Systems-Genetics-Based Inference of a Core Regulatory Network Underlying White Fat Browning

Li, Yongguo; Schwalie, Petra; Bast‐Habersbrunner, Andrea; Mocek, Sabine; Russeil, Julie; Fromme, Tobias; Deplancke, Bart

doi:10.1016/j.celrep.2019.11.053

Cited by 11 publications

(15 citation statements)

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“…Supporting this hypothesis, Ctcflos