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

Nature volume 454, pages 1000–1004 (2008)Cite this article

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.

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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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Authors and Affiliations

  1. Section on Obesity and Hormone Action, and,,

    Yu-Hua Tseng, Tim J. Schulz, Tian Lian Huang, Jonathon N. Winnay, Cullen M. Taniguchi, Thien T. Tran, Ryo Suzuki, Daniel O. Espinoza, Yuji Yamamoto & C. Ronald Kahn

  2. Section on Cell and Molecular Physiology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, 02215, USA ,

    Rohit N. Kulkarni

  3. Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, 02215, USA,

    Efi Kokkotou

  4. Department of Biochemistry, Northwestern University, Evanston, Illinois 60208, USA,

    Molly J. Ahrens & Andrew T. Dudley

  5. Division of Pediatric Endocrinology, University of Iowa Children’s Hospital, Iowa City, Iowa 52242, USA,

    Andrew W. Norris

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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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