Abstract

Brown fat can increase energy expenditure and protect against obesity through a specialized program of uncoupled respiration. Here we show by in vivo fate mapping that brown, but not white, fat cells arise from precursors that express Myf5, a gene previously thought to be expressed only in the myogenic lineage. We also demonstrate that the transcriptional regulator PRDM16 (PRD1-BF1-RIZ1 homologous domain containing 16) controls a bidirectional cell fate switch between skeletal myoblasts and brown fat cells. Loss of PRDM16 from brown fat precursors causes a loss of brown fat characteristics and promotes muscle differentiation. Conversely, ectopic expression of PRDM16 in myoblasts induces their differentiation into brown fat cells. PRDM16 stimulates brown adipogenesis by binding to PPAR-γ (peroxisome-proliferator-activated receptor-γ) and activating its transcriptional function. Finally, Prdm16-deficient brown fat displays an abnormal morphology, reduced thermogenic gene expression and elevated expression of muscle-specific genes. Taken together, these data indicate that PRDM16 specifies the brown fat lineage from a progenitor that expresses myoblast markers and is not involved in white adipogenesis.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004)

  2. 2.

    et al. Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization. J. Cell Sci. 103, 931–942 (1992)

  3. 3.

    & Analysis of uncoupling protein and its mRNA in adipose tissue deposits of adult humans. Int. J. Obes. Relat. Metab. Disord. 16, 383–390 (1992)

  4. 4.

    , , , & Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity. J. Clin. Invest. 102, 412–420 (1998)

  5. 5.

    , & Developmental origin of fat: tracking obesity to its source. Cell 131, 242–256 (2007)

  6. 6.

    & Regulatory circuits controlling white versus brown adipocyte differentiation. Biochem. J. 398, 153–168 (2006)

  7. 7.

    & Molecular regulation of adipogenesis. Annu. Rev. Cell Dev. Biol. 16, 145–171 (2000)

  8. 8.

    , & Unexpected evidence for active brown adipose tissue in adult humans. Am. J. Physiol. Endocrinol. Metab. 293, E444–E452 (2007)

  9. 9.

    et al. FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. Cell 106, 563–573 (2001)

  10. 10.

    , & Hypertrophy of brown adipocytes in brown and white adipose tissues and reversal of diet-induced obesity in rats treated with a beta3-adrenoceptor agonist. Biochem. Pharmacol. 54, 121–131 (1997)

  11. 11.

    , , , & Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter prevents genetic obesity. J. Clin. Invest. 96, 2914–2923 (1995)

  12. 12.

    et al. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 366, 740–742 (1993)

  13. 13.

    et al. RIP140-targeted repression of gene expression in adipocytes. Mol. Cell. Biol. 25, 9383–9391 (2005)

  14. 14.

    et al. Retinoblastoma protein functions as a molecular switch determining white versus brown adipocyte differentiation. Proc. Natl Acad. Sci. USA 101, 4112–4117 (2004)

  15. 15.

    et al. Rb and p107 regulate preadipocyte differentiation into white versus brown fat through repression of PGC-1alpha. Cell Metab. 2, 283–295 (2005)

  16. 16.

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

  17. 17.

    et al. Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex. Genes Dev. 22, 1397–1409 (2008)

  18. 18.

    , , & Early myotome specification regulates PDGFA expression and axial skeleton development. Development 127, 5059–5070 (2000)

  19. 19.

    et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1, 4 (2001)

  20. 20.

    , , , & Rb is required for progression through myogenic differentiation but not maintenance of terminal differentiation. J. Cell Biol. 166, 865–876 (2004)

  21. 21.

    , , & Asymmetric self-renewal and commitment of satellite stem cells in muscle. Cell 129, 999–1010 (2007)

  22. 22.

    et al. Pitx2 promotes development of splanchnic mesoderm-derived branchiomeric muscle. Development 133, 4891–4899 (2006)

  23. 23.

    et al. Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes. Am. J. Physiol. Cell Physiol. 279, C670–C681 (2000)

  24. 24.

    et al. PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol. Cell 4, 585–595 (1999)

  25. 25.

    et al. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol. Cell 4, 611–617 (1999)

  26. 26.

    , & Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid- activated transcription factor. Cell 79, 1147–1156 (1994)

  27. 27.

    , & Transdifferentiation of myoblasts by the adipogenic transcription factors PPAR gamma and C/EBP alpha. Proc. Natl Acad. Sci. USA 92, 9856–9860 (1995)

  28. 28.

    et al. Peroxisome proliferator-activated receptor alpha activates transcription of the brown fat uncoupling protein-1 gene. A link between regulation of the thermogenic and lipid oxidation pathways in the brown fat cell. J. Biol. Chem. 276, 1486–1493 (2001)

  29. 29.

    , , , & Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta), a novel PGC-1-related transcription coactivator associated with host cell factor. J. Biol. Chem. 277, 1645–1648 (2002)

  30. 30.

