Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
NIHR Oxford Biomedical Research Centre, Oxford University Hospital NHS Trust, Oxford, UK.
Int J Obes (Lond). 2019 Dec;43(12):2458-2468. doi: 10.1038/s41366-019-0421-1. Epub 2019 Jul 19.
Bone morphogenetic proteins (BMPs) regulate adipogenesis but it is not clear whether they influence regional adipose tissue (AT) development in humans.
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.
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.
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).
These data implicate BMP2-SMAD1/5/8 signalling in depot-specific preadipocyte development and abdominal AT expansion in humans.
骨形态发生蛋白（BMPs）调节脂肪生成，但尚不清楚它们是否会影响人体局部脂肪组织（AT）的发育。
描述 BMP2 的表达、BMP2-SMAD1/5/8 信号转导以及 BMP2 对人皮下腹部和臀部 AT 及其前体脂肪细胞增殖和脂肪生成的潜在影响。
通过 qPCR 和 Western blot 测量整个 AT 和永生化前体脂肪细胞中的 BMP2 表达；通过 ELISA 测量分泌/循环的 BMP2。通过荧光测定法评估 BMP2 对前体脂肪细胞增殖的影响。通过 qPCR 测定脂肪生成标志物和细胞三酰基甘油（TAG）积累，确定 BMP2 对永生化前体脂肪细胞脂肪生成的影响。通过 Western blot 和 ID1 表达的 qPCR 评估永生化前体脂肪细胞中的 BMP2-SMAD1/5/8 信号转导。
BMP2 在腹部和臀部 AT 和前体脂肪细胞中表达和释放。外源性 BMP2 剂量依赖性地仅促进腹部前体脂肪细胞的脂肪生成；50ng/ml BMP2 增加了 PPARG2 表达（与载体相比增加了 10 倍，p<0.001）和 TAG 积累（与载体相比增加了 3 倍；p<0.001）。BMP2 刺激腹部和臀部前体脂肪细胞的 SMAD1/5/8 磷酸化和 ID1 表达，但这被 1μM K02288 型 1 BMP 受体抑制剂阻断（p<0.001）。500nM K02288 的共同给药也抑制了 50ng/ml BMP2 在腹部细胞中的促脂肪生成作用；TAG 积累的抑制率超过 90%（p<0.001），PPARG2 表达的抑制率约为 50%（p<0.001）。内源性铁调节因子红细胞生成素减少了皮下腹部前体脂肪细胞中约 30%的 BMP2-SMAD1/5/8 信号转导（p<0.01），这表明它在能量缺乏期间限制了人体最大的 AT 库的扩张中发挥作用。此外，BMP2 附近与腰围-臀围比增加的常见多态性是一个 eQTL，与腹部和臀部 AT 中约 15%的 BMP2 表达降低（p<0.05）以及男性腹部 AT 中脂肪细胞大小改变相关（p<0.05）。
这些数据表明，BMP2-SMAD1/5/8 信号转导参与了人类特定部位前体脂肪细胞发育和腹部 AT 的扩张。
