p53 Activation in adipocytes of obese mice.
The tumor suppressor p53 is a transcription factor that activates or represses its target genes after various genotoxic stresses. We have previously shown that sterol regulatory element-binding protein-1 (SREBP-1), a key transcriptional regulator of triglyceride synthesis, and the lipogenic enzymes under its control are markedly suppressed in adipocytes from genetically obese ob/ob mice. Here we demonstrate that p53 and its target genes are highly induced in adipocytes of ob/ob mice in a fed state, leading to the negative regulation of SREBP-1 and thereby lipogenic genes. In fact, disruption of p53 in ob/ob mice completely suppressed the p53-regulated genes to wild-type levels and partially restored expression of lipogenic enzymes. Consistently, reporter gene analysis showed that p53 overexpression suppressed the promoter activity of the SREBP-1c gene and its downstream genes. Thus, the activation of p53 might constitute a negative feedback loop against excess fat accumulation in adipocytes. In conclusion, we discovered a novel role of p53 in the pathophysiology of obesity.
Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Naoya
N
Yahagi
Hitoshi
H
Shimano
Takashi
T
Matsuzaka
Yuho
Y
Najima
Motohiro
M
Sekiya
Yoshimi
Y
Nakagawa
Tomohiro
T
Ide
Sachiko
S
Tomita
Hiroaki
H
Okazaki
Yoshiaki
Y
Tamura
Yoko
Y
Iizuka
Ken
K
Ohashi
Takanari
T
Gotoda
Ryozo
R
Nagai
Satoshi
S
Kimura
Shun
S
Ishibashi
Jun-Ichi
J
Osuga
Nobuhiro
N
Yamada
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D005838:Genotype; D015151:Immunoblotting; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014158:Transcription, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D008156:Luciferases