Beyond the bone: Bone morphogenetic protein signaling in adipose tissue

Abstract

The bone morphogenetic proteins (BMPs) belong to the same superfamily as related to transforming growth factor β (TGFβ), growth and differentiation factors (GDFs), and activins. They were initially described as inducers of bone formation but are now known to be involved in morphogenetic activities and cell differentiation throughout the body, including the development of adipose tissue and adipogenic differentiation. BMP4 and BMP7 are the most studied BMPs in adipose tissue, with major roles in white adipogenesis and brown adipogenesis, respectively, but other BMPs such as BMP2, BMP6, and BMP8b as well as some inhibitors and modulators have been shown to also affect adipogenesis. It has become ever more important to understand adipose regulation, including the BMP pathways, in light of the strong links between obesity and metabolic and cardiovascular disease. In this review, we summarize the available information on BMP signaling in adipose tissue using preferentially articles that have appeared in the last decade, which together demonstrate the importance of BMP signaling in adipose biology.

Keywords: adipogenesis; bone morphogenetic protein (BMP); obesity.

Figure 1:. Schematic overview of the BMP signaling system and associated transcription factors relevant for adipogenesis.

Top, BMP dimers bind to a complex consisting of BMPRI and BMPRII, or are sequestered by BMP inhibitors. In canonical BMP signaling, the type II receptor phosphorylates (activates) the type I receptor, which in turn activates regulatory SMAD1/5/8. The R-SMADs combine with SMAD4, a co-SMAD, and enters the nucleus to regulate gene expression together with the appropriate co-activators and repressors. The R-SMADs can also be inhibited by the I-SMADs. In non-canonical BMP signaling, MAPK, ERK, JNK, and p38 are activated. Bottom, transcription factors known to affect adipocyte differentiation. BMP, bone morphogenetic protein; BMPRI, BMP type I receptor; BMPRII, BMP type II receptor; R-SMAD, regulatory SMAD; I-SMAD, inhibitory SMAD; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; JNK, Jun N-terminal kinase; p38, p38 mitogen-activated protein kinase; Ebf2, early B-cell factor 2; Zfp423, zinc finger protein 423; Pparγ, peroxisome proliferator-activated receptor γ; Prdm16, PR domain containing 16.

Figure 2:. Schematic summary of BMP action on white and brown adipocytes based on current knowledge.

The + and - signs indicate largely stimulating and inhibitory action, respectively. ActRIIB, activin type IIB receptor; ALK, activin receptor-like kinase; BAMBI, BMP and activin membrane-bound inhibitor; BMP, bone morphogenetic protein; BMPRII, BMP type II receptor; MGP, matrix Gla protein.