title: Novel repressor regulates insulin sensitivity through interaction with Foxo1.
abstract: Forkhead box-containing protein o (Foxo) 1 is a key transcription factor in insulin and glucose metabolism. We identified a Foxo1-CoRepressor (FCoR) protein in mouse adipose tissue that inhibits Foxo1's activity by enhancing acetylation via impairment of the interaction between Foxo1 and the deacetylase Sirt1 and via direct acetylation. FCoR is phosphorylated at Threonine 93 by catalytic subunit of protein kinase A and is translocated into nucleus, making it possible to bind to Foxo1 in both cytosol and nucleus. Knockdown of FCoR in 3T3-F442A cells enhanced expression of Foxo target and inhibited adipocyte differentiation. Overexpression of FCoR in white adipose tissue decreased expression of Foxo-target genes and adipocyte size and increased insulin sensitivity in Lepr(db/db) mice and in mice fed a high-fat diet. In contrast, Fcor knockout mice were lean, glucose intolerant, and had decreased insulin sensitivity that was accompanied by increased expression levels of Foxo-target genes and enlarged adipocytes. Taken together, these data suggest that FCoR is a novel repressor that regulates insulin sensitivity and energy metabolism in adipose tissue by acting to fine-tune Foxo1 activity.
authors.affiliation: Frontier Medicine on Metabolic Syndrome, Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. jnakae35@sc.itc.keio.ac.jp
authors.forename: Jun
authors.initials: J
authors.lastname: Nakae
authors.forename: Yongheng
authors.initials: Y
authors.lastname: Cao
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Hakuno
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takemori
authors.forename: Yoshinaga
authors.initials: Y
authors.lastname: Kawano
authors.forename: Risa
authors.initials: R
authors.lastname: Sekioka
authors.forename: Takaya
authors.initials: T
authors.lastname: Abe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyonari
authors.forename: Toshiya
authors.initials: T
authors.lastname: Tanaka
authors.forename: Juro
authors.initials: J
authors.lastname: Sakai
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Takahashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
mesh_terms: D000107:Acetylation; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D056970:Co-Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D007333:Insulin Resistance; D051379:Mice; D018345:Mice, Knockout; D056564:Sirtuin 1 / Q000378:metabolism
chemical_list: D056970:Co-Repressor Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1