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Dissociation of the glucose and lipid regulatory functions of FoxO1 by targeted knockin of acetylation-defective alleles in mice.

FoxO1 integrates multiple metabolic pathways. Nutrient levels modulate FoxO1 acetylation, but the functional consequences of this posttranslational modification are unclear. To answer this question, we generated mice bearing alleles that encode constitutively acetylated and acetylation-defective FoxO1 proteins. Homozygosity for an allele mimicking constitutive acetylation (Foxo1(KQ/KQ)) results in embryonic lethality due to cardiac and angiogenesis defects. In contrast, mice homozygous for a constitutively deacetylated Foxo1 allele (Foxo1(KR/KR)) display a unique metabolic phenotype of impaired insulin action on hepatic glucose metabolism but decreased plasma lipid levels and low respiratory quotient that are consistent with a state of preferential lipid usage. Moreover, Foxo1(KR/KR) mice show a dissociation between weight gain and insulin resistance in predisposing conditions (high fat diet, diabetes, and insulin receptor mutations), possibly due to decreased cytokine production in adipose tissue. Thus, acetylation inactivates FoxO1 during nutrient excess whereas deacetylation selectively potentiates FoxO1 activity, protecting against excessive catabolism during nutrient deprivation.

Pubmed ID: 22055502

Authors

  • Banks AS
  • Kim-Muller JY
  • Mastracci TL
  • Kofler NM
  • Qiang L
  • Haeusler RA
  • Jurczak MJ
  • Laznik D
  • Heinrich G
  • Samuel VT
  • Shulman GI
  • Papaioannou VE
  • Accili D

Journal

Cell metabolism

Publication Data

November 2, 2011

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK057539
  • Agency: NIDDK NIH HHS, Id: DK059635
  • Agency: NIDDK NIH HHS, Id: DK079496
  • Agency: NIDDK NIH HHS, Id: DK63608
  • Agency: NHLBI NIH HHS, Id: HL087123
  • Agency: NHLBI NIH HHS, Id: P01 HL087123
  • Agency: NHLBI NIH HHS, Id: P01 HL087123-05
  • Agency: NIDDK NIH HHS, Id: R01 DK040936
  • Agency: NIDDK NIH HHS, Id: R01 DK057539
  • Agency: NIDDK NIH HHS, Id: R01 DK057539-11
  • Agency: NIDDK NIH HHS, Id: R01 DK064819
  • Agency: NIDDK NIH HHS, Id: R01 DK064819-09
  • Agency: NIDDK NIH HHS, Id: R37 DK058282
  • Agency: NIDDK NIH HHS, Id: R37 DK058282-11
  • Agency: NIDDK NIH HHS, Id: U24 DK059635

Mesh Terms

  • Acetylation
  • Adipose Tissue
  • Alleles
  • Animals
  • Body Weight
  • Cytokines
  • Diet, High-Fat
  • Forkhead Transcription Factors
  • Gene Expression
  • Gene Knock-In Techniques
  • Genotype
  • Glucose
  • Homozygote
  • Insulin
  • Insulin Resistance
  • Lipid Metabolism
  • Liver
  • Mice
  • Mice, Transgenic
  • Phenotype
  • Protein Processing, Post-Translational
  • Receptor, Insulin
  • Signal Transduction