FoxO1 Deacetylation Decreases Fatty Acid Oxidation in β-Cells and Sustains Insulin Secretion in Diabetes

Ja Young Kim-Muller, Young Jung R. Kim, Jason Fan, Shangang Zhao, Alexander S. Banks, Marc Prentki, Domenico Accili

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


Pancreatic β-cell dysfunction contributes to onset and progression of type 2 diabetes. In this stateβ-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 deacetylationdependent 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 onlyβ2% 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 protectsβ-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.

Original languageEnglish (US)
Pages (from-to)10162-10172
Number of pages11
JournalJournal of Biological Chemistry
Issue number19
StatePublished - May 6 2016
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry
  • Cell Biology


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