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

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.

PPARγ ligand production is tightly linked to clonal expansion during initiation of adipocyte differentiation

“…IE-G). Therefore, our data and those of others ( 23,24 ) point to an inhibitory role for p53 in adipose conversion.…”

Metabolic epistasis among apoptosis-inducing factor and the mitochondrial import factor CHCHD4

“…30 Finally, it is possible that Chchd4 deficiency affects non-mitochondrial signaling pathways by virtue of its capacity to regulate the subcellular localization of p53, 31 a master transcription factor that controls the differentiation of both white and brown fat cells. 32,33 Future work must distinguish between these possibilities.…”

TAp63gamma is required for the late stages of myogenesis

“…37,41,42 p63 and p73 proteins share more than 60% of amino acids identity within the DNA-binding domain and possibly regulate overlapping set of target genes. 37,[43][44][45][46][47][48][49][50][51] In muscle differentiation, the functions of the individual members are distinct but complementary: while p53 transactivates RB gene, p63 and p73 induce the transcription of p57, which maintains Rb in an active, hypo-phosphorylated state, 18 also allowing execution of the later steps in skeletal myogenesis. 16 So far, the engagement of p53 family members in myogenesis has been demonstrated only in the early stage of in vitro muscle differentiation linked to permanent cell cycle exit.…”