New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure

By Y. Tseng, E. Kokkotou, Tim J. Schulz, Tian Lian Huang, Jonathon N. Winnay, Cullen M. Taniguchi, Thien T. Tran, R. Suzuki, Daniel O. Espinoza, Yuji Yamamoto and 6 more. Nature, 2008

1,069 citations recorded by the source corpus.

Adipose tissue is central to the regulation of energy balance. Two functionally different types of fat are present in mammals: white adipose tissue, the primary site of triglyceride storage, and brown adipose tissue, which is specialized in energy expenditure and can counteract obesity. Factors that specify the developmental fate and function of white and brown adipose tissue remain poorly understood. Here we demonstrate that whereas some members of the family of bone morphogenetic proteins (BMPs) support white adipocyte differentiation, BMP7 singularly promotes differentiation of brown preadipocytes even in the absence of the normally required hormonal induction cocktail. BMP7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate PRDM16 (PR-domain-containing 16; ref. 4) and PGC-1α (peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1α; ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (UCP1) and adipogenic transcription factors PPARγ and CCAAT/enhancer-binding proteins (C/EBPs), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (MAP) kinase-(also known as Mapk14) and PGC-1-dependent pathways. Moreover, BMP7 triggers commitment of mesenchymal progenitor cells to a brown adipocyte lineage, and implantation of these cells into nude mice results in development of adipose tissue containing mostly brown adipocytes. Bmp7 knockout embryos show a marked paucity of brown fat and an almost complete absence of UCP1. Adenoviral-mediated expression of BMP7 in mice results in a significant increase in brown, but not white, fat mass and leads to an increase in energy expenditure and a reduction in weight gain. These data reveal an important role of BMP7 in promoting brown adipocyte differentiation and thermogenesis in vivo and in vitro, and provide a potential new therapeutic approach for the treatment of obesity.

Subfields: Biochemistry, Cancer Research, Physiology

View Paper: https://www.semanticscholar.org/paper/2ded6231cc6ea9be9abc1c2dd1e1ca0bf918f292

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In Biochemistry

1. B. Spiegelman
2. P. Seale
3. Gerald I. Shulman
4. Jun Wu
5. Toren Finkel
6. S. Kajimura
7. N. Tonks

In Cancer Research

1. B. Spiegelman
2. Gerald I. Shulman
3. Xiaolu Yang
4. E. Rosen

In Physiology

1. S. Kajimura
2. B. Spiegelman
3. P. Seale
4. Jun Wu
5. P. Cohen
6. Toren Finkel
7. Gerald I. Shulman
8. Steven P. Gygi

Citations in the corpus

• Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis. (2015, neutral): “As listed in Figure 3, such factors include BMP4 (66), BMP7 (67, 68), BMP8b (69), FGF19 (70, 71), FGF21 (72, 73), growth differentiation fac-tor-5 (GDF5) (74), natriuretic peptides (75), prostaglandins (76, 77), VEGF (78, 79), and β -aminoisobutyric acid (BAIBA) (80).”
• Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling (2011, background): “Further, the TGF-b superfamily member, BMP7, is also implicated in brown adipogenesis (Tseng et al., 2008).”
• Brown and beige fat: Physiological roles beyond heat-generation (2015, background): “Loss of BMP7 or BMP-receptor signaling results in a near-complete absence of BAT development (Schulz et al., 2013; Tseng et al., 2008).”
• Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. (2013, neutral): “Discussion The advances in brown adipose cell biology during the last decade have increased our understanding of the cellular origin (27–29), function (8, 13, 29), and adult human tissue distribution (2, 3, 7, 9) of BAT.”
• Adaptive thermogenesis in adipocytes: is beige the new brown? (2013, background): “Mesenchymal progenitor cells are committed to a brown cell fate upon BMP7 treatment, and adenoviral overexpression of BMP7 in mice increases energy expenditure and protects against dietinduced weight gain (Tseng et al. 2008).”
• Adipose Tissue Remodeling: Its Role in Energy Metabolism and Metabolic Disorders (2016, background): “Bone morphogenetic proteins (BMPs) 4 and 7 are also associated with the browning of adipocytes (60, 61).”
• p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase (2011, methodology): “To assess the effect of p53 on lipid accumulation, we treated p 5+/+ and p 5−/− MEF cells with a combination of insulin, rosiglitazone, dexamethasone and isobutylmethylxanthine, which stimulates lipogenesi”
• Bone Morphogenetic Protein (BMP) signaling in development and human diseases (2014, critical): “Mice studies have generally led to the belief that BMP4 induces stem cells to differentiate along the white adipocyte lineage, whereas BMP7 induces brown adipocyte differentiation.(60) However, recent studies have indicated that BMP4 induces white-to-brown transition.”
• Ablation of PRDM16 and Beige Adipose Causes Metabolic Dysfunction and a Subcutaneous to Visceral Fat Switch (2014, background): “Mice with defective BAT develop obesity and insulin resistance (Feldmann et al., 2009; Hamann et al., 1996; Tseng et al., 2008).”
• A PGC1α-dependent myokine that drives browning of white fat and thermogenesis (2012, background): “In contrast, BMP7, reported as a potent inducer of brownin”