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PRDM16 controls a brown fat/skeletal muscle switch

Nature volume 454, pages 961–967 (2008)Cite this article

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.

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Figure 1: Knockdown of PRDM16 in primary brown fat cells induces skeletal myogenesis.
Figure 2: Brown fat and skeletal muscle arise from Myf5 -expressing precursors.
Figure 3: PRDM16 stimulates brown adipocyte differentiation in skeletal myoblasts.
Figure 4: PRDM16 binds and activates the transcriptional function of PPAR-γ.
Figure 5: Altered morphology and dysregulated gene expression in Prdm16 -deficient brown fat.

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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.

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Authors and 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

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Correspondence to Bruce M. Spiegelman.

Supplementary information

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. (PDF 4428 kb)

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Seale, P., Bjork, B., Yang, W. et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961–967 (2008). https://doi.org/10.1038/nature07182

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