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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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BackgroundWhole-exome sequencing identifies variants in invasive pituitary adenomas
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BackgroundThe Multi-zinc Finger Protein ZNF217 Contacts DNA through a Two-finger Domain
Nunez, N., Clifton, M. K., Funnell, A. P. W., Artuz, C. M., Hallal, S., Quinlan, K. G. R., Font, J. S., Vandevenne, M. S., Setiyaputra, S., Pearson, R. C. M., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.301234 · Cited by 36
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“In this respect, it is noteworthy that PRDM16 was suggested to augment PPARGC1a activity through replacing the corepressors COOH-terminal binding proteins (CtBPs) (30), with which p53 is known to interact (42).”
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“In addition, recent studies showed that active and hypermetabolic BAT exists in several regions of adult humans (23) and that white adipocytes can transdifferentiate into brown adipocytes and vice versa (24, 25).”
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“Consistent with this, Ucp1 mRNA expression was decreased by ∼92% in BAT from Ad-GsKO, whereas expression of Serpina3k, a relatively WAT-specific marker (16), was increased >10-fold (Fig.”
BackgroundFat tissues, the brite and the dark sides
Chen, Y., Pan, R., & Pfeifer, A. (2016) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-016-1884-8 · Cited by 36
“PRDM16 forms complexes with other regulatory factors including PPARγ, PGC-1α/β, euchromatic histone-lysine N-methyltransferase 1 (EHMT1), Cterminal-binding proteins (CtBPs), and early B cell factor-2 (EBF2) [20, 21, 30, 34, 41, 42].”
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“In addition, PRDM16 is identified as a highly expressed gene in brown fat tissue and drives a brown fat-selective transcriptional program [43,44].”
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“PRDM2 action in response to oestrogen levels, and PRDM16 function during brown fat specification (7,32,33).”
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Flouris, A. D., Dinas, P. C., Valente, A., Andrade, C. M. B., Kawashita, N. H., & Sakellariou, P. (2017) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2016-0048 · Cited by 37
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“Additionally, it has been suggested that PRDM16 binds to specific TFs linked to the promoters/enhancers of target genes, further guiding the recruitment of PGC1a or CtBPs to initiate the formation of a co-activator or a co-repressor complex (87).”
BackgroundEpigenetic interaction between UTX and DNMT1 regulates diet-induced myogenic remodeling in brown fat
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“…factors such as PR domain containing 16 (PRDM16), a master regulator of brown fat determination and uncoupled protein 1 (UCP1), a key regulator of brown fat thermogenesis (Ahmadian et al., 2011; Bostrom et al., 2012; Kajimura et al., 2008; Seale et al., 2008; Seale et al., 2011; Sun et al., 2011).”
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“The expression levels of the set of WAT-selective genes that were defined by Kajimura et al [30] were specifically examined in our microarray analyses (Additional file 6).”
BackgroundAdipocyte transdifferentiation and its molecular targets
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“It represses the expression of white adipocyte or skeletal muscle specific genes through regulated association with the C-terminal binding protein 1 (CtBP1) and CtBP2 (Farmer, 2008; Kajimura et al., 2008; Vernochet et al., 2009).”
BackgroundThermogenic adipocytes: lineage, function and therapeutic potential
Pollard, A., & Carling, D. (2020) · Biochemical Journal · doi:10.1042/bcj20200298 · Cited by 30
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“differentiation (37, 38); tumor progression locus 2 (Tpl2),”
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“Previous studies showed that the regulated docking of the CtBP proteins on PRDM16 protein controls the brown and white fat-selective gene programs [12]; further studies suggested that reduction of PRDM16 was associated with a large increase in the expression of myogenic genes, including myogenic differentiation antige…”
BackgroundHe, L., Jones, J. A., He, W., Bjork, B. C., Wen, J., & Dai, Q. (2021) · Development · doi:10.1242/dev.194670 · Cited by 27
“The PR domain-containing (PRDM) family protein PRDM16 is a key transcriptional regulator in diverse cell types (Aguilo et al., 2011; Chuikov et al., 2010; Kajimura et al., 2008).”
BackgroundGarcia, M. D. C., Pazos, P., Lima, L., & Diéguez, C. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19092569 · Cited by 27
“Of note, PRDM16 by its own or in association with other chromatin modifying enzymes, the carboxy-terminal binding proteins (CTBP1 and CTBP2), acts as major activator of the beige fat program [67].”
BackgroundLi, X., Wang, J., Jiang, Z., Guo, F., Soloway, P. D., & Zhao, R. (2015) · Gene · doi:10.1016/j.gene.2015.06.017 · Cited by 25
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“259 Furthermore, PRDM16 triggers the expression of genes involved in the 260 synthesis of proteins associated with the characteristics of brown adipocytes 261 [30-32].”
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“CtBP2, together with CtBP1, is involved in lipid metabolism and storage by forming a PRDM16/CtBP complex and mediating the repression of white fat genes cooperating with C/EBPa (Kajimura et al. 2008; Vernochet et al. 2009).”
BackgroundThermogenic Fat: Development, Physiological Function, and Therapeutic Potential
Brandão, B. B., Poojari, A., & Rabiee, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115906 · Cited by 25
“Transcriptional repressors such as Ctbp1 and Ctbp2 (90,146) suppress the WAT gene expression and promote the browning of WAT.”
BackgroundNishikata, I., Nakahata, S., Saito, Y., Kaneda‐Nakashima, K., Ichihara, E., Yamakawa, N., & Morishita, K. (2011) · Oncogene · doi:10.1038/onc.2011.132 · Cited by 24
“Moreover, MEL1/ PRDM16 also has two CIMs, PFDLT (aa588–592) and PLDLS (aa 616–620), and was reported to directly interact with a CtBP co-repressor complex on the promoter of white fat-specific genes (Kajimura et al., 2008).”
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“This gene recently is reported to be the principal regulator of brown adipocyte tissue formation and function [10,11].”
BackgroundBrown Fat Develops a Brite Future
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The Genetics of Brown Adipose Tissue
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Association of single nucleotide polymorphism Rs2236518 in PRDM16 gene with BMI in Chinese males
Yue, H., He, J., Ke, Y., Zhang, H., Wang, C., Hu, W., Gu, J., Fu, W., Hu, Y.-Q., Li, M., et al. (2013) · Acta Pharmacologica Sinica · doi:10.1038/aps.2012.201 · Cited by 23
Investigation of adipocyte proteome during the differentiation of brown preadipocytes
Kamal, A. H. M., Kim, W. K., Cho, K., Park, A., Min, J., Han, B., Park, S. G., Lee, S. C., & Bae, K. (2013) · Journal of Proteomics · doi:10.1016/j.jprot.2013.10.005 · Cited by 23
“The transcriptional regulation of brown adipocyte differentiation has been relatively well characterized with PRDM16 as the master regulator, which induces a complete program of brown fat differentiation, including the activation of thermogenic genes including UCP1 and PGC-1α [65–67].”
BackgroundEpigenetic dynamics of the thermogenic gene program of adipocytes
Yi, D., Nguyen, H. P., & Sul, H. S. (2020) · Biochemical Journal · doi:10.1042/bcj20190599 · Cited by 23
Control of Adipose Cell Browning and Its Therapeutic Potential
Lizcano, F., & Arroyave, F. (2020) · Metabolites · doi:10.3390/metabo10110471 · Cited by 23
“The formation of a repressor complex of PRDM16 with CtBP1 and CtBP2 reduces WAT adipogenesis [127].”
BackgroundAdipose tissue and age‑dependent insulin resistance: New insights into WAT browning (Review)
Wu, C., Yu, P., & Sun, R. (2021) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2021.4904 · Cited by 25
“For example, PGc‑1α expression levels, a co‑activator of PPARγ, were upregulated upon cold exposure.”
BackgroundInfluentialInter-organ regulation of adipose tissue browning
Wang, S., & Yang, X. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2420-x · Cited by 23
“One of these regulators is PRDM16 that is highly expressed in inguinal white fat relative to other white fat depots in mice and plays a key role in regulating the determination and activation of beige adipocytes [21, 56, 89, 110].”
BackgroundC-terminal binding protein: A metabolic sensor implicated in regulating adipogenesis
Jack, B. H. A., Pearson, R. C. M., & Crossley, M. (2011) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2011.01.017 · Cited by 22
Yu, H., Neale, G. A. M., Zhang, H., Lee, H. M., Ma, Z., Zhou, S., Forget, B. G., & Sorrentino, B. P. (2014) · Blood · doi:10.1182/blood-2013-10-534735 · Cited by 22
Transcriptional brakes on the road to adipocyte thermogenesis
Shao, M., & Gupta, R. K. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2018.05.010 · Cited by 22
“Likewise, PRMD16 interacts with CtBP1/2 to suppress the gene program characteristic of white adipocytes [57].”
BackgroundRepin1 maybe involved in the regulation of cell size and glucose transport in adipocytes
Ruschke, K., Illés, M., Kern, M., Klöting, I., Faßhauer, M., Schön, M. R., Kosacka, J., Fitzl, G., Kovacs, P. L., Stümvoll, M., et al. (2010) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2010.08.049 · Cited by 22
Klingenspor, M., Bast‐Habersbrunner, A., Bolze, F., Li, Y., Maurer, S., Schweizer, S., Willershäuser, M., & Fromme, T. (2017) · Springer eBooks · doi:10.1007/978-3-319-52031-5_4 · Cited by 21
Senese, R., Cioffi, F., Matteis, R. D., Petito, G., de Lange, P., Silvestri, E., Lombardi, A., Moreno, M., Goglia, F., & Lanni, A. (2019) · Cells · doi:10.3390/cells8030256 · Cited by 21
“Conversely, PRDM16 induces BAT-specific genes by associating with the transcriptional coactivators PGC-1α and PGC-1β [52].”
BackgroundYildiz, O., Downes, G. B., & Sagerström, C. G. (2019) · Neural Development · doi:10.1186/s13064-019-0129-x · Cited by 20
Mishra, B. K., Madhu, S. V., Aslam, M., Agarwal, V., & Banerjee, B. D. (2021) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2021.109115 · Cited by 20
Transcriptional repression of beige fat innervation via a YAP/TAZ-S100B axis
Huang, X., Li, X., Shen, H., Zhao, Y., Zhou, Z., Wang, Y., Yao, J., Xue, K., Wu, D., & Qiu, Y. (2023) · Nature Communications · doi:10.1038/s41467-023-43021-8 · Cited by 21
Gene expression changes in the secondary palate and mandible of Prdm16 −/− mice
Warner, D. R., Wells, J. P., Greene, R. M., & Pisano, M. (2012) · Cell and Tissue Research · doi:10.1007/s00441-012-1525-2 · Cited by 20
“PRDM16 is a member of a family of at least 16 structurally related proteins characterized by a PRDIBF1 and RIZ1 homologous domain (hence its abbreviation); it has two putative DNA-binding domains and might function as a transcriptional coactivator/repressor (Kajimura et al. 2008).”
InfluentialAlternative Splicing Regulates Prdm1/Blimp-1 DNA Binding Activities and Corepressor Interactions
Morgan, M. A., Mould, A. W., Li, L., Robertson, E. J., & Bikoff, E. K. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00174-12 · Cited by 20
“CtBP associations with numerous zinc finger proteins, including Prdm3 and Prdm16, have been characterized (27, 28).”
BackgroundYang, J., Yang, J., Wang, L., Moore, A. V., Liang, S. H., & Ran, C. (2017) · Scientific Reports · doi:10.1038/s41598-017-09018-2 · Cited by 20
““Browning”, a process of turning WAT into BAT (43-45) represents an exciting approach for converting “bad fat” to “good fat” (BAT and beige fat).”
BackgroundPRDM16 regulates smooth muscle cell identity and atherosclerotic plaque composition
Tan, J. M. E., Cheng, L., Calhoun, R. P., Weller, A. H., Drareni, K., Fong, S., Barbara, E., Lim, H., Xue, C., Winter, H., et al. (2025) · Nature Cardiovascular Research · doi:10.1038/s44161-025-00737-8 · Cited by 19
Self-citationStelmańska, E., Szrok-Jurga, S., & Świerczyński, J. (2014) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2014.11.017 · Cited by 19
“Although examining the effect of progesterone on adipose tissue differentiation was not an objective of this study, we decided to verify the effect of this hormone on PPARG (nuclear receptor prerequisite for the differentiation of adipocytes [32]) mRNA level in our experimental model.”
Generation of a multipurpose Prdm16 mouse allele by targeted gene trapping
Strassman, A., Schnütgen, F., Dai, Q., Jones, J. C., Gomez, A. C., Pitstick, L. D., Holton, N. E., Moskal, R., Leslie, E., von Melchner, H., et al. (2017) · Disease Models & Mechanisms · doi:10.1242/dmm.029561 · Cited by 18
“…gene trap mice can be used to dissect the function of Prdm16 in brown adipose differentiation, hematopoiesis or neurogenesis, just to name a few of the pleiotropic consequences of Prdm16 null mutations (Aguilo et al., 2011; Chuikov et al., 2010; Kajimura et al., 2008; Seale et al., 2008, 2007).”
