title: Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice.
abstract: The CBP protein (cAMP response element binding protein (CREB) binding protein) is a co-activator for several transcription factors with a wide range of important biological functions, such as sterol regulatory element binding proteins (SREBPs), CCAAT/enhancer-binding proteins (C/EBPs), nuclear receptors (including peroxisome proliferator-activated receptors, PPARs), and signal transducers and activators of transcription (STATs). In contrast to these individual transcription factors, the biological roles of CBP are poorly understood. CBP enhances transcriptional activities via histone acetylation and the recruitment of additional co-activators such as SRC (steroid coactivator)-1 (ref. 9). To identify its physiological functions using a loss-of-function mutant, we analyzed CBP-deficient mice. As Crebbp null mice (Crebbp-/-) died during embryogenesis, we used Crebbp+/- mice. Unexpectedly, Crebbp+/- mice showed markedly reduced weight of white adipose tissue (WAT) but not of other tissues. Despite this lipodystrophy, Crebbp+/- mice showed increased insulin sensitivity and glucose tolerance and were completely protected from body weight gain induced by a high-fat (HF) diet. We observed increased leptin sensitivity and increased serum adiponectin levels in Crebbp+/- mice. These increased effects of insulin-sensitizing hormones secreted from WAT may explain, at least in part, the phenotypes of Crebbp+/- mice. This study demonstrates that CBP may function as a 'master-switch' between energy storage and expenditure.
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Yamauchi
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oike
authors.forename: Junji
authors.initials: J
authors.lastname: Kamon
authors.forename: Hironori
authors.initials: H
authors.lastname: Waki
authors.forename: Kajuro
authors.initials: K
authors.lastname: Komeda
authors.forename: Atsuko
authors.initials: A
authors.lastname: Tsuchida
authors.forename: Yukari
authors.initials: Y
authors.lastname: Date
authors.forename: Meng-Xian
authors.initials: MX
authors.lastname: Li
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miki
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Akanuma
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kimura
authors.forename: Takeyori
authors.initials: T
authors.lastname: Saheki
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Nakazato
authors.forename: Takeshi
authors.initials: T
authors.lastname: Naitoh
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yamamura
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D000273:Adipose Tissue / Q000473:pathology; D002001:Adipose Tissue, Brown / Q000473:pathology; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D050882:CREB-Binding Protein; D048429:Cell Size; D004268:DNA-Binding Proteins / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D004734:Energy Metabolism; D006579:Heterozygote; D007333:Insulin Resistance / Q000235:genetics* / Q000502:physiology; D008060:Lipodystrophy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D004041:Dietary Fats; D009687:Nuclear Proteins; D012333:RNA, Messenger; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D015534:Trans-Activators; D014157:Transcription Factors; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse