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PRDM16 controls a brown fat/skeletal muscle switch
Open accessAbstract
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-gamma (peroxisome-proliferator-activated receptor-gamma) 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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“Emerging evidence suggests that brown adipocytes located in different anatomical locations may arise from different developmental origins.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [92]
In the citing paper
“Most recently, lineage-tracing studies have indicated that myf5-expressing progenitors can give rise to both skeletal muscle and the preformed BAT, in the interscapular and peri-renal depots 92 (Figure 3).”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [92]
In the citing paper
“However, not all brown fat cells are derived from myf5-expressing progenitors. For example, the brown fat cells emerging in white fat in response to β3-adrenergic stimulation are not marked by the myf5-driven fluorescent protein 92.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [92]
In the citing paper
“Current data suggest that in rodents, PRDM16 plays an important role in specifying brown fat cell fate for the interscapular, but not systemic brown adipose depots 92.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [92]
In the citing paper
“The genetic program leading to brown adipose tissue development, and potentially to the high abundance of mitochondria, is initiated by the zinc-finger protein PRDM16 (202)(203)(204).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [203]
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Citations
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Pathophysiology of obesity and its associated diseases
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Wang, G.-X., Zhao, X.-Y., Meng, Z., Kern, M., Dietrich, A., Chen, Z., Cozacov, Z., Zhou, D., Okunade, A. L., Su, X., et al. (2014) · Nature Medicine · doi:10.1038/nm.3713 · Cited by 515
Immune Regulation of Metabolic Homeostasis in Health and Disease
Brestoff, J. R., & Artis, D. (2015) · Cell · doi:10.1016/j.cell.2015.02.022 · Cited by 510
PER2 controls lipid metabolism by direct regulation of PPARγ
Grimaldi, B., Bellet, M. M., Katada, S., Astarita, G., Hirayama, J., Amin, R. H., Granneman, J. G., Piomelli, D., Leff, T., & Sassone-Corsi, P. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.10.005 · Cited by 489
“We analyzed the expression of the adipogenic marker Adiponectin and the BAT-specific genes Ucp1 and Cidea in pre-adipocyte 3T3-L1 cells.”
BackgroundInfluentialLee, J.-E., Wang, C., Xu, S., Cho, Y.-W., Wang, L., Feng, X., Baldridge, A., Sartorelli, V., Zhuang, L., Peng, W., et al. (2013) · eLife · doi:10.7554/elife.01503 · Cited by 522
“C/EBP not only controls the 5 induction of PPAR and C/EBP expression but also acts as a pioneer factor to facilitate the genomic binding of PPAR , C/EBP and other adipogenic TFs during adipogenesis (Siersbaek et al., 2011).”
BackgroundThe Regulation and Physiology of Mitochondrial Proton Leak
Divakaruni, A. S., & Brand, M. D. (2011) · Physiology · doi:10.1152/physiol.00046.2010 · Cited by 514
Mitochondrial dysfunction in obesity
Bournat, J. C., & Brown, C. (2010) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0b013e32833c3026 · Cited by 488
“Also, PRDM16 interacts with C-terminal binding proteins, CtBP1 and Ct-BP2, to repress white adipocyte genes [47], and reducing PRDM16 in brown adipocytes blocks mitochondrial gene expression and increases myogenic markers [48].”
BackgroundBrown versus White Adipose Tissue: A Mini-Review
Saely, C. H., Geiger, K. D., & Drexel, H. (2010) · Gerontology · doi:10.1159/000321319 · Cited by 487
The adipose organ of obesity-prone C57BL/6J mice is composed of mixed white and brown adipocytes
Vitali, A., Murano, I., Zingaretti, M. C., Frontini, A., Ricquier, D., & Cinti, S. (2012) · Journal of Lipid Research · doi:10.1194/jlr.m018846 · Cited by 487
A Smooth Muscle-Like Origin for Beige Adipocytes
Long, J. Z., Svensson, K. J., Tsai, L. T.-Y., Zeng, X., Roh, H. C., Kong, X., Rao, R. R., Lou, J., Lokurkar, I. A., Baur, W. E., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.03.025 · Cited by 459
“Cell Culture Retrovirus production and infection from pMSCV-PRDM16 or pMSCV-GFP was performed as described previously (Seale et al., 2008).”
