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Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex
Open accessAbstract
Brown fat is a specialized tissue that can dissipate energy and counteract obesity through a pattern of gene expression that greatly increases mitochondrial content and uncoupled respiration. PRDM16 is a zinc-finger protein that controls brown fat determination by stimulating brown fat-selective gene expression, while suppressing the expression of genes selective for white fat cells. To determine the mechanisms regulating this switching of gene programs, we purified native PRDM16 protein complexes from fat cells. We show here that the PRDM16 transcriptional holocompex contains C-terminal-binding protein-1 (CtBP-1) and CtBP-2, and this direct interaction selectively mediates the repression of white fat genes. This repression occurs through recruiting a PRDM16/CtBP complex onto the promoters of white fat-specific genes such as resistin, and is abolished in the genetic absence of CtBP-1 and CtBP-2. In turn, recruitment of PPAR-γ-coactivator-1α (PGC-1α) and PGC-1β to the PRDM16 complex displaces CtBP, allowing this complex to powerfully activate brown fat genes, such as PGC-1α itself. These data show that the regulated docking of the CtBP proteins on PRDM16 controls the brown and white fat-selective gene programs.
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“This effect depends on the interaction of PRDM16 with PGC-1α/β, PPARγ and C/EBPβ, while binding of PRDM16 to CtBP-1 and CtBP-2 suppresses expression of white fat-selective genes 171,172.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [171]
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“The transcriptional coactivator peroxisome proliferator-activated receptor-c coactivator (PGC)-1a has previously been shown to drive the formation of brown fat gene program [13] in addition to playing a role in regulation of capillarization [14,15] and expression of oxidative proteins in skeletal muscle [15,16] and ox…”
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“PRD1-BF1-RIZ1 homologous domain-containing protein 16 (PRDM16) is a critical regulator of the brown fat-selective gene program in brown and beige adipocytes (Seale et al , 2007, 2008, 2011; Kajimura et al , 2008; Ohno et al , 2012; Harms et al , 2015).”
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The conserved NAD(H)-dependent corepressor CTBP-1 regulates Caenorhabditis elegans life span
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Genetic and epigenetic control of adipose development
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“A genome-wide screen for transcriptional regulators enriched in brown fat cells led to the identification of PRDM16, a zinc-figure protein as a dominant regulator of the brown fat differentiation program, which has the ability to induce UCP1 and PGC1-a, and suppress genes that are selectively expressed in white adipos…”
BackgroundCtBP maintains cancer cell growth and metabolic homeostasis via regulating SIRT4
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“According to previous studies, CtBP is involved in repressing the differentiation and maintaining the proliferation of progenitor cells from multiple tissues.(41,44,45) Thus, CtBP may be critical to maintain the proliferation of the progenitor cells in different tissues by regulating the cellular metabolic pathways.”
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“Other studies by Spiegelman and collaborators have shown that PRDM16 does have the ability to simultaneously repress and activate genes through a mutually exclusive interaction with either CtBP corepressors or PGC-1α/β coactivators, respectively (Kajimura et al., 2008).”
BackgroundCombating Obesity With Thermogenic Fat: Current Challenges and Advancements
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“On the other hand, PPARγ is a member of the nuclear receptor super-family of ligand-activated transcription factors and is a prerequisite for the differentiation of adipocytes [38].”
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“Expresion of brown adipocyte-specific genes, such as UCP-1, PGC-1 and ig.”