    , & The occurrence of brown adipose tissue in outdoor workers. Eur. J. Appl. Physiol. Occup. Physiol. 46, 339–345 (1981)

  31. 31.

    et al. Genetic variability affects the development of brown adipocytes in white fat but not in interscapular brown fat. J. Lipid Res. 48, 41–51 (2007)

  32. 32.

    , , , & Ectopic brown adipose tissue in muscle provides a mechanism for differences in risk of metabolic syndrome in mice. Proc. Natl Acad. Sci. USA 104, 2366–2371 (2007)

  33. 33.

    , & Muscle satellite cells are multipotential stem cells that exhibit myogenic, osteogenic, and adipogenic differentiation. Differentiation 68, 245–253 (2001)

  34. 34.

    , & Skeletal muscle satellite cells can spontaneously enter an alternative mesenchymal pathway. J. Cell Sci. 117, 5393–5404 (2004)

  35. 35.

    et al. Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages. Proc. Natl Acad. Sci. USA 104, 4401–4406 (2007)

  36. 36.

    et al. Beta-catenin activation is necessary and sufficient to specify the dorsal dermal fate in the mouse. Dev. Biol. 296, 164–176 (2006)

  37. 37.

    et al. Genetic analysis of adipogenesis through peroxisome proliferator-activated receptor gamma isoforms. J. Biol. Chem. 277, 41925–41930 (2002)

  38. 38.

    , , , & MyoD is required for myogenic stem cell function in adult skeletal muscle. Genes Dev. 10, 1173–1183 (1996)

  39. 39.

    , , & Differential roles of insulin receptor substrates in brown adipocyte differentiation. Mol. Cell. Biol. 24, 1918–1929 (2004)

  40. 40.

    et al. Examination of micro-tip reversed-phase liquid chromatographic extraction of peptide pools for mass spectrometric analysis. J. Chromatogr. A 826, 167–181 (1998)

  41. 41.

    et al. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 83, 803–812 (1995)

  42. 42.

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

  43. 43.

    & Episomal vectors rapidly and stably produce high-titer recombinant retrovirus. Hum. Gene Ther. 7, 1405–1413 (1996)

  44. 44.

    et al. Hic-5 regulates an epithelial program mediated by PPARgamma. Genes Dev. 19, 362–375 (2005)

Download references

Acknowledgements

We thank V. Seale and F. LeGrand for help with the lineage tracing studies and R. Gupta for discussions. We are grateful to P. Soriano for the Myf5-Cre mice and F. Constantini for the R26R3-YFP reporter mice. P.S. is supported by a fellowship from the American Heart Association. S. Kajimura is supported by a fellowship from the Japan Society for the Promotion of Science. S.D. is supported by the Susan Komen Breast Cancer Foundation. This work is funded by the Picower Foundation and a National Institutes of Health grant to B.M.S. and an National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases grant to M.A.R.

Author Contributions P.S. and B.M.S. conceived and designed the experiments. P.S., W.Y., S. Kajimura, S.C. and H.M.C. performed the experiments. P.S. analysed the data. B.B., S. Kuang, A.S., S.D., H.E., P.T., M.A.R. and D.R.B. contributed reagents/materials/analysis tools. P.S. and B.M.S. wrote the paper.

Author information

Affiliations

  1. Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, 1 Jimmy Fund Way, Boston, Massachusetts 02115, USA

    • Patrick Seale
    • , Wenli Yang
    • , Shingo Kajimura
    • , Sherry Chin
    • , Srikripa Devarakonda
    • , Heather M. Conroe
    •  & Bruce M. Spiegelman
  2. Genetics Division, Brigham and Women’s Hospital, Harvard Medical School, New Research Building, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA

    • Bryan Bjork
    •  & David R. Beier
  3. The Sprott Center for Stem Cell Research, Ottawa Health Research Institute, Molecular Medicine Program, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada

    • Shihuan Kuang
    • , Anthony Scimè
    •  & Michael A. Rudnicki
  4. Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA

    • Hediye Erdjument-Bromage
    •  & Paul Tempst

Authors

  1. Search for Patrick Seale in:

  2. Search for Bryan Bjork in:

  3. Search for Wenli Yang in:

  4. Search for Shingo Kajimura in:

  5. Search for Sherry Chin in:

  6. Search for Shihuan Kuang in:

  7. Search for Anthony Scimè in:

  8. Search for Srikripa Devarakonda in:

  9. Search for Heather M. Conroe in:

  10. Search for Hediye Erdjument-Bromage in:

  11. Search for Paul Tempst in:

  12. Search for Michael A. Rudnicki in:

  13. Search for David R. Beier in:

  14. Search for Bruce M. Spiegelman in:

Corresponding author

Correspondence to Bruce M. Spiegelman.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Figures S1-S8 with Legends and Supplementary Tables S1-S2. The Supplementary Figure provide data that examines the origin of various BAT depots and defines the role of PRDM16 in specifying BAT cell fate. Table S1 is a list of proteins identified in the PRDM16 protein complex. Table S2 provides primer sequences.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature07182

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.