The <scp>TBLR1</scp> / <scp>TBL1</scp> Co‐Factor Complex Acts as a Transcriptional Checkpoint in the Brown Adipose Tissue Response to Prolonged Cold Exposure

Brown adipose tissue (BAT) is a key thermogenic organ, whose activation in response to cold environmental temperatures and β-adrenergic stimulation requires the proper function of the NCOR/HDAC3 corepressor complex in brown adipocytes. The NCOR/HDAC3 complex is large and multi-component, including the transducin beta-like 1 (TBL1) and TBL1-related 1 (TBLR1) proteins. Loss of TBL1 in the hepatocytes and TBLR1 in the white adipocytes has been shown to impair fasting- and β-adrenergic-induced lipolysis. However, their roles in BAT thermogenesis remain unknown. Here, we report that deletion of TBLR1 alone in brown adipocytes does not impair the adaptive thermogenic response to prolonged cold exposure. In contrast, simultaneous deletion of TBL1 and TBLR1 dampens β-adrenergic-induced lipolysis and mitochondrial respiration in cultured mouse brown adipocytes. Transgenic mice with UCP1-Cre mediated double deletion of TBLR1 and TBL1 exhibit reduced whole-body energy expenditure during prolonged cold exposure, lower core body temperature, increased appearance of unilocular adipocytes in BAT, and suppressed expression of metabolic and myogenic PRDM16 target genes. Also, we present some evidence that TBLR1 and TBL1 interact with HDAC3 and PRDM16 in brown adipocytes, potentially suggesting a direct involvement in the PRDM16-controlled transcriptional program. These findings identify the TBLR1/TBL1 complex as a critical regulator of BAT adaptation to prolonged cold and systemic energy homeostasis, shedding light on the context-dependent functions of corepressor complexes.

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Journal
The FASEB Journal
Published
2025-08-11
DOI
https://doi.org/10.1096/fj.202402993rrr
Primary Topic
Adipose Tissue and Metabolism
Type
article
Field-Weighted Citation Impact
0.00

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article

The TBLR1 / TBL1 Co‐Factor Complex Acts as a Transcriptional Checkpoint in the Brown Adipose Tissue Response to Prolonged Cold Exposure

Alexander Bartelt, Wenfei Sun, Katarina Klepac, Daniela Hass et al.
The FASEB Journal
Adipose Tissue and Metabolism
article

The TBLR1 / TBL1 Co‐Factor Complex Acts as a Transcriptional Checkpoint in the Brown Adipose Tissue Response to Prolonged Cold Exposure

Alexander Bartelt, Wenfei Sun, Katarina Klepac, Daniela Hass, Amit Mhamane, Elena Sophie Vogl, Christian Wolfrum, Rabih El‐Merahbi, Ana Jimena Alfaro, Foivos‐Filippos Tsokanos, Julia Szendrödi, Doris Kaltenecker, Mauricio Berriel Díaz, Pauline Morigny, Yongguo Li, Horst Zitzelsberger, Anastasia Georgiadi, Sultan Aydın Köker, Stephan Herzig, Claudia‐Eveline Molocea, Adriano Maida, K. Unger, Anne Loft, Peter Weber, A. Jha, Karin Cicatelli
article en

Abstract

Brown adipose tissue (BAT) is a key thermogenic organ, whose activation in response to cold environmental temperatures and β-adrenergic stimulation requires the proper function of the NCOR/HDAC3 corepressor complex in brown adipocytes. The NCOR/HDAC3 complex is large and multi-component, including the transducin beta-like 1 (TBL1) and TBL1-related 1 (TBLR1) proteins. Loss of TBL1 in the hepatocytes and TBLR1 in the white adipocytes has been shown to impair fasting- and β-adrenergic-induced lipolysis. However, their roles in BAT thermogenesis remain unknown. Here, we report that deletion of TBLR1 alone in brown adipocytes does not impair the adaptive thermogenic response to prolonged cold exposure. In contrast, simultaneous deletion of TBL1 and TBLR1 dampens β-adrenergic-induced lipolysis and mitochondrial respiration in cultured mouse brown adipocytes. Transgenic mice with UCP1-Cre mediated double deletion of TBLR1 and TBL1 exhibit reduced whole-body energy expenditure during prolonged cold exposure, lower core body temperature, increased appearance of unilocular adipocytes in BAT, and suppressed expression of metabolic and myogenic PRDM16 target genes. Also, we present some evidence that TBLR1 and TBL1 interact with HDAC3 and PRDM16 in brown adipocytes, potentially suggesting a direct involvement in the PRDM16-controlled transcriptional program. These findings identify the TBLR1/TBL1 complex as a critical regulator of BAT adaptation to prolonged cold and systemic energy homeostasis, shedding light on the context-dependent functions of corepressor complexes.

The FASEB JournalVol. 39(15)
German Cancer Research Center (DE), Heidelberg University (DE), Board of the Swiss Federal Institutes of Technology (CH), University Hospital Bonn (DE), University Hospital Heidelberg (DE), Helmholtz Zentrum München (DE), Institute for Sports Medicine (DE), Comprehensive Cancer Center Mainfranken (DE), Translational Research in Oncology (FR), Gesellschaft für Hochschulforschung (DE), German Centre for Cardiovascular Research (DE), Diabetesinstitut Heidelberg (DE), Else Kröner-Fresenius-Stiftung (DE), Deutsches Diabetes-Zentrum e.V. (DE), German Center for Diabetes Research (DE), Deutsches Konsortium für Translationale Krebsforschung (DE), Heinrich Heine University Düsseldorf (DE), Tumkur University (IN), Technical University of Munich (DE), Ludwig-Maximilians-Universität München (DE)
Deutsches Zentrum für Herz-Kreislaufforschung, Deutscher Akademischer Austauschdienst, Deutsche Forschungsgemeinschaft, Austrian Science Fund
Openalex Percentile: Top 74%
Adipose Tissue and Metabolism
DOIOpen Access PDFOpenAlex
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