Bone morphogenetic protein 2 is a depot-specific regulator of human adipogenesis

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 proadipogenic effect of 50 ng/ml BMP2 in abdominal cells; >90% inhibition of TAG accumulation (p < 0.001) and similar to 50% inhibition of PPARG2 expression (p < 0.001). The endogenous iron regulator erythroferrone reduced BMP2-SMAD1/5/8 signalling by similar to 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 similar to 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.