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“Interestingly, rosiglitazone increased mRNA levels of the orphan nuclear receptor SHP (NROB2), a negative regulator of PGC- expression and energy expenditure in brown adipocytes (40), and reduced those of both SIRT3, a protein involved in the control of BAT PGC- expression and mitochondrial biogenesis (31), and PRDM16…”
BackgroundRegulation of adipocyte thermogenesis: mechanisms controlling obesity
Hussain, M. F., Roesler, A. A., & Kazak, L. (2020) · FEBS Journal · doi:10.1111/febs.15331 · Cited by 60
Uncovering the Role of p38 Family Members in Adipose Tissue Physiology
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“Using previously published PRDM16 ChIP-seq data in both brown adipose tissue and WAT from WT and PRDM16KO mice, 48,49 we identified a PRDM16-binding site located within the promoter region of the Negr1 gene (Figure S8D) and found that the promoter region shows an RNA polymerase II (RNA Pol II) peak…”
A cellular perspective of adipogenesis transcriptional regulation
Kuri‐Harcuch, W., Velez‐delValle, C., Vazquez‐Sandoval, A., Hernández‐Mosqueira, C., & Fernández-Sánchez, V. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27060 · Cited by 59
“The complex PRDM16‐PGC1α competes three‐dimensionally with CtBP1 and CtBP2, which can interact with PLDLS motif in the RD domain of PRDM16, forming a repressor complex, which has an impact over the main white fat genes such of Resistin, Angiotensinogen, WDNM1‐ like, SERPINA3K, EDNRA, PSAT, and ANXA1 (Kajimura et al.,…”
BackgroundInfluentialFunctions of Prdm16 in thermogenic fat cells
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“This pattern of Prdm16 regulation is absolutely dependent on its interaction with CtBP1 or CtBP2 through the second of two 5-amino acid CtBP-interaction motifs in Prdm16.(53) Interestingly, Prdm16 can be sumoylated at a four amino acid motif at the N-terminal end of the RD and just before the first CtBP motif.”
BackgroundInfluentialSelf-citationEpigenetic regulation of adipocyte differentiation and adipogenesis
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“In addition, PPARγ is a prerequisite for the differentiation of both brown and white adipocytes ( Kajimura et al., 2008 ).”
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“Moreover, such increased recruitment of beige cells has been shown to compensate for decreased BAT thermogenesis, and the specific loss of beige adipocytes due to adipose tissue–specific deletion of a transcriptional factor involved in Ucp1 expression (32), PRDM16, was shown to cause obesity (32,33).”
BackgroundLipoma in dogs under primary veterinary care in the UK: prevalence and breed associations
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MicroRNAs in brown and beige fat
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Recent advance in brown adipose physiology and its therapeutic potential
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Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology
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“participate in brown fat lineage determination [118, 120, 121].”
The regulation of glucose and lipid homeostasis via PLTP as a mediator of BAT–liver communication
Sponton, C. H., Hosono, T., Taura, J., Jedrychowski, M. P., Yoneshiro, T., Wang, Q., Takahashi, M., Matsui, Y., Ikeda, K., Oguri, Y., et al. (2020) · EMBO Reports · doi:10.15252/embr.201949828 · Cited by 55
“We found that PLTP expression in BAT and iWAT was not altered by cold exposure (Fig EV1C and D), whereas PLTP is regulated by the PRDM16-PPAR c complex, the master regulator of brown/beige fat development (Seale et al , 2007; Kajimura et al , 2008).”
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“Meanwhile, markers of white adipocytes (31), such as Agt, phosphoserine aminotransferase (Psat), and endothelian receptor type A (Ednra), increased markedly by 90 6 24.”
BackgroundBrown adipose tissue and novel therapeutic approaches to treat metabolic disorders
Román, S., Agil, A., Perán, M., Alvaro-Galue, E., Ruiz‐Ojeda, F. J., Fernández‐Vázquez, G., & Marchal, J. A. (2014) · Translational research · doi:10.1016/j.trsl.2014.11.002 · Cited by 54
Beige Fat Maintenance; Toward a Sustained Metabolic Health
Rabiee, A. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00634 · Cited by 53
Renaissance of Brown Adipose Tissue
Tews, D., & Wabitsch, M. (2011) · Hormone Research in Paediatrics · doi:10.1159/000324806 · Cited by 51
“PR domain zinc finger protein 16 (PRDM16) is highly expressed in brown adipocytes compared to white adipocytes. It forms a complex with C/EBP-β which leads to enhanced expression of PPAR-γ [”
BackgroundPromoting brown and beige adipocyte biogenesis through the PRDM16 pathway
Kajimura, S. (2015) · International Journal of Obesity Supplements · doi:10.1038/ijosup.2015.4 · Cited by 52
Self-citationWu, H., li, X., & Shen, C. Y. (2020) · Physiological Research · doi:10.33549/physiolres.934411 · Cited by 53
“PGC-1α transposable CtBP binds to PRDM16 and forms a PRDM16/PGC-1α transcriptional complex that activates BAC-specific genes, including PGC-1α (Shingo Kajimura et al. 2008).”