InfluentialSelf-citationIdentification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat
Schulz, T. J., Huang, T. L., Tran, T. T., Zhang, H., Townsend, K. L., Shadrach, J. L., Cerletti, M., McDougall, L. E., Giorgadze, N., Tchkonia, T., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1010929108 · Cited by 479
Cyclooxygenase-2 Controls Energy Homeostasis in Mice by de Novo Recruitment of Brown Adipocytes
Vegiopoulos, A., Müller‐Decker, K., Strzoda, D., Schmitt, I. M., Chichelnitskiy, E., Ostertag, A., Díaz, M. B., Rozman, J., de Angelis, M. H., Nüsing, R. M., et al. (2010) · Science · doi:10.1126/science.1186034 · Cited by 463
Distribution and Development of Brown Adipocytes in the Murine and Human Adipose Organ
Frontini, A., & Cinti, S. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.03.004 · Cited by 484
“Of interest, two master regulators of brown phenotype induction, PRDM16 and BMP7, have recently been identified (Seale et al., 2007; Seale et al., 2008; Tseng et al., 2008).”
BackgroundAdipose tissue angiogenesis as a therapeutic target for obesity and metabolic diseases
Cao, Y. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd3055 · Cited by 453
“Maintenance of the brown fat phenotype requires persistent expression of PR domain zinc finger protein 16 (PRDM16”
BackgroundAdipose tissue stem cells meet preadipocyte commitment: going back to the future
Cawthorn, W. P., Scheller, E. L., & MacDougald, O. A. (2011) · Journal of Lipid Research · doi:10.1194/jlr.r021089 · Cited by 467
Berberine activates thermogenesis in white and brown adipose tissue
Zhang, Z., Zhang, H., Li, B., Meng, X.-J., Wang, J., Zhang, Y., Yao, S., Ma, Q., Jin, L., Yang, J., et al. (2014) · Nature Communications · doi:10.1038/ncomms6493 · Cited by 445
Genetic and functional characterization of clonally derived adult human brown adipocytes
Shinoda, K., Luijten, I. H. N., Hasegawa, Y., Hong, H., Sonne, S. B., Kim, M., Xue, R., Chondronikola, M., Cypess, A. M., Tseng, Y., et al. (2015) · Nature Medicine · doi:10.1038/nm.3819 · Cited by 439
Self-citationGupta, R. K., Mepani, R. J., Kleiner, S., Lo, J. C., Khandekar, M. J., Cohen, P., Frontini, A., Bhowmick, D. C., Ye, L., Cinti, S., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.01.010 · Cited by 426
“This data suggest that despite the distinct origin of WAT and classical BAT depots during early embryogenesis (Seale et al., 2008), committed brown and white adipocytes may independently pass through a pericyte lineage.”
BackgroundSelf-citationKajimura, S., & Saito, M. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021113-170252 · Cited by 439
“committed skeletal muscle precursors (29).”
Self-citationTranscriptional Control of Brown Fat Development
Kajimura, S., Seale, P., & Spiegelman, B. M. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.03.005 · Cited by 430
“In fact, PRDM16 interacts with a variety of canonical DNA-binding transcription factors, such as PPARa, PPARg, p53, and several members of the C/EBP family (Kajimura et al., 2009; Seale et al., 2008).”
BackgroundInfluentialSelf-citationPeirce, V. J., Carobbio, S., & Vidal‐Puig, A. (2014) · Nature · doi:10.1038/nature13477 · Cited by 430
The genetic contribution to non-syndromic human obesity
Walley, A. J., Asher, J. E., & Froguel, P. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2594 · Cited by 412
“These findings, and recent discoveries elucidating the developmental pathways involved in BAT formation and differentiation, notably the roles of PR domain zinc finger protein 16 (PRDM16”
BackgroundBianco, P. (2014) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100913-013132 · Cited by 414
Temperature-Acclimated Brown Adipose Tissue Modulates Insulin Sensitivity in Humans
Lee, P., Smith, S., Linderman, J. D., Courville, A. B., Brychta, R. J., Dieckmann, W., Werner, C., Chen, K. Y., & Celi, F. S. (2014) · Diabetes · doi:10.2337/db14-0513 · Cited by 411
Cao, L., Choi, E., Liu, X., Martin, A. S., Wang, C., Xu, X., & During, M. J. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.06.020 · Cited by 390
“Recent studies have shown that BAT and skeletal muscle originate from Myf5+ precursors with Prdm16 controlling classical brown adipocyte fate (Seale et al., 2008), and transgenic expression of Prdm16 in fat tissue induces the brown-like cells in subcutaneous WAT but not intraabdominal WAT depots…”
BackgroundInfluentialPrdm16 Is Required for the Maintenance of Brown Adipocyte Identity and Function in Adult Mice
Harms, M., Ishibashi, J., Wang, W., Lim, H., Goyama, S., Sato, T., Kurokawa, M., Won, K., & Seale, P. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.03.007 · Cited by 393
“The precursor cells in the embryo that give rise to brown adipocytes and skeletal muscle are developmentally related (Atit et al., 2006; Lepper and Fan, 2010; Seale et al., 2008).”
BackgroundInfluentialSelf-citationBrown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat
Schulz, T. J., Huang, P. C., Huang, T. L., Xue, R., McDougall, L. E., Townsend, K. L., Cypess, A. M., Mishina, Y. M., Gussoni, E., & Tseng, Y. (2013) · Nature · doi:10.1038/nature11943 · Cited by 389
The Vascular Endothelium of the Adipose Tissue Gives Rise to Both White and Brown Fat Cells
Tran, K., Gealekman, O., Frontini, A., Zingaretti, M. C., Morroni, M., Giordano, A., Smorlesi, A., Perugini, J., Matteis, R. D., Sbarbati, A., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.01.008 · Cited by 396
“A vascular origin for white and brown adipocytes may seem to be in contradiction with the work of Seale et al., in which a common origin of BAT and skeletal muscle cells (Seale et al., 2008) was proposed.”
ResultInducible lineage tracing of Pax7‐descendant cells reveals embryonic origin of adult satellite cells
Lepper, C., & Fan, C. (2010) · genesis · doi:10.1002/dvg.20630 · Cited by 377
“5>16.5 embryos, most if not all b-gal1 cells corresponded to the embryonic muscle anlagen; none were in the dorsal dermis or BAT.”
BackgroundMethodInfluentialCheng, L., Wang, J., Dai, H., Duan, Y., An, Y., Shi, L., Lv, Y., Li, H., Wang, C., Ma, Q., et al. (2021) · Adipocyte · doi:10.1080/21623945.2020.1870060 · Cited by 404
Brown fat as a therapy for obesity and diabetes
Cypess, A. M., & Kahn, C. R. (2010) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0b013e328337a81f · Cited by 376
Bjørndal, B., Burri, L., Staalesen, V., Skorve, J., & Berge, R. K. (2011) · Journal of Obesity · doi:10.1155/2011/490650 · Cited by 395
“AMPK: Adenosine monophosphate-activated protein kinase BAT: Brown adipose tissue CPT: Carnitine palmitoyltransferase CVD: Cardiovascular disease DMT2: Diabetes mellitus type 2 dSAT: Deep subcutaneous adipose tissue EAT: Epicardial adipose tissue FFA: Free fatty acid IMAT: Intermuscular adipose tissue ME: Mesenteric ad…”
BackgroundInfluentialOntology-Based Meta-Analysis of Global Collections of High-Throughput Public Data
Kupershmidt, I., Su, Q. J., Grewal, A., Sundaresh, S., Halperin, I., Flynn, J. F., Shekar, M., Wang, H. H., Park, J. R., Cui, W., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013066 · Cited by 365
“demonstrated that brown fat cell precursors can turn into muscle cells upon the loss of PRDM16 protein”
BackgroundEBF2 Determines and Maintains Brown Adipocyte Identity
Rajakumari, S., Wu, J., Ishibashi, J., Lim, H., Giang, A.-H., Won, K., Reed, R. R., & Seale, P. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.01.015 · Cited by 375
Self-citationRosell, M., Kaforou, M., Frontini, A., Okolo, A., Chan, Y., Nikolopoulou, E., Millership, S. J., Fenech, M. E., MacIntyre, D. A., Turner, J. O., et al. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00473.2013 · Cited by 376
Adipocytes arise from multiple lineages that are heterogeneously and dynamically distributed
Sánchez-Gurmaches, J., & Guertin, D. A. (2014) · Nature Communications · doi:10.1038/ncomms5099 · Cited by 360
Targeting thermogenesis in brown fat and muscle to treat obesity and metabolic disease
Betz, M. J., & Enerbäck, S. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.132 · Cited by 373
Cinti, S. (2012) · Disease Models & Mechanisms · doi:10.1242/dmm.009662 · Cited by 370
“…groups using different experimental approaches support the idea that brown-like adipocytes arising in predominantly white fat depots in response to cold exposure are ontogenically different from those in the classic interscapular BAT (Atit et al., 2006; Seale et al., 2008; Petrovic et al., 2010).”
BackgroundInfluentialBone and muscle: Interactions beyond mechanical
Brotto, M. A. P., & Bonewald, L. F. (2015) · Bone · doi:10.1016/j.bone.2015.02.010 · Cited by 347
“Pedersen and colleagues were the first research group to invent the term, ‘myokines,’ and since then, other muscle secreted factors have been documented by several research labs, including IL-8 that seems to stimulate angiogenesis(10), brain-derived neutrophic factor (BDNF)(11), irisin, a potent regulator of the conve…”
BackgroundHui, X. H., Gu, P., Zhang, J., Nie, T., Pan, Y., Wu, D., Feng, T., Zhong, C., Wang, Y., Lam, K. S. L., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.06.004 · Cited by 355
Metadata
- Authors
- Seale, P., Bjork, B., Yang, W., Kajimura, S., Chin, S., Kuang, S., Scimè, A., Devarakonda, S., Conroe, H. M., Erdjument-Bromage, H., Tempst, P., Rudnicki, M. A., Beier, D. R., & Spiegelman, B. M.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Spiegelman, Bruce M.
- ORCID
- Venue
- Nature
- Published
- 2008-08
- Volume
- 454
- Issue
- 7207
- Pages
- 961-967
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2583329
- OpenAlex
- W2104827888
- Cited by
- 2,347
- References
- 44
- Citations by year
- 2026: 77 · 2025: 71 · 2024: 118 · 2023: 115 · 2022: 129 · 2021: 134 · 2020: 141 · 2019: 134 · 2018: 168 · 2017: 165 · 2016: 139 · 2015: 167 · 2014: 157 · 2013: 181 · 2012: 134
- FWCI
- 71.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- American Heart Association
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK031405)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR044031)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- PRDM16, brown adipose tissue, skeletal muscle, Myf5, brown adipogenesis, PPARγ, thermogenesis, myogenesis, energy expenditure, obesity
- MeSH terms
- Animals, Adipose Tissue, Brown, Cell Differentiation, Cell Line, Chlorocebus aethiops, DNA-Binding Proteins, Male, Transcription Factors, Muscle, Skeletal, Gene Expression Regulation, Developmental, COS Cells, Muscle Development, PPAR gamma, Mice, Myogenic Regulatory Factor 5, Adipocytes, Brown, Adipocytes, White
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