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

A Corrigendum to this article was published on 07 May 2009

Abstract

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 obesity1. Factors that specify the developmental fate and function of white and brown adipose tissue remain poorly understood2,3. 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.

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Figure 1: BMP7 induces brown, but not white, preadipocyte differentiation, and the essential role of p38 MAPK in BMP7-induced thermogenesis.
Figure 2: Molecular mechanisms by which BMP7 induces brown adipogenesis and mitochondrial biogenesis.
Figure 3: BMP7 triggers commitment of mesenchymal progenitor cells to brown adipocyte lineage in vitro and in vivo.
Figure 4: Evidence for an essential role of BMP7 in BAT development, and regulation of whole-body energy expenditure by loss-of-function and gain-of-function approaches.

References

  1. Gesta, S., Tseng, Y. H. & Kahn, C. R. Developmental origin of fat: tracking obesity to its source. Cell 131, 242–256 (2007)

    CAS  Article  Google Scholar 

  2. Farmer, S. R. Transcriptional control of adipocyte formation. Cell Metab. 4, 263–273 (2006)

    CAS  Article  Google Scholar 

  3. Rosen, E. D. & MacDougald, O. A. Adipocyte differentiation from the inside out. Nature Rev. Mol. Cell Biol. 7, 885–896 (2006)

    CAS  Article  Google Scholar 

  4. Seale, P. et al. Transcriptional control of brown fat determination by PRDM16. Cell Metab. 6, 38–54 (2007)

    CAS  Article  Google Scholar 

  5. Puigserver, P. et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829–839 (1998)

    CAS  Article  Google Scholar 

  6. Chen, D., Zhao, M. & Mundy, G. R. Bone morphogenetic proteins. Growth Factors 22, 233–241 (2004)

    CAS  Article  Google Scholar 

  7. Tseng, Y. H. & He, T. C. Bone morphogenetic proteins and adipocyte differentiation. Cellscience Rev. 3, 342–360 (2007)

    Google Scholar 

  8. Wang, E. A., Israel, D. I., Kelly, S. & Luxenberg, D. P. Bone morphogenetic protein-2 causes commitment and differentiation in C3H10T1/2 and 3T3 cells. Growth Factors 9, 57–71 (1993)

    CAS  Article  Google Scholar 

  9. Tang, Q. Q., Otto, T. C. & Lane, M. D. Commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc. Natl Acad. Sci. USA 101, 9607–9611 (2004)

    ADS  CAS  Article  Google Scholar 

  10. Klein, J. et al. β3-adrenergic stimulation differentially inhibits insulin signaling and decreases insulin induced glucose uptake in brown adipocytes. J. Biol. Chem. 274, 34795–34802 (1999)

    CAS  Article  Google Scholar 

  11. Ducy, P., Zhang, R., Geoffroy, V., Ridall, A. L. & Karsenty, G. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89, 747–754 (1997)

    CAS  Article  Google Scholar 

  12. Canalis, E., Economides, A. N. & Gazzerro, E. Bone morphogenetic proteins, their antagonists, and the skeleton. Endocr. Rev. 24, 218–235 (2003)

    CAS  Article  Google Scholar 

  13. Puigserver, P. et al. Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARγ coactivator-1. Mol. Cell 8, 971–982 (2001)

    CAS  Article  Google Scholar 

  14. Cao, W. et al. p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene. Mol. Cell. Biol. 24, 3057–3067 (2004)

    CAS  Article  Google Scholar 

  15. Uldry, M. et al. Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation. Cell Metab. 3, 333–341 (2006)

    CAS  Article  Google Scholar 

  16. Tseng, Y. H. et al. Prediction of preadipocyte differentiation by gene expression reveals role of insulin receptor substrates and necdin. Nature Cell Biol. 7, 601–611 (2005)

    CAS  Article  Google Scholar 

  17. Nedergaard, J., Connally, E. & Cannon, B. Brown Adipose Tissue (eds Trayhurn, P. & Nicholls, D. G.) 152–213 (Arnold, 1986)

    Google Scholar 

  18. Varga, A. C. & Wrana, J. L. The disparate role of BMP in stem cell biology. Oncogene 24, 5713–5721 (2005)

    CAS  Article  Google Scholar 

  19. Darlington, G. J., Ross, S. E. & MacDougald, O. A. The role of C/EBP genes in adipocyte differentiation. J. Biol. Chem. 273, 30057–30060 (1998)

    CAS  Article  Google Scholar 

  20. Wu, Z. et al. Cross-regulation of C/EBPαand PPARγ controls the transcriptional pathway of adipogenesis and insulin sensitivity. Mol. Cell 3, 151–158 (1999)

