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Status |
Public on May 10, 2016 |
Title |
FoxO1 Deacetylation Decreases Fatty Acid Oxidation in beta-cells and Sustains Insulin Secretion in Diabetes |
Organism |
Mus musculus |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
Pancreatic beta-cell dysfunction contributes to onset and progression of type 2 diabetes. In this state beta-cells become metabolically inflexible, losing the ability to select between carbohydrates and lipids as substrates for mitochondrial oxidation. These changes lead to beta-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 > 4,000 genes regulated in response to re-feeding. But this narrow swath includes key genes required for beta-cell identity, lipid metabolism, and mitochondrial fatty acid and solute transport. The data support the notion that deacetylated FoxO1 protects beta-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.
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Overall design |
Examined 2 different feeding state and 2 different genotypes
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Contributor(s) |
Kim YR |
Citation(s) |
26984405 |
NIH grant(s) |
Grant ID |
Grant title |
Affiliation |
Name |
R01 DK064819 |
Mechanisms of Beta Cell Failure |
Trustees of Columbia University in the City of New York |
ACCILI |
R01 DK057539 |
Role of Forkhead Proteins in Insulin Action |
Trustees of Columbia University in the City of New York |
ACCILI |
P30 DK063608 |
Diabetes and Endocrinology Research Center: ADMINISTRATIVE CORE: Admin Core: Animal Phenotyping: Genomics Core: Hormone & Metabolites: Islet and Immunology: Pilot and Feasibility: Protein Production Core |
Trustees of Columbia University in the City of New York |
ACCILI |
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Submission date |
Feb 08, 2016 |
Last update date |
May 15, 2019 |
Contact name |
Youngjung Rachel Kim |
E-mail(s) |
rachelyjk@gmail.com
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Organization name |
Columbia University
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Department |
Medicine
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Lab |
c/o Dr. Domenico Accili, MD
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Street address |
1150 St. Nicholas Ave
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City |
New York |
State/province |
NY |
ZIP/Postal code |
10032 |
Country |
USA |
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Platforms (1) |
GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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Samples (4)
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Relations |
BioProject |
PRJNA311151 |
SRA |
SRP069755 |