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p53 Activation in adipocytes of obese mice
Naoya Yahagi1, Hitoshi Shimano, Takashi Matsuzaka
1Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Abstract:
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.
Insights
The tumor suppressor p53 negatively regulates fat accumulation in obesity by suppressing lipogenic genes. Disrupting p53 in obese mice partially restored fat-producing enzyme expression, revealing p53's role in obesity pathophysiology.
Area of Science:
- Molecular Biology
- Metabolic Diseases
- Cellular Biology
Background:
- The tumor suppressor p53 is a transcription factor involved in cellular responses to genotoxic stress.
- Sterol regulatory element-binding protein-1 (SREBP-1) regulates triglyceride synthesis and lipogenic enzymes.
- SREBP-1 and lipogenic enzymes are suppressed in adipocytes of genetically obese ob/ob mice.
Purpose of the Study:
- To investigate the role of p53 in regulating SREBP-1 and lipogenic genes in obesity.
- To determine if p53 activation contributes to the suppression of fat accumulation in adipocytes.
Main Methods:
- Analysis of p53 and its target gene expression in adipocytes from obese ob/ob mice.
- Genetic disruption of p53 in ob/ob mice.
- Reporter gene assays to assess the effect of p53 on SREBP-1c promoter activity.
Main Results:
- p53 and its target genes were highly induced in adipocytes of fed ob/ob mice.
- p53 activation led to negative regulation of SREBP-1 and lipogenic genes.
- Disruption of p53 in ob/ob mice normalized p53-regulated genes and partially restored lipogenic enzyme expression.
- p53 overexpression suppressed SREBP-1c promoter activity.
Conclusions:
- p53 activation acts as a negative feedback mechanism against excessive fat accumulation in adipocytes.
- p53 plays a novel role in the pathophysiology of obesity by regulating lipogenesis.