Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice.
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.
Yamauchi
Toshimasa
T
Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Oike
Yuichi
Y
Kamon
Junji
J
Waki
Hironori
H
Komeda
Kajuro
K
Tsuchida
Atsuko
A
Date
Yukari
Y
Li
Meng-Xian
MX
Miki
Hiroshi
H
Akanuma
Yasuo
Y
Nagai
Ryozo
R
Kimura
Satoshi
S
Saheki
Takeyori
T
Nakazato
Masamitsu
M
Naitoh
Takeshi
T
Yamamura
Kenichi
K
Kadowaki
Takashi
T
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
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