BackgroundNeuronal UCP1 expression suggests a mechanism for local thermogenesis during hibernation
Laursen, W. J., Mastrotto, M., Pesta, D. H., Funk, O. H., Goodman, J. B., Merriman, D. K., Ingolia, N. T., Shulman, G. I., Bagriantsev, S. N., & Gracheva, E. O. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1421419112 · Cited by 55
The Adipokines in Cancer Cachexia
Mannelli, M., Gamberi, T., Magherini, F., & Fiaschi, T. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21144860 · Cited by 53
“PPARγ co-activators—peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α and PGC1β—participate in brown adipocyte differentiation by impairing c/EBPs network and promoting the expression of brown-specific genes [25].”
BackgroundImprinted lncRNA Dio3os preprograms intergenerational brown fat development and obesity resistance
Chen, Y., Yang, Q., Hu, Y., Liu, X., de Avila, J. M., Zhu, M. J., Nathanielsz, P. W., & Du, . (2021) · Nature Communications · doi:10.1038/s41467-021-27171-1 · Cited by 50
Afzaal, A., Rehman, K., Kamal, S., & Akash, M. S. H. (2022) · Journal of Biochemical and Molecular Toxicology · doi:10.1002/jbt.23047 · Cited by 49
Zhang, X., Tian, Y., Zhang, H., Kavishwar, A., Lynes, M. D., Brownell, A., Sun, H., Tseng, Y., Moore, A. V., & Ran, C. (2015) · Scientific Reports · doi:10.1038/srep13116 · Cited by 48
“Browning of white adipose tissue could be achieved through several approaches, including small molecule stimulation such as β 3-adrenoceptor agonist (CL316,243), PPAR-gamma ligand (rosiglitazone), treatment with hormones and cytokines, and genetic manipulation 19–21, 26,29,85 .”
BackgroundMethodAdipose tissue insulin receptor knockdown via a new primate-derived hybrid recombinant AAV serotype
Liu, X., Magee, D., Wang, C., McMurphy, T. B., Slater, A., During, M. J., & Cao, L. (2014) · Molecular Therapy — Methods & Clinical Development · doi:10.1038/mtm.2013.8 · Cited by 46
Crespo, I., & del Sol, A. (2013) · Stem Cells · doi:10.1002/stem.1473 · Cited by 47
“Several examples of these binary cell fate choice mechanisms have emerged in the last ten years [5-14].”
BackgroundImplantation of engineered adipocytes suppresses tumor progression in cancer models
Nguyen, H. P., An, K., Ito, Y., Kharbikar, B. N., Sheng, R. R., Paredes, B., Murray, E., Pham, K., Brück, M., Zhou, X., et al. (2025) · Nature Biotechnology · doi:10.1038/s41587-024-02551-2 · Cited by 49
A New Role for Browning as a Redox and Stress Adaptive Mechanism?
Jeanson, Y., Carrière, A., & Casteilla, L. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00158 · Cited by 49
“Various co-regulators, such as peroxisome proliferator-activated receptor coactivator-1α (PGC-1α) and the positive regulatory domain containing-16 protein (PRDM16) are also crucial.”
BackgroundPGC-1α Mediates Differentiation of Mesenchymal Stem Cells to Brown Adipose Cells
Huang, P., Chen, Y., Chen, L.-H., Juan, C., Ku, H., Wang, S., Chiou, S., Chiou, G., Chi, C., Hsu, C.-C., et al. (2011) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.7401 · Cited by 49
Brown adipose tissue growth and development: significance and nutritional regulation
Satterfield, M. C. (2010) · Frontiers in bioscience · doi:10.2741/3807 · Cited by 46
Dietary polyphenols turn fat “brown”: A narrative review of the possible mechanisms
Hu, J., Wang, Z., Tan, B. K., & Christian, M. (2020) · Trends in Food Science & Technology · doi:10.1016/j.tifs.2020.01.013 · Cited by 47
Redundant roles of PRDM family members in zebrafish craniofacial development
Ding, H., Clouthier, D. E., & Artinger, K. (2012) · Developmental Dynamics · doi:10.1002/dvdy.23895 · Cited by 40
Yang, R., Xue, H., Yu, L., Velayos‐Baeza, A., Monaco, A. P., & Liu, F. (2016) · PLoS ONE · doi:10.1371/journal.pone.0153534 · Cited by 46
“Similar approaches have been successfully used to show that the zinc finger protein PRDM16 (PR domain containing 16) specifies the brown fat lineage from a progenitor by binding to the transcription factors PPARγ [24] and C/EBPβ [25], as well as the transcriptional repressor CtBP [26].”
