.affiliation: From the Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, New York 10032, Merck Research Laboratories, Boston, Massachusetts 02816.
authors.forename: Ja Young
authors.initials: JY
authors.lastname: Kim-Muller
authors.affiliation: From the Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, New York 10032.
authors.forename: Young Jung R
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: From the Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, New York 10032.
authors.forename: Jason
authors.initials: J
authors.lastname: Fan
authors.affiliation: Molecular Nutrition Unit and Montreal Diabetes Research Center at the CRCHUM and Departments of Nutrition and Biochemistry and Department of Molecular Medicine, Université de Montréal, Montréal, H2X 0A9, Canada, and.
authors.forename: Shangang
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Brigham and Women's Hospital, Boston, Massachusetts 02115.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Banks
authors.affiliation: Molecular Nutrition Unit and Montreal Diabetes Research Center at the CRCHUM and Departments of Nutrition and Biochemistry and Department of Molecular Medicine, Université de Montréal, Montréal, H2X 0A9, Canada, and.
authors.forename: Marc
authors.initials: M
authors.lastname: Prentki
authors.affiliation: From the Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, New York 10032, da230@columbia.edu.
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
mesh_terms: D000107:Acetylation; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D050356:Lipid Metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D010084:Oxidation-Reduction
chemical_list: D005227:Fatty Acids; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin
keywords: FOXO; RNA sequencing; beta cell (B-cell); beta cell failure; gene knock-in; insulin secretion; lipid metabolism; mice; mitochondrial function; mitochondrial metabolism; pancreas; solute transporters