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Emerging roles for the transforming growth factor-{beta} superfamily in regulating adiposity and energy expenditure
Nader Zamani1, Chester W Brown
1Baylor College of Medicine, Houston, Texas 77030, USA.
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.
Insights
Members of the Transforming Growth Factor-beta (TGF-β) superfamily regulate adipogenesis and energy expenditure. Specific members like BMP7 promote brown fat development, while others inhibit it, offering potential therapeutic targets for obesity.
Area of Science:
- Cellular and Molecular Biology
- Endocrinology
- Developmental Biology
Background:
- Transforming Growth Factor-beta (TGF-β) superfamily members are crucial regulators of cellular differentiation and development.
- Adipogenesis, the process of fat cell formation, is significantly influenced by TGF-β superfamily signaling.
- Dysregulation of adiposity and energy expenditure is linked to metabolic diseases like obesity.
Purpose of the Study:
- To elucidate the diverse roles of TGF-β superfamily signaling in adipocyte development and energy homeostasis.
- To differentiate the specific functions of various TGF-β superfamily members, such as BMPs and GDFs, in white and brown adipogenesis.
- To explore the potential of targeting TGF-β superfamily pathways for obesity treatment.
Main Methods:
- Review of existing literature on TGF-β superfamily signaling in adipogenesis and energy expenditure.
- Analysis of studies using cell culture and animal models to investigate the effects of specific ligands (e.g., BMP4, BMP7, GDF8) on adipocyte differentiation.
- Examination of the molecular mechanisms, including Smad signaling and the regulation of key adipogenic factors (C/EBP, PPAR-γ).
Main Results:
- Bone morphogenetic protein (BMP) 4 generally promotes white adipocyte differentiation.
- BMP7 selectively regulates brown adipogenesis, while TGF-β and activin A inhibit adipocyte development.
- Activins and BMP7 impact energy expenditure by modulating mitochondrial biogenesis and function.
- Growth differentiation factor (GDF) 8 and GDF3 exhibit versatile mechanisms affecting adiposity in vivo.
Conclusions:
- TGF-β superfamily signaling pathways exhibit complex and context-dependent effects on adipogenesis and energy balance.
- Specific ligands like BMP7 and GDF8 play distinct roles in regulating fat cell development and function.
- The intricate regulation of adiposity by the TGF-β superfamily presents promising therapeutic avenues for combating human obesity and related conditions.
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