title: Dissociation of the glucose and lipid regulatory functions of FoxO1 by targeted knockin of acetylation-defective alleles in mice.
abstract: 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.
authors: Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
authors: Alexander S
authors: AS
authors: Banks
authors: Ja Young
authors: JY
authors: Kim-Muller
authors: Teresa L
authors: TL
authors: Mastracci
authors: Natalie M
authors: NM
authors: Kofler
authors: Li
authors: L
authors: Qiang
authors: Rebecca A
authors: RA
authors: Haeusler
authors: Michael J
authors: MJ
authors: Jurczak
authors: Dina
authors: D
authors: Laznik
authors: Garrett
authors: G
authors: Heinrich
authors: Varman T
authors: VT
authors: Samuel
authors: Gerald I
authors: GI
authors: Shulman
authors: Virginia E
authors: VE
authors: Papaioannou
authors: Domenico
authors: D
authors: Accili
mesh_terms: D000107:Acetylation; D000273:Adipose Tissue / Q000196:embryology / Q000378:metabolism*; D000483:Alleles; D000818:Animals; D001835:Body Weight; D016207:Cytokines / Q000378:metabolism; D059305:Diet, High-Fat; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D055879:Gene Knock-In Techniques; D005838:Genotype; D005947:Glucose / Q000378:metabolism*; D006720:Homozygote; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000196:embryology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011499:Protein Processing, Post-Translational; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D016207:Cytokines; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D011972:Receptor, Insulin; D005947:Glucose