Cell Metabolism
Volume 14, Issue 5, 2 November 2011, Pages 587-597
Journal home page for Cell Metabolism

Article
Dissociation of the Glucose and Lipid Regulatory Functions of FoxO1 by Targeted Knockin of Acetylation-Defective Alleles in Mice

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Summary

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 (Foxo1KQ/KQ) results in embryonic lethality due to cardiac and angiogenesis defects. In contrast, mice homozygous for a constitutively deacetylated Foxo1 allele (Foxo1KR/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, Foxo1KR/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.

Highlights

► FoxO1 acetylation results in its loss of function ► Homozygosity for acetylated Foxo1 alleles phenocopies Foxo1 knockout ► Homozygosity for deacetylated Foxo1 alleles impairs glucose metabolism and lowers TG ► Deacetylation regulates FoxO1 target gene selection during nutrient deprivation

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These authors contributed equally to this work