Diabetes 2013 Aug-13

 

p53 is required for brown adipogenic differentiation and has a protective role against diet-induced obesity.

Cell Death Differ. 2013 May;20(5):774-83.

Molchadsky A, Ezra O, Amendola PG, Krantz D, Kogan-Sakin I, Buganim Y, Rivlin N, Goldfinger N, Folgiero V, Falcioni R, Sarig R, Rotter V.

Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

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.

PMID: 23412343

 

Supplementary

The adipose tissue of mammals consists of two functional types; white adipose tissue (WAT) and brown adipose tissue (BAT). WAT is the predominant type of adipose tissue in human adults. WAT primarily contributes to energy storage and the regulation of energy balance at large. BAT emerges during foetal development. Its principal function is to generate heat by fat burning. The process of thermogenesis is considered to be of most importance among newborns. During adolescence BAT depots regress and until recently the well accepted notion was that BAT does not play significant role in adult humans. However, morphological studies have recently detected metabolically active BAT in adult individuals.

Obesity is associated with an expansion of WAT depots. Disruption of normal metabolic homeostasis in obesity leads to the development of several pathological conditions such as insulin resistance, type 2 diabetes and cardiovascular diseases. Additionally, recent epidemiological data suggest that obesity is associated with increased risk for development of a variety of cancers.

Results from several studies suggested that increasing BAT mass or activity could be a useful approach to limit obesity and its associated disease states.

p53, the well known tumor suppressor is central for the induction of growth arrest and apoptosis to prevent cancer development. Notably, p53 has also been demonstrated as an important regulator of development and differentiation programs, either via its control of cell proliferation or by regulating the expression of specific genes involved in these specific programs. This multitask protein may either induce or suppress key differentiation factors depending on the specific cellular fate.

The bourgeoning epidemic of obesity is a major cause of morbidity and mortality and constitutes a huge economic burden for society. Balancing between white and brown adipogenic differentiation plays an important role in maintaining an organism’s normal metabolic homeostasis. A deeper understanding of the pathways and intermediates between the stem cells and the two types of mature adipocytes may yield therapeutic interventions to prevent obesity and its associated disorders. In this study we set out to examine the involvement of p53 in differentiation of both white and brown adipocytes. By using several mouse and human in vitro models, we demonstrate that p53 inhibits white adipogenesis, and suggest for the first time that p53 may antagonize diet induced obesity. In contrast to the suppressive effect p53 seem to exert on white adipocyte differentiation, we report that p53 is required for proper brown adipocyte differentiation program both in vitro and in vivo.

Our findings demonstrate that p53 deficiency results in altered differentiation, as well as increased WAT accumulation and may provide a link between obesity, impaired metabolism and cancer.

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Figure 1: p53 regulates adipogenic differentiation in a dichotomic fashion. Wild type p53 suppresses white adipogenic differentiation in mesenchymal precursors, committed pre-adipocytes, along with exerting a protective effect against diet-induced obesity in mice. On the contrary, wild type p53 contributes to proper brown adipocyte differentiation both in vivo and in myoblasts that were introduced with key BAT transcription factor, PRDM16. Moreover, mutant p53 attenuates the induction of brown adipogenic differentiation in these cells.

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