title: Promyelocytic leukemia inhibits adipogenesis, and loss of promyelocytic leukemia results in fat accumulation in mice.
abstract: 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 (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, particularly subcutaneous fat mass, in the 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 and peroxisome proliferator-activated receptor-γ. We found that the Sirt1-NCor-SMRT corepressor complex, which represses pparg transcription, does not bind to the pparg promoter efficiently upon PML depletion. On the basis of 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.
authors.affiliation: Laboratory of Obesity and Aging Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. KimMK@mail.nih.gov
authors.forename: Myung K
authors.initials: MK
authors.lastname: Kim
authors.forename: Shutong
authors.initials: S
authors.lastname: Yang
authors.forename: Kyoung-Hwa
authors.initials: KH
authors.lastname: Lee
authors.forename: Jee-Hyun
authors.initials: JH
authors.lastname: Um
authors.forename: Mengyang
authors.initials: M
authors.lastname: Liu
authors.forename: Hyeog
authors.initials: H
authors.lastname: Kang
authors.forename: Sung Jun
authors.initials: SJ
authors.lastname: Park
authors.forename: Jay H
authors.initials: JH
authors.lastname: Chung
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D050156:Adipogenesis / Q000235:genetics*; D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins