Köker Sahika Cingir, Tsokanos Foivos-Filippos, El-Merahbi Rabih, Jha Ankush Kumar, Cicatelli Karin, Weber Peter, Mhamane Amit, Kaltenecker Doris, Morigny Pauline, Loft Anne, Klepac Katarina, Maida Adriano, Molocea Claudia-Eveline, Hass Daniela, Vogl Elena Sophie, Alfaro Ana Jimena, Sun Wenfei, Zitzelsberger Horst, Unger Kristian, Szendrödi Julia, Li Yongguo, Diaz Mauricio Berriel, Wolfrum Christian, Bartelt Alexander, Herzig Stephan, Georgiadi Anastasia
Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich (HMGU), Neuherberg, Germany.
Joint Heidelberg-IDC Transnational Diabetes Program, Heidelberg University Hospital, Heidelberg, Germany.
FASEB J. 2025 Aug 15;39(15):e70886. doi: 10.1096/fj.202402993RRR.
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.
棕色脂肪组织（BAT）是一个关键的产热器官，其在响应寒冷环境温度和β-肾上腺素能刺激时的激活需要棕色脂肪细胞中NCOR/HDAC3共抑制复合物的正常功能。NCOR/HDAC3复合物很大且由多个组分组成，包括转导素β样1（TBL1）和TBL1相关蛋白1（TBLR1）。已证明肝细胞中TBL1的缺失和白色脂肪细胞中TBLR1的缺失会损害禁食和β-肾上腺素能诱导的脂肪分解。然而，它们在BAT产热中的作用仍然未知。在这里，我们报告，仅在棕色脂肪细胞中缺失TBLR1不会损害对长时间冷暴露的适应性产热反应。相反，同时缺失TBL1和TBLR1会抑制培养的小鼠棕色脂肪细胞中β-肾上腺素能诱导的脂肪分解和线粒体呼吸。UCP1-Cre介导的TBLR1和TBL1双缺失的转基因小鼠在长时间冷暴露期间表现出全身能量消耗减少、核心体温降低、BAT中单泡脂肪细胞的出现增加以及代谢和肌源性PRDM16靶基因的表达受到抑制。此外，我们提供了一些证据表明TBLR1和TBL1在棕色脂肪细胞中与HDAC3和PRDM16相互作用，这可能表明它们直接参与了PRDM16控制的转录程序。这些发现确定了TBLR1/TBL1复合物是BAT适应长时间寒冷和全身能量稳态的关键调节因子，揭示了共抑制复合物的上下文依赖性功能。