    CAS  Article  Google Scholar 

  21. Tseng, Y. H., Kriauciunas, K. M., Kokkotou, E. & Kahn, C. R. Differential roles of insulin receptor substrates in brown adipocyte differentiation. Mol. Cell. Biol. 24, 1918–1929 (2004)

    CAS  Article  Google Scholar 

  22. Dudley, A. T., Lyons, K. M. & Robertson, E. J. A requirement for bone morphogenetic protein-7 during development of the mammalian kidney and eye. Genes Dev. 9, 2795–2807 (1995)

    CAS  Article  Google Scholar 

  23. Luo, G. et al. BMP-7 is an inducer of nephrogenesis, and is also required for eye development and skeletal patterning. Genes Dev. 9, 2808–2820 (1995)

    CAS  Article  Google Scholar 

  24. Jin, W. et al. Schnurri-2 controls BMP-dependent adipogenesis via interaction with Smad proteins. Dev. Cell 10, 461–471 (2006)

    CAS  Article  Google Scholar 

  25. Cheng, H. et al. Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs). J. Bone Joint Surg. Am. 85-A, 1544–1552 (2003)

    Article  Google Scholar 

  26. Zeisberg, M. et al. BMP-7 counteracts TGF-β1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nature Med. 9, 964–968 (2003)

    CAS  Article  Google Scholar 

  27. Ozkaynak, E. et al. OP-1 cDNA encodes an osteogenic protein in the TGF-β family. EMBO J. 9, 2085–2093 (1990)

    CAS  Article  Google Scholar 

  28. Tobin, J. F. & Celeste, A. J. Bone morphogenetic proteins and growth differentiation factors as drug targets in cardiovascular and metabolic disease. Drug Discov. Today 11, 405–411 (2006)

    CAS  Article  Google Scholar 

  29. Fasshauer, M. et al. Essential role of insulin receptor substrate-2 in insulin stimulation of glut4 translocation and glucose uptake in brown adipocytes. J. Biol. Chem. 275, 25494–25501 (2000)

    CAS  Article  Google Scholar 

  30. Fasshauer, M. et al. Essential role of insulin receptor substrate 1 in differentiation of brown adipocytes. Mol. Cell. Biol. 21, 319–329 (2001)

    CAS  Article  Google Scholar 

  31. Tseng, Y. H., Ueki, K., Kriauciunas, K. M. & Kahn, C. R. Differential roles of insulin receptor substrates in the anti-apoptotic function of insulin-like growth factor-1 and insulin. J. Biol. Chem. 277, 31601–31611 (2002)

    CAS  Article  Google Scholar 

  32. Hauner, H. et al. Promoting effect of glucocorticoids on the differentiation of human adipocyte precursor cells cultured in a chemically defined medium. J. Clin. Invest. 84, 1663–1670 (1989)

    CAS  Article  Google Scholar 

  33. Godin, R. E., Takaesu, N. T., Robertson, E. J. & Dudley, A. T. Regulation of BMP7 expression during kidney development. Development 125, 3473–3482 (1998)

    CAS  PubMed  Google Scholar 

  34. Bandyopadhyay, A. et al. Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis. PLoS Genet. 2, e216 (2006)

    Article  Google Scholar 

  35. Ueki, K., Kondo, T., Tseng, Y. H. & Kahn, C. R. Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse. Proc. Natl Acad. Sci. USA 101, 10422–10427 (2004)

    ADS  CAS  Article  Google Scholar 

  36. Laustsen, P. G. et al. Lipoatrophic diabetes in Irs1-/-/Irs3-/- double knockout mice. Genes Dev. 16, 3213–3222 (2002)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We acknowledge T.-C. He for providing adenoviruses expressing BMPs. We thank M. Rourk and L. Mazzola for help with the animal experiments, J. Hu, C. Cahill, A. McSweeney, L. Polivy and R. Bronson for technical assistance, and P. Zhang for statistical consultation. We thank A. Butte and P. Laustsen for inputs on initiation of this project. We thank M. Uldry and B. Spiegelman for providing the PGC-1 null cells. This work was supported in part by the National Institutes of Health grants R01 DK077097, R21 DK070722, P30 DK46200 and P30 DK040561 (to Y.-H.T.), R01 DK67536 (to R.N.K.), K08 DK64906 (to A.W.N.) and R01 DK 060837 (to C.R.K), the Tanita Healthy Weight Community, and the Eleanor and Miles Shore 50th Anniversary Scholar Program from Harvard Medical School (to Y.-H.T.).

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Correspondence to Yu-Hua Tseng.

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Tseng, YH., Kokkotou, E., Schulz, T. et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454, 1000–1004 (2008). https://doi.org/10.1038/nature07221

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