Wu, F., Yang, X.-P., Hu, M., Shao, Q., Fang, K., Li, J.-B., Zhao, Y., Xu, L.-J., Zou, X., Lu, F.-E., et al. (2020) · Phytomedicine · doi:10.1016/j.phymed.2020.153258 · Cited by 19
Christian, M., & Parker, M. G. (2009) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjp035 · Cited by 21
Becerril, S., Rodrı́guez, A., Catalán, V., Sáinź, N., Ramírez, B., Gómez‐Ambrosi, J., & Frühbeck, G. (2012) · Physiological Genomics · doi:10.1152/physiolgenomics.00039.2012 · Cited by 18
“genic function and phenotype of BAT (25, 40), as well as Ucp3, which participates not only in lipid metabolism and defense against reactive oxygen species, but also in adaptive thermogenesis (45).”
BackgroundLeszczyński, P., Śmiech, M., Parvanov, E. D., Watanabe, C., Mizutani, K., & Taniguchi, H. (2020) · Cells · doi:10.3390/cells9122603 · Cited by 19
“(B) PRDM3/16 and FOG1/2 by interaction with CtBP or NuRD complex negatively regulate gene expression during cellular differentiation [15,61,74,167,168].”
BackgroundErythropoietin reduces fat mass in female mice lacking estrogen receptor alpha
Lee, J., Walter, M. F., Korach, K. S., & Noguchi, C. T. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101142 · Cited by 18
“In our study, in the female mice, EPO suppressed WAT-associated genes such as resistin, which is known to promote insulin resistance [65], Ednra, Psat1, Wdnm1-like protein, and Serpina3k [66,67], and EPO activated brown fat-specific mitochondrial protein and UCP1 protein”
BackgroundSelenium and selenoproteins in thermogenic adipocytes
Shimada, B. K., Watanabe, L. M., Swanson, S. M., Toh, P., & Seale, L. A. (2022) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2022.109445 · Cited by 19
Molecular targets for management of diabetes: Remodelling of white adipose to brown adipose tissue
Chand, S., Tripathi, A. S., Dewani, A. P., & Sheikh, N. W. A. (2024) · Life Sciences · doi:10.1016/j.lfs.2024.122607 · Cited by 18
Subash‐Babu, P., & Alshatwi, A. A. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.01.084 · Cited by 18
Transcriptional and epigenetic control of adipocyte remodeling during obesity
Barilla, S., Treuter, E., & Venteclef, N. (2021) · Obesity · doi:10.1002/oby.23248 · Cited by 20
“Furthermore, PRDM16 represses the expression of resistin by interacting with the corepressor Cterminal- binding protein 1 and 2, whereas the recruitment of PGC1α to PRDM16 displaces Cterminal- binding protein, allowing PRDM16 to activate the expression of brown fat genes (78).”
Backgroundβ-arrestin-1 contributes to brown fat function and directly interacts with PPARα and PPARγ
Wang, C., Zeng, X., Zhou, Z., Zhao, J., & Pei, G. (2016) · Scientific Reports · doi:10.1038/srep26999 · Cited by 18
“Meanwhile, PPAR γ promotes and maintains the stable differentiation of brown adipocyte in cooperation with diverse cofactors such as C/EBPs and PRDM16 30 .”
Ablation of Prdm16 and beige fat identity causes vascular remodeling and elevated blood pressure
Koenen, M., Becher, T., Pagano, G., Gaudio, I. D., Barrero, J. A., Montezano, A. C. I., Ortiz, J. R., Lin, Z., Gómez-Banoy, N., Amblard, R., et al. (2026) · Science · doi:10.1126/science.ady8644 · Cited by 20
Androgen Receptor is a Negative Regulator of PRDM16 in Beige Adipocyte
Zhao, S., Nie, T., Li, L., Long, Q., Gu, P., Zhang, Y., Sun, W., Lin, Z., Liu, Q., Qi, Y., et al. (2023) · Advanced Science · doi:10.1002/advs.202300070 · Cited by 18
Lactate shuttling drives the browning of white adipose tissue after burn
Barayan, D., Abdullahi, A., Knuth, C. M., Khalaf, F., Rehou, S., Screaton, R. A., & Jeschke, M. G. (2023) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00084.2023 · Cited by 18
The thermogenic circuit: Regulators of thermogenic competency and differentiation
Lynes, M. D., & Tseng, Y. (2015) · Genes & Diseases · doi:10.1016/j.gendis.2015.03.001 · Cited by 18
“These two proteins are known to further recruit histone deacetylase enzymes to modify chromatin.(57,58) Moreover, the PRDM16 complex also contains the protein euchromatic histone-lysine Nmethyltransferase 1 (EHMT1) which is required to suppress myogenic differentiation of precursor cells by methylating histones associ…”
Background
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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