MethodUCP1 protein: The molecular hub of adipose organ plasticity
Cinti, S. (2016) · Biochimie · doi:10.1016/j.biochi.2016.09.008 · Cited by 46
Zhang, L., Li, H., Ge, C., Li, M., Zhao, F., Hou, H.-L., Zhu, M.-X., Tian, H., Zhang, L.-X., Chen, T.-Y., et al. (2014) · Oncotarget · doi:10.18632/oncotarget.2524 · Cited by 44
“CtBP and PRDM16 co-control the brown and white fat-selective gene programs [47].”
BackgroundByun, J. S., & Gardner, K. L. (2013) · International Journal of Cell Biology · doi:10.1155/2013/647975 · Cited by 44
“Another pathway through which CtBP controls adipocyte growth and differentiation is through the transcription factor PRDM16 that recruits CtBP to shut down genes that promote white adipose cell growth and differentiation and eventually exchanges CtBP factors for PGC-1α andPPARγ to drive the expression of brown fat gen…”
BackgroundHan, Y., Wu, J., Shen, J., Chen, L., He, T., Jin, M., & Liu, H. (2017) · Scientific Reports · doi:10.1038/s41598-017-01206-4 · Cited by 45
PRDM16 suppresses HIF-targeted gene expression in kidney cancer
Kundu, A., Nam, H., Shelar, S. B., Chandrashekar, D. S., Brinkley, G. J., Karki, S., Mitchell, T., Livi, C. B., Buckhaults, P., Kirkman, R. L., et al. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20191005 · Cited by 43
A chromatin perspective of adipogenesis
Musri, M. M., Gomis, R., & Párrizas, M. (2010) · Organogenesis · doi:10.4161/org.6.1.10226 · Cited by 44
Dual functions of TAF7L in adipocyte differentiation
Zhou, H., Kaplan, T., Li, Y., Grubisic, I., Zhang, Z., Wang, P. J., Eisen, M. B., & Tjian, R. (2013) · eLife · doi:10.7554/elife.00170 · Cited by 49
“We also note that although TAF7L protein levels become highly elevated when MSCs differentiate into adipocytes, its mRNA levels increase only modestly (∼2×) compared to typical adipocyte marker genes such as Fabp4 and Glut4 during adipogensis (Kajimura et al., 2008; Seale et al., 2008).”
Zhang, W., Xu, J., Li, J., Guo, T., Jiang, D., Feng, X., Ma, X., He, L., Wu, W., Yin, M.-X., et al. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.003608 · Cited by 43
“For example, RIP140 interacts with CtBPs and colocalizes with an enhancer of UCP1 to mediate gene repression (19).”
BackgroundInfluentialIvanochko, D., Halabelian, L., Henderson, E., Savitsky, P. A., Jain, H., Marcon, E., Duan, S., Hutchinson, A., Seitova, A., Baršytė-Lovejoy, D., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky1192 · Cited by 43
“Both PRDM3 and PRDM16 bind to Cterminal binding protein (CtBP) through canonical PLDLS CtBP-binding sites located between the two zinc finger clusters, which can promote cellular growth by repressing transcription downstream of transforming growth factor- signaling (34,35).”
BackgroundWu, M., Chou, H., & Huang, C. (2014) · Marine Drugs · doi:10.3390/md12020964 · Cited by 42
“Prdm16 activates a robust brown fat phenotype, including the induction of PGC-1α, UCP1 and Dio2 [42–44].”
BackgroundThe Genetics of Brown Adipocyte Induction in White Fat Depots
Kozak, L. P. (2011) · Frontiers in Endocrinology · doi:10.3389/fendo.2011.00064 · Cited by 41
“The molecular analysis of Ucp1 regulation has not revealed any brown fat specific signaling or transcription molecules; however, a regulatory model in which brown fat specific expression is determined by a modular molecular mechanism is consistent with existing data (Hansen and Kristiansen,2006; Kajimura et al., 2008).”
