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De novo reconstruction of human adipose reveals conserved lncRNAs as regulators of brown adipogenesis

ABSTRACT: Obesity has emerged as a formidable health crisis due to its association with metabolic risk factors such as diabetes, dyslipidaemia and hypertension. Recent work has demonstrated the multifaceted roles of lncRNAs in regulating mouse adipose development, but its implication in human adipocytes remain largely unknown at least partially due to the lack of a comprehensive lncRNA catalog, particularly those specifically expressed in brown adipose tissue (BAT). In this study, we performed deep RNA-seq on adult subcutaneous, omental and fetal brown adipose tissues to de novo construct a catalog of 3,149 adipose active lncRNAs of which 1,351 are specifically detected in BAT. We further identified 318 lncRNAs conserved between human and mouse which, compared with non-conserved ones, are more broadly expressed in multiple cell types. One of these, lnc-dPRDM16, is transcribed divergently from Prdm16, tightly correlated with Prdm16 (R ≥ 0.7) in both mouse and human, and co-expressed (R ≥ 0.7) with protein-coding genes enriched in lipid and fatty acid catabolic processes. Loss of function of lnc-dPRDM16 led to a down-regulation of Prdm16 and an obvious reduction of adipogenesis in brown adipocyte culture. Together, our work has provided a comprehensive human adipose catalog built from diverse fat types, which when applied to our roadmap, identifies lnc-dPRDM16 as a promising modulator of adipose development for future clinical research.

ORGANISM(S): Homo sapiens

PROVIDER: GSE97205 | GEO | 2018/04/16

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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De novo reconstruction of human adipose reveals conserved lncRNAs as regulators of brown adipogenesis

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