The function of the tumor suppressor promyelocytic leukemia (PML) protein is disrupted in promyelocytic leukemia. PML has been reported to function as a negative regulator of mTOR(the mammalian target of rapamycin) and nuclear Akt under some conditions. mTOR and Akt pathways regulate a diverse array of pathways including those that control insulin signaling, energy metabolism, growth, cellular survival and lifespan. Although the PML-mTOR/Akt link suggests that PML may have metabolic functions in the whole organism, very little is known about the metabolic functions of PML. Here we report that PML -/- mice did not show any significant metabolic defects. There was no impairment in the mTOR/Akt or AMPK signaling in white adipose tissue, liver or muscle. However, despite having normal food intake and activity levels, PML -/- mice gained body weight faster and had more fat mass, in particular, subcutaneous fat mass, in diet-induced obesity model. Using in vitro adipogenesis models, we discovered that PML is a suppressor of adipogenesis. PML expression decreased during adipogenesis and was undetectable in fully differentiated adipocytes. Loss of PML increased expression of the adipogenic transcription factors, CCAAT/enhancer binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ). We found that the Sirt1/NCor/SMRT corepressor complex, which represses pparg transcription, does not bind to the pparg promoter efficiently upon PML depletion. Based on these findings, we propose that PML is a negative regulator of the adipogenic transcription factors and that in times of energy excess, PML may limit fat accumulation by suppressing the differentiation of preadipocytes into adipocytes.
- Promyelocytic leukemia (PML) protein
- Copyright © 2011, American Journal of Physiology - Endocrinology and Metabolism