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The TBLR1/TBL1 co-factor complex acts as a transcriptional checkpoint in the brown adipose tissue response to prolonged cold exposure

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 found that TBLR1 and TBL1 interact with HDAC3 and PRDM16 in brown adipocytes, suggesting a direct involvement in PRDM16-controlled transcriptional program. These findings identify 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE298802 | GEO | 2025/08/02

REPOSITORIES: GEO

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Project description:Objective Brown adipose tissue (BAT) plays an important role in mammalian thermogenesis through the expression of uncoupling protein 1 (UCP1). Our previous study identified cytoplasmic polyadenylation element binding protein 2 (CPEB2) as a key regulator that activates the translation of Ucp1 with a long 3′-untranslated region (Ucp1L) in response to adrenergic signaling. Mice lacking CPEB2 or Ucp1L exhibited reduced UCP1 expression and impaired thermogenesis; however, only CPEB2-null mice displayed obesogenic phenotypes. Hence, this study aims to investigate how CPEB2-controlled translation impacts body weight. Methods Body weight measurements were conducted on mice with global knockout (KO) of CPEB2, UCP1 or Ucp1L, as well as those with conditional knockout of CPEB2 in neurons or adipose tissues. RNA sequencing coupled with bioinformatics analysis was used to identify dysregulated gene expression in CPEB2-deficient BAT. The role of CPEB2 in regulating PRD1-BF1-RIZ1 homologous-domain containing 16 (PRDM16) expression was subsequently confirmed by RT-qPCR, Western blotting, polysomal profiling and luciferase reporter assays. Adeno-associated viruses (AAV) expressing CPEB2 or PRDM16 were delivered into BAT to assess their efficacy in mitigating weight gain in CPEB2-KO mice. Results We validated that defective BAT function contributed to the increased weight gain in CPEB2-KO mice. Transcriptomic profiling revealed upregulated expression of genes associated with muscle development in CPEB2-KO BAT. Given that both brown adipocytes and myocytes stem from myogenic factor 5-expressing precursors, with their cell-fate differentiation regulated by PRDM16, we identified that Prdm16 was translationally upregulated by CPEB2. Ectopic expression of PRDM16 in CPEB2-deprived BAT restored gene expression profiles and decreased weight gain in CPEB2-KO mice. Conclusions In addition to Ucp1L, activation of Prdm16 translation by CPEB2 is critical for sustaining brown adipocyte function. These findings unveil a new layer of post-transcriptional regulation governed by CPEB2, fine-tuning thermogenic and metabolic activities of brown adipocytes to control body weight.

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The TBLR1/TBL1 co-factor complex acts as a transcriptional checkpoint in the brown adipose tissue response to prolonged cold exposure

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