Tob2 inhibits peroxisome proliferator-activated receptor γ2 expression by sequestering Smads and C/EBPα during adipocyte differentiation.
Adipogenesis is an important component of adipose tissue development and is critically related to obesity. A cascade of transcription factors is involved in adipogenesis, in which peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding proteins (C/EBPs) play pivotal roles. Bone morphogenetic proteins (BMPs) and Smad proteins are implicated in this cascade, although the precise regulatory mechanisms have yet to be elucidated. Here, we show that Tob2, a member of the Tob/BTG antiproliferative protein family, inhibits adipogenesis by interfering with Smad signaling. tob2 expression is downregulated in the white adipose tissue of high-fat diet-induced or genetically mutated obese mice. Consistent with this, tob2(-/-) mice exhibit increased adiposity with augmented expression of the genes encoding the type 1A BMP receptor (BMPR1A) and PPARγ2 as well as their target genes. We further show accelerated adipogenesis in primary tob2(-/-) preadipocytes. Furthermore, exogenously expressed Tob2 inhibits adipogenic differentiation of 3T3-L1 preadipocytes: the Tob2 protein suppresses PPARγ2 transcription by inhibiting BMP2-induced Smad1/5 phosphorylation through its interaction with Smad6 and by sequestering C/EBPα from the PPARγ2 promoter. Thus, Tob2 negatively regulates adipogenesis by inhibiting PPARγ2 expression.
Division of Oncology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Akinori
A
Takahashi
Masahiro
M
Morita
Kazumasa
K
Yokoyama
Toru
T
Suzuki
Tadashi
T
Yamamoto
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D050156:Adipogenesis / Q000235:genetics* / Q000502:physiology*; D050154:Adiposity / Q000235:genetics / Q000502:physiology; D000818:Animals; D001483:Base Sequence; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D059305:Diet, High-Fat; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D008954:Models, Biological; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D051905:Smad6 Protein / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; D018797:Cell Cycle Proteins; D047495:PPAR gamma; D034741:RNA, Small Interfering; D051785:Smad Proteins; D051905:Smad6 Protein; C497803:Smad6 protein, mouse; C485732:Tob2 protein, mouse