Abstract
Proper regulation of white and brown adipogenic differentiation is important for maintaining an organism’s metabolic profile in a homeostatic state. The recent observations showing that the p53 tumor suppressor plays a role in metabolism raise the question of whether it is involved in the regulation of white and brown adipocyte differentiation. By using several in vitro models, representing various stages of white adipocyte differentiation, we found that p53 exerts a suppressive effect on white adipocyte differentiation in both mouse and human cells. Moreover, our in vivo analysis indicated that p53 is implicated in protection against diet-induced obesity. In striking contrast, our data shows that p53 exerts a positive regulatory effect on brown adipocyte differentiation. Abrogation of p53 function in skeletal muscle committed cells reduced their capacity to differentiate into brown adipocytes and histological analysis of brown adipose tissue revealed an impaired morphology in both embryonic and adult p53-null mice. Thus, depending on the specific adipogenic differentiation program, p53 may exert a positive or a negative effect. This cell type dependent regulation reflects an additional modality of p53 in maintaining a homeostatic state, not only in the cell, but also in the organism at large.
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Abbreviations
- AdipoQ:
-
Adiponectin
- AP-2:
-
Adipocyte-Fatty-Acid-Binding-Protein
- hASC:
-
human Adipose-derived stem cells
- ATCC:
-
American Type Culture Collection
- BAT:
-
brown adipose tissue
- CEBPa:
-
CCAAT-Enhancer-Binding-Protein-α
- ChIP:
-
chromatin immunoprecipitaion
- Cidea:
-
Cell Death-Inducing DNA Fragmentation Factor-like Effector A
- Elovl3:
-
Elongation of Very Long chain fatty acids gene 3
- GAPDH:
-
glyceraldehyde-3-phosphate dehydrogenase
- HFD:
-
high fat high sucrose diet
- HPRT:
-
hypoxanthine phosphoribosyltransferase
- KO:
-
knockout
- MEFs:
-
mouse embryonic fibroblasts
- mutp53:
-
p53R172H
- ND:
-
normal chow diet
- PGC-1α:
-
PPARγ Coactivator-1α
- PPARγ:
-
Peroxisome Proliferator-Activated-Receptor-γ
- PRDM16:
-
Positive-Regulatory-Domain-Containing-16
- shRNA:
-
short hairpin RNA
- UCP-1:
-
Uncoupling Protein-1
- WAT:
-
white adipose tissue
- wt:
-
wild type
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Acknowledgements
This research was supported by a Center of Excellence grant from Flight Attendant Medical Research Institute (FAMRI), Yad Abraham Center for Cancer Diagnosis and Therapy and by EC FP7-INFLACARE number-223151. VR is the incumbent of the Norman and Helen Asher Professorial Chair Cancer Research at the Weizmann institute. ED is the incumbent of the Henry J Leir Professorial Chair. We are grateful to Dr. Ori Brenner for pathological analysis and to Dr. Inbal Biton and Dr. Michael Tzoory for technical assistance.
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Molchadsky, A., Ezra, O., Amendola, P. et al. p53 is required for brown adipogenic differentiation and has a protective role against diet-induced obesity. Cell Death Differ 20, 774–783 (2013). https://doi.org/10.1038/cdd.2013.9
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DOI: https://doi.org/10.1038/cdd.2013.9
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