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Identification of BCL11B as a regulator of adipogenesis.

ABSTRACT: The differentiation of preadipocytes into adipocytes is controlled by several transcription factors, including peroxisome proliferator-activated receptor ? (PPAR?) and CCAAT/enhancer-binding protein ? (C/EBP?), which are known as master regulators of adipogenesis. BCL11B is a zinc finger-type transcription factor that regulates the development of the skin and central nervous and immune systems. Here, we found that BCL11B was expressed in the white adipose tissue (WAT), particularly the subcutaneous WAT and that BCL11B(-/-) mice had a reduced amount of subcutaneous WAT. During adipogenesis, BCL11B expression transiently increased in 3T3-L1 preadipocytes and mouse embryonic fibroblasts (MEFs). The ability for adipogenesis was reduced in BCL11B knockdown 3T3-L1 cells and BCL11B(-/-) MEFs, whereas the ability for osteoblastogenesis was unaffected in BCL11B(-/-) MEFs. Luciferase reporter gene assays revealed that BCL11B stimulated C/EBP? activity. Furthermore, the expression of downstream genes of the Wnt/?-catenin signaling pathway was not suppressed in BCL11B(-/-) MEFs during adipogenesis. Thus, this study identifies BCL11B as a novel regulator of adipogenesis, which works, at least in part, by stimulating C/EBP? activity and suppressing the Wnt/?-catenin signaling pathway.

SUBMITTER: Inoue J

PROVIDER: S-EPMC5010073 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Identification of BCL11B as a regulator of adipogenesis.

Inoue Jun J Ihara Yusuke Y Tsukamoto Daisuke D Yasumoto Keisuke K Hashidume Tsutomu T Kamimura Kenya K Nakai Yuji Y Hirano Shigeki S Shimizu Makoto M Kominami Ryo R Sato Ryuichiro R

Scientific reports 20160902

The differentiation of preadipocytes into adipocytes is controlled by several transcription factors, including peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), which are known as master regulators of adipogenesis. BCL11B is a zinc finger-type transcription factor that regulates the development of the skin and central nervous and immune systems. Here, we found that BCL11B was expressed in the white adipose tissue (WAT), particularly the subcutane ...[more]

PMID: 27586877

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Project description:BACKGROUND:Bone morphogenetic proteins (BMPs) regulate adipogenesis but it is not clear whether they influence regional adipose tissue (AT) development in humans. OBJECTIVE:To characterise BMP2 expression, BMP2-SMAD1/5/8 signalling, and BMP2's potential effect on proliferation and adipogenesis in human subcutaneous abdominal and gluteal AT and its constituent preadipocytes. METHODS:BMP2 expression was measured in whole AT and immortalised preadipocytes via qPCR and Western blot; secreted/circulating BMP2 was measured by ELISA. The effect of BMP2 on preadipocyte proliferation was evaluated using a fluorescent assay. BMP2's effect on adipogenesis in immortalised preadipocytes was determined via qPCR of adipogenic markers and cellular triacylglycerol (TAG) accumulation. BMP2-SMAD1/5/8 signalling was assessed in immortalised preadipocytes via Western blot and qPCR of ID1 expression. RESULTS:BMP2 was expressed and released by abdominal and gluteal AT and preadipocytes. Exogenous BMP2 dose dependently promoted adipogenesis in abdominal preadipocytes only; 50?ng/ml BMP2 increased PPARG2 expression (10-fold compared to vehicle, p?<?0.001) and TAG accumulation (3-fold compared to vehicle; p?<?0.001). BMP2 stimulated SMAD1/5/8 phosphorylation and ID1 expression in abdominal and gluteal preadipocytes but this was blocked by 500?nM K02288, a type 1 BMP receptor inhibitor (p?<?0.001). Co-administration of 500?nM K02288 also inhibited the pro-adipogenic effect of 50?ng/ml BMP2 in abdominal cells; >90% inhibition of TAG accumulation (p?<?0.001) and ~50% inhibition of PPARG2 expression (p?<?0.001). The endogenous iron regulator erythroferrone reduced BMP2-SMAD1/5/8 signalling by ~30% specifically in subcutaneous abdominal preadipocytes (p?<?0.01), suggesting it plays a role in restricting the expansion of the body's largest AT depot during energy deficiency. Additionally, a waist-hip ratio-increasing common polymorphism near BMP2 is an eQTL associated with ~15% lower BMP2 expression in abdominal and gluteal AT (p?<?0.05) as well as altered adipocyte size in male abdominal AT (p?<?0.05). CONCLUSIONS:These data implicate BMP2-SMAD1/5/8 signalling in depot-specific preadipocyte development and abdominal AT expansion in humans.

Dataset Information

Identification of BCL11B as a regulator of adipogenesis.

Publications

Identification of BCL11B as a regulator of adipogenesis.

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