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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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Self-citationMir193b–365 is essential for brown fat differentiation
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BackgroundHuman Multipotent Adipose-Derived Stem Cells Differentiate into Functional Brown Adipocytes
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“Use of various GST-PRDM16 fusion proteins indicated that Zfp516 can directly interact with PRDM16 AA881-1038, a region shown to interact with other transcription factors (Kajimura et al., 2008) (Figure 2A, bottom right).”
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“The zinc-finger transcriptional factor PRD1-BF1-RIZ1 homologous domain-containing protein 16 (PRDM16) is a powerful driver of brown and beige adipocyte identity (Cohen et al., 2014; Harms et al., 2015; Ishibashi and Seale, 2015; Kajimura et al., 2008; Ohno et al., 2013; Seale et al., 2007, 2011).”
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“PRDMs’ molecular mechanisms in transcriptional regulation Name Common alias HMT activity (in complex) Consensus sequence Binding partners PRDM1 BLIMP1 (Prmt5 H2AR3me2s, H4R3me2s [14]), (G9a H3K9me2 [9]) Yes [99] G9a [9], HDAC2 [13], IRF4 [100], LSD1 [15], PRMT5 [14], TLE1, TLE2 [18] PRDM2 RIZ1/2 H3K9me2 [6] ER [101],…”
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“To validate this finding, we focused on 20 of the most widely used WAT markers (Kajimura et al., 2008; Seale et al., 2007; Villanueva et al., 2013; Waldén et al., 2012) (Figures 5G and S6F) and confirmed by qPCR their upregulation upon lnc-BATE1 KD by either siRNAs (16 out of 19 genes upregulated, mean 3.”
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“The mechanism regulating this process appears to involve mutually exclusive interactions of PRDM16 with either PGC-1 / to activate the brown genes or with CtBPs to suppress the white genes (26).”
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“Recent evidence indicates that there are two distinct types of brown fat cells: an myf-5-positive, UCP1-positive classical brown fat cell and an myf-5-negative, UCP1-positive beige fat cell that is present in WAT (5, 29, 30).”
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“…Adenovirus Vector Biolabs Cat# ADV-260890 eGFP adenovirus Vector Biolabs Cat# 1060 Biological Samples Purified GST-fused PRDM16 fragments Kajimura et al., 2008 N/A Human tissue samples This paper N/A Chemicals, Peptides, and Recombinant Proteins Flag peptide Sigma-Aldrich Cat#…”
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“These findings are in contrast to inbred strains of mice, including B6, fed rosiglitazone, which directly activates PPARg, and MAT increases significantly in parallel with bone loss (Ackert-Bicknell and Rosen, 2006; Lazarenko et al., 2007; Ackert-Bicknell et al., 2009).”
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“Thus, when PRDM16 is expressed in mouse white fat preadipocytes or white adipocytes, brown fat differentiation is induced, including activation of thermogenic and mitochondrial genes (34, 74, 75).”
BackgroundMolecular determinants of brown adipocyte formation and function: Figure 1.
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“bind to Prdm16 and inhibit its ability to stimulate expression of brown and beige adipocyte-selective genes and thermogenesis (144,320).”
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BackgroundOntogenesis of muscle and adipose tissues and their interactions in ruminants and other species
Bonnet, M., Cassar‐Malek, I., Chilliard, Y., & Picard, B. B. (2010) · animal · doi:10.1017/s1751731110000601 · Cited by 168
“, 2008), while suppressing the expression of genes specific for white fat cells (Kajimura et al., 2008).”
BackgroundJones, A. W. E., Yao, Z., Vicencio, J. M., Karkucińska‐Więckowska, A., & Szabadkai, G. (2011) · Mitochondrion · doi:10.1016/j.mito.2011.09.009 · Cited by 149
“Alternatively, it has been recently proposed that increased AMP/ATP ratios, due tomitochondrial dysfunctionwould lead to activation of AMPK, which has been shown to signal energy depletion to Sirt1 by increasing absolute NAD+ levels (reviewed in (Jeninga et al., 2010)).”
BackgroundInfluentialVillanueva, C. J., Vergnes, L., Wang, J., Drew, B. G., Hong, C., Tu, Y., Hu, Y., Xu, P., Xu, F., Sáez, E., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.01.016 · Cited by 152
“, 2011), and Prdm16 also suppresses the expression of certain WAT-selective transcripts (Kajimura et al., 2008).”
BackgroundHarms, M., Lim, H., Ho, Y., Shapira, S. N., Ishibashi, J., Rajakumari, S., Steger, D. J., Lazar, M. A., Won, K., & Seale, P. (2015) · Genes & Development · doi:10.1101/gad.252734.114 · Cited by 143
“PRDM16 activates genes that are expressed at higher levels in brown relative to white adipocytes (BAT-selective), such as Ucp1 , Ppar a , and Ppargc1a , while also suppressing the expression of certain WAT-selective genes (Kajimura et al. 2008; Harms et al. 2014).”
InfluentialSelf-citationTranscriptional Regulatory Circuits Controlling Brown Fat Development and Activation
Seale, P. (2015) · Diabetes · doi:10.2337/db15-0203 · Cited by 145
“Additionally, PRDM16 is believed to directly bind to certain white fat genes and repress their expression through recruiting repressive complexes containing CtBP1,2 and/or EHMT1 (40,45).”
Self-citationRachid, T. L., Penna‐de‐Carvalho, A., Bringhenti, I., Águila, M. B., Mandarim‐de‐Lacerda, C. A., & Souza‐Mello, V. (2015) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2014.12.027 · Cited by 143
“PRDM16 can enhance the expression of representative BAT genes in the sWAT and suppress genes related to the WAT phenotype (Kajimura et al., 2008).”
Zhang, X., Zhang, Q.-X., Wang, X., Zhang, L., Qu, W., Bao, B., Liu, C.-A., & Liu, J. (2016) · International Journal of Obesity · doi:10.1038/ijo.2016.108 · Cited by 143
Nguyen, H. P., Yi, D., Lin, F., Viscarra, J. A., Nakamura-Tabuchi, C., Ngo, K., Shin, G., Lee, A. Y.-F., Wang, Y., & Sul, H. S. (2020) · Molecular Cell · doi:10.1016/j.molcel.2019.12.002 · Cited by 133
“Cell culture—Brown adipocyte differentiation was performed as described in (Kajimura et al., 2008).”
MethodShaik Mohamed Sayed, U. F., Moshawih, S., Goh, H. P., Kifli, N., Gupta, G., Singh, S. K., Chellappan, D. K., Dua, K., Hermansyah, A., Ser, H. L., et al. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1182937 · Cited by 136
“Contrarily, the repression of WAT-specific genes is caused by the interaction of PRDM16 with C-terminal binding protein (CtBP) 1 and 2 at the promoter domains of WAT genes (Kajimura et al., 2008).”
BackgroundBrown adipose tissue—a new role in humans?
Lidell, M. E., & Enerbäck, S. (2010) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2010.64 · Cited by 131
“The investigators also found that the transcriptional regulator PR domain zinc finger protein 16 (PRDM16), previously shown to be essential for determination of the brown adipocyte phenotype”
BackgroundApelin Enhances Brown Adipogenesis and Browning of White Adipocytes
Than, A., He, H. L., Chua, S. H., Xu, D., Sun, L., Leow, M. K., & Chen, P. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.643817 · Cited by 124
“This is consistent with previous reports (49, 52).”
ResultThe Multifaceted Roles of PRDM16: Adipose Biology and Beyond
Chi, J., & Cohen, P. (2015) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2015.11.005 · Cited by 129
“In addition, PRDM16 also complexes with C-terminal binding proteins 1,2 (CTBP1,2) to repress particular white-specific genes, such as resistin and angiotensinogen, by acting directly on their promoters (Figure 3C) [38].”
Wang, L., Teng, R., Di, L., Rogers, H. M., Wu, H., Kopp, J. B., & Noguchi, C. T. (2013) · Diabetes · doi:10.2337/db13-0518 · Cited by 124
Emerging roles for XBP1, a sUPeR transcription factor
He, Y., Sun, S.-Y., Sha, H.-B., Liu, Z., Yang, L., Xue, Z., Chen, H., & Qi, L. (2010) · Gene Expression · doi:10.3727/105221610x12819686555051 · Cited by 122
“In support of previous reports (11), XBP1 did indeed bind to the core enriched white adipose gene that was repressed by PR domain containing 16 (PRDM16), a brown fat- “ACGT” element under physiological conditions, but XBP1 targets were also enriched in additional distinct specific transcriptional activator (36,77).”
BackgroundWu, R., Zhang, Q.-H., Lu, Y.-J., Ren, K., & Yi, G.-H. (2015) · DNA and Cell Biology · doi:10.1089/dna.2014.2552 · Cited by 116
“For example, fat deposits were absent in XBP1-deficient neonates (Lee et al ., 2005), and XBP1 was highly expressed in both embryonic adipose deposits (Clauss et al ., 1993) and white adipose cells (Kajimura et al ., 2008).”
Kinameri, E., Inoue, T., Aruga, J., Imayoshi, I., Kageyama, R., Shimogori, T., & Moore, A. W. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003859 · Cited by 122
“Interestingly, Prdm proteins associate with a wide range of chromatin-remodelling enzymes and also act predominantly as transcription repressors [16,40–44].”
BackgroundInfluentialEvaluation of markers of beige adipocytes in white adipose tissue of the mouse
Garcia, R. A. G., Roemmich, J. N., & Claycombe, K. (2016) · Nutrition & Metabolism · doi:10.1186/s12986-016-0081-2 · Cited by 118
“In comparison, markers associated with white adipocytes, Serpina3k [12], Wdnm1-like [8], and ASC1 [9] were greater in the cells that were not treated with rosiglitazone (Fig.”
BackgroundInfluentialRecent advances in adaptive thermogenesis: potential implications for the treatment of obesity
Wijers, S. L. J., Saris, W. H. M., & Lichtenbelt, W. D. V. M. (2009) · Obesity Reviews · doi:10.1111/j.1467-789x.2008.00538.x · Cited by 119
“PRDM16 inhibits the formation of white adipose tissue and promotes the formation of BAT by binding to C-terminal-binding protein-1 and -2 and PPARg-coactivator-1a and -1b (63).”
BackgroundPost-translational control of beige fat biogenesis by PRDM16 stabilization
Wang, Q., Li, H., Tajima, K., Verkerke, A. R. P., Taxin, Z. H., Hou, Z.-S., Cole, J. B., Li, F., Wong, J., Abe, I., et al. (2022) · Nature · doi:10.1038/s41586-022-05067-4 · Cited by 118
Self-citationBrown Adipose Tissue and Its Role in Insulin and Glucose Homeostasis
Maliszewska, K., & Kretowski, A. J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041530 · Cited by 124
“Brown pre-adipocytes decrease the expression of PRDM16, resulting in differentiation into skeletal muscle cells [140].”
BackgroundAn integrated epigenomic analysis for type 2 diabetes susceptibility loci in monozygotic twins
Yuan, W., Xia, Y., Bell, C. G., Yet, İ., Ferreira, T. C., Ward, K. J., Gao, F., Loomis, A. K., Hyde, C. L., Wu, H., et al. (2014) · Nature Communications · doi:10.1038/ncomms6719 · Cited by 117
The Role of CtBP1 in Oncogenic Processes and Its Potential as a Therapeutic Target
Blevins, M. A., Huang, M., & Zhao, R. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0592 · Cited by 114
“A major advantage of targeting CtBP1 is that CtBP1 expression levels are generally low or absent in many adult tissues, with the exception of the brain, adipose tissue, and skeletal muscle (3, 117, 118); therefore, negative side effects in response to a CtBP1-targeting therapy would likely be limited.”
Molchadsky, A., Ezra, O., Amendola, P. G., Krantz, D., Kogan-Sakin, I., Buganim, Y., Rivlin, N., Goldfinger, N., Folgiero, V., Falcioni, R., et al. (2013) · Cell Death and Differentiation · doi:10.1038/cdd.2013.9 · Cited by 117
“transcription factor Positive-Regulatory-Domain-Containing16 (PRDM16) has been identified as the key molecular switch committing skeletal muscle progenitors into the development of brown adipocytes.(10,11) Adipocyte-Fatty-Acid-Binding Protein (AP-2) and Adiponectin (AdipoQ) are crucial for the differentiation of both…”
BackgroundBougarne, N., Paumelle, R., Caron, S., Hennuyer, N., Mansouri, R. M., Gervois, P. P., Staels, B., Haegeman, G., & Bosscher, K. D. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0806742106 · Cited by 110
“In support, ligand-dependent and ligand-independent regulations of nuclear receptor biology, mainly with respect to coregulator associations, have been reported before (8).”
BackgroundTranscriptional Control of Brown and Beige Fat Development and Function
Shapira, S. N., & Seale, P. (2018) · Obesity · doi:10.1002/oby.22334 · Cited by 111
“PRDM16 also represses white fat and muscle gene expression though interactions with co-repressor complexes (60, 61).”
BackgroundSelf-citationLafontan, M. (2011) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00168.2011 · Cited by 118
The biology of PGC-1α and its therapeutic potential
Handschin, C. (2009) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2009.03.006 · Cited by 108
Dietary alpha‐ketoglutarate promotes beige adipogenesis and prevents obesity in middle‐aged mice
Tian, Q., Zhao, J., Yang, Q., Wang, B., de Avila, J. M., Zhu, M. J., & Du, . (2019) · Aging Cell · doi:10.1111/acel.13059 · Cited by 108
Role of histone methylation and demethylation in adipogenesis and obesity
Okamura, M., Inagaki, T., Tanaka, T., & Sakai, J. (2010) · Organogenesis · doi:10.4161/org.6.1.11121 · Cited by 104
Ohyama, K., Nogusa, Y., Shinoda, K., Suzuki, K., Bannai, M., & Kajimura, S. (2016) · Diabetes · doi:10.2337/db15-0662 · Cited by 103
Self-citationPRDM16 Maintains Homeostasis of the Intestinal Epithelium by Controlling Region-Specific Metabolism
Stine, R. R., Sakers, A. P., TeSlaa, T. A., Kissig, M., Stine, Z. E., Kwon, C. W., Cheng, L., Lim, H., Kaestner, K. H., Rabinowitz, J. D., et al. (2019) · Cell stem cell · doi:10.1016/j.stem.2019.08.017 · Cited by 103
Self-citationLangin, D. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2009.09.008 · Cited by 107
Choi, J. S., Kim, J., Ali, M. Y., Min, B.-S., Kim, G., & Jung, H. A. (2014) · Fitoterapia · doi:10.1016/j.fitote.2014.08.006 · Cited by 99
Côté, S., Gagné‐Ouellet, V., Guay, S., Allard, C., Houde, A.-A., Perron, P., Baillargeon, J., Gaudet, D., Guérin, R., Brisson, D., et al. (2016) · Clinical Epigenetics · doi:10.1186/s13148-016-0239-9 · Cited by 98
“Through its interaction with the Cterminal binding protein 2 (CTBP2) transcriptional co-repressor, PRDM16 blocks the induction of the genes required for muscle cell or white adipocyte differentiation from myogenic factor 5-positive (MYF5+) (precursor brown adipocytes) or MYF5-negative (MYF5−) cells (likely precursors…”
BackgroundDeciphering adipose tissue heterogeneity
Lynes, M. D., & Tseng, Y. (2017) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13398 · Cited by 96
The origin, molecular regulation and therapeutic potential of myogenic stem cell populations
Otto, A., Collins‐Hooper, H., & Patel, K. (2009) · Journal of Anatomy · doi:10.1111/j.1469-7580.2009.01138.x · Cited by 94
“PRDM16 drives the brown fat lineage through forming a transcriptional complex with C-terminal binding protein 1 or 2, whereby it acts to repress white fat-specific genes, or complexing with PGC1-a, and PGC1-b whereby it enhances expression of brown fat genes (Kajimura et al. 2008).”
BackgroundShinoda, K., Ohyama, K., Hasegawa, Y., Chang, H., Ogura, M., Sato, A., Hong, H., Hosono, T., Sharp, L. Z., Scheel, D. W., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.09.029 · Cited by 94
“The beige adipocytes express high levels of Ucp1 and Pgc1a expression in response to cAMP stimuli, and low levels of WAT-selective genes (Kajimura et al., 2008).”
BackgroundSelf-citationIida, S., Chen, W., Nakadai, T., Ohkuma, Y., & Roeder, R. G. (2015) · Genes & Development · doi:10.1101/gad.252809.114 · Cited by 96
“…several transcription activators and cofactors that include PPARg (Seale et al. 2008), C/EBPb (Kajimura et al. 2009), and PGC-1a (Seale et al. 2007; Kajimura et al. 2008), and roles for ZF1 in C/EBPb-related (Kajimura et al. 2009) and EHMT1-related (Ohno et al. 2013) adipogenic functions have been…”
BackgroundInfluentialZeng, X., Jedrychowski, M. P., Chen, Y., Serag, S., Lavery, G. G., Gygi, S. P., & Spiegelman, B. M. (2016) · Genes & Development · doi:10.1101/gad.285312.116 · Cited by 93
“Consistent with this, PRDM16 was found to physically associate with the transcriptional corepressors CTBP1 and CTBP2, and its ability to repress some WAT-selective genes in adipocytes is dependent on these corepressors (Kajimura et al. 2008).”
BackgroundSelf-citation
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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