Emerging roles for the transforming growth factor-{beta} superfamily in regulating adiposity and energy expenditure

Abstract

Members of the TGF-β superfamily regulate many aspects of development, including adipogenesis. Studies in cells and animal models have characterized the effects of superfamily signaling on adipocyte development, adiposity, and energy expenditure. Although bone morphogenetic protein (BMP) 4 is generally considered a protein that promotes the differentiation of white adipocytes, BMP7 has emerged as a selective regulator of brown adipogenesis. Conversely, TGF-β and activin A inhibit adipocyte development, a process augmented in TGF-β-treated cells by Smads 6 and 7, negative regulators of canonical TGF-β signaling. Other superfamily members have mixed effects on adipogenesis depending on cell culture conditions, the timing of expression, and the cell type, and many of these effects occur by altering the expression or activities of proteins that control the adipogenic cascade, including members of the CCAAT/enhancer binding protein family and peroxisome proliferator-activated receptor-γ. BMP7, growth differentiation factor (GDF) 8, and GDF3 are versatile in their mechanisms of action, and altering their normal expression characteristics has significant effects on adiposity in vivo. In addition to their roles in adipogenesis, activins and BMP7 regulate energy expenditure by affecting the expression of genes that contribute to mitochondrial biogenesis and function. GDF8 signals through its own receptors during adipogenesis while antagonizing BMP7, an example of a ligand from one major branch of the superfamily regulating the other. With such intricate relationships that ultimately affect adiposity, TGF-β superfamily signaling holds considerable promise as a target for treating human obesity and its comorbidities.

Fig. 1.

TGF-β superfamily signaling. A, A superfamily dimer associates with type I and type II receptors, followed by receptor autophosphorylation (diagonal arrow). Subsequently, a R-Smad (Smads 1/5/8 for BMP signaling and Smads 2/3 for TGF-β/activin/GDF8 signaling) is phosphorylated and associates with Smad4 (Co-Smad, common to all Smad complexes). Receptor signaling induces an equilibrium shift of Smad complexes to the nucleus, resulting in direct effects on the expression of up to hundreds of target genes. Inhibitory Smads (I-Smads, Smads 6/7) block the association of R-Smads with Co-Smads or target ligand/receptor complexes for degradation, thereby antagonizing downstream signaling. B, Many superfamily members contribute to adipogenesis or mature adipocyte function. BMP7 is antagonized by activin A and GDF8—the latter competes with BMP7 for ActRIIB. p38 MAPK is activated by non-Smad-mediated (noncanonical) BMP7 signaling, and participates in brown adipogenesis, inducing the transcription of several genes important for mitochondrial biogenesis and function. BMP4 signaling is antagonistic to this effect by decreasing Ucp1 expression while simultaneously supporting white adipocyte differentiation. In mature adipocytes, GDF3 signaling is likely mediated by Alk7, ActRIIB, and the EGF-CFC co-receptor, Cripto, and enhances the expression of PPAR-γ. The inhibitory role of GDF8 and TGF-β during white adipogenesis is mediated by Smad3 and is complemented by the actions of Smads 6 and 7. The dashed lines represent signaling events in which not all intermediates are shown.

Fig. 2.

Established contributions of TGF-β superfamily members to adipogenesis. MSCs have the capacity to differentiate into different cell types, including adipocytes and myocytes. Under normal conditions, WAT contains mostly white adipocytes and a relatively small number of brown adipocytes. The brown adipocytes in WAT (left) may differentiate from a Myf5⁻ precursor, although the presence of this cell type within WAT (with the capacity to differentiate into either white or brown adipocytes) has not been definitively established. In addition, mature white adipocytes may have the ability to reversibly transdifferentiate into cells that have many of the characteristics of brown adipocytes. Although BMP3 has been shown to stimulate the proliferation of MSCs and preadipocytes, TGF-β and activin A enhance the proliferation of adipocyte precursors while also inhibiting their subsequent differentiation. BMP2 and BMP4 primarily support white adipocyte differentiation, whereas BMP7 has emerged as a factor that promotes brown adipogenesis, although the precise mechanisms in some contexts have not been resolved. The MSCs can alternatively give rise to a Myf5⁺ progenitor that has the ability to differentiate into either myocytes or brown adipocytes (right). Brown adipocytes arising from Myf5⁺ progenitors are predominantly located in brown adipose depots. Increased or decreased signaling by superfamily ligands (see “signaling” at the bottom of the figure), in vivo, can have stimulatory or inhibitory effects (“effect”) on adipose and muscle mass (“tissue”). Proteins with positive effects on adipocyte differentiation or function are associated with pointed arrows, whereas those with negative/inhibitory effects are indicated by blunt arrows. Question marks denote processes or cell types for which there is supporting evidence, but that have not been unequivocally established. ESC, Embryonic stem cell.