ResultChung, Y. W., Ahmad, F., Tang, Y., Hockman, S. C., Kee, H. J., Berger, K., Guirguis, E., Choi, Y. H., Schimel, D., Aponte, A. M., et al. (2017) · Scientific Reports · doi:10.1038/srep40445 · Cited by 45
RNA Binding Protein Ybx2 Regulates RNA Stability During Cold-Induced Brown Fat Activation
Xu, D., Xu, S., Kyaw, A. M. M., Lim, Y. C., Chia, S. Y., Siang, D. T. C., Alvarez‐Dominguez, J. R., Chen, P., Leow, M. K., & Sun, L. (2017) · Diabetes · doi:10.2337/db17-0655 · Cited by 40
PGC-1β mediates adaptive chemoresistance associated with mitochondrial DNA mutations
Yao, Z., Jones, A. W. E., Fassone, E., Sweeney, M. G., Lebiedzińska, M., Suski, J. M., Wieckowski, M. R., Tajeddine, N., Hargreaves, I. P., Yasukawa, T., et al. (2012) · Oncogene · doi:10.1038/onc.2012.259 · Cited by 42
Shull, L. C., Kim, H. M., Lencer, E. S., Goyama, S., Kurokawa, M., Costello, J. C., Jones, K. L., & Artinger, K. (2022) · Development · doi:10.1242/dev.200082 · Cited by 36
“Browning” of adipose tissue – regulation and therapeutic perspectives
Peschechera, A., & Eckel, J. (2013) · Archives of Physiology and Biochemistry · doi:10.3109/13813455.2013.796995 · Cited by 42
“binding proteins (CtBP1 and 2), well-known co-repressor proteins (Kajimura et al., 2008).”
BackgroundResultChoi, J., Kim, K., Koh, E., & Lee, B.-Y. (2017) · Nutrients · doi:10.3390/nu9040342 · Cited by 42
“AMPK is a multiple nutrient sensor and a key energy balance interactor of ermogeni transcription factors including PRDM16 [44,45].”
BackgroundAnde, S., Klarmann, K. D., Gavrilova, O., & Keller, J. R. (2011) · The FASEB Journal · doi:10.1096/fj.11-190892 · Cited by 42
“Single-cell suspensions of adipocytes were prepared from fat pads of 12-wk-old male mice, as described previously (25, 26).”
Method
Metadata
- Authors
- Kajimura, S., Seale, P., Tomaru, T., Erdjument-Bromage, H., Cooper, M. P., Ruas, J. L., Chin, S., Tempst, P., Lazar, M. A., & Spiegelman, B. M.
- Affiliations
- Harvard University (US)
- University of Pennsylvania (US)
- Memorial Sloan Kettering Cancer Center (US)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2008-05-15
- Volume
- 22
- Issue
- 10
- Pages
- 1397-1409
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC2377193
- OpenAlex
- W2163468424
- Cited by
- 468
- References
- 78
- Citations by year
- 2026: 12 · 2025: 25 · 2024: 13 · 2023: 16 · 2022: 18 · 2021: 21 · 2020: 25 · 2019: 22 · 2018: 27 · 2017: 35 · 2016: 30 · 2015: 46 · 2014: 33 · 2013: 28 · 2012: 32
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Wenner-Gren Foundation
- University of Pittsburgh
- National Institutes of Health (CA08748)
- National Cancer Institute (P30-CA-08748, CA08748, P30CA008748)
- National Institute of Diabetes and Digestive and Kidney Diseases (R37 DK-31405, P01DK049210, DK 49210, R37DK031405)
- 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 › Genomics and Chromatin Dynamics
- Keywords
- PRDM16, brown adipose tissue, white adipose tissue, transcriptional repression, PGC-1α, PGC-1β, resistin, transcriptional complex, gene expression regulation, obesity
- MeSH terms
- Alcohol Oxidoreductases, Animals, Adipose Tissue, Brown, Cell Differentiation, Chlorocebus aethiops, DNA-Binding Proteins, Gene Expression Regulation, Genes, Regulator, Models, Biological, Phosphoproteins, Protein Binding, Transcription Factors, Transcription, Genetic, 3T3 Cells, COS Cells, 3T3-L1 Cells, Multiprotein Complexes, Mice, Adipose Tissue, White, Co-Repressor Proteins
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