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.

Differential roles for the coactivators CBP and p300 on TCF/β-catenin-mediated survivin gene expression

“…Our study presents strong evidence that CBP and p300 have distinct functions in the regulation of survivin transcription. The results are consistent with recent publications suggesting nonredundant roles for CBP and p300 in cell growth, differentiation and development, in spite of their high degree of homology (Kawasaki et al, 1998;Yao et al, 1998;Kung et al, 2000;Yamauchi et al, 2002;Roth et al, 2003). Rebel et al (2002), using a hematopoietic stem cell (HSC) model, concluded that CBP but not p300 is essential for HSC self-renewal, whereas p300 is critical for proper hematopoietic differentiation.…”

Specific inhibition of CBP/β-catenin interaction rescues defects in neuronal differentiation caused by a presenilin-1 mutation

“…We recently demonstrated that CBP and p300 have distinct functions in the regulation of TCF͞␤-catenin-mediated survivin transcription (53). The results are consistent with recent publications suggesting nonredundant roles for CBP and p300 in cell growth, differentiation, and development, despite their high degree of homology (54)(55)(56)(57)(58). Rebel et al (59), using a hematopoietic stem cell (HSC) model, concluded that CBP (and not p300) is essential for HSC self-renewal, whereas p300 is critical for proper hematopoietic differentiation.…”

Oncogenic steroid receptor coactivator-3 is a key regulator of the white adipogenic program

“…For instance, mice with a heterozygous deficiency in the coregulator CREB-binding protein (CBP) are lipodystrophic, and they are protected from diet-induced obesity (29). The phenotypic similarities between the SRC-3 Ϫ/Ϫ and CBP ϩ/Ϫ mice could in part be explained by the established fact that SRC-3 and CBP usually act in concert to regulate gene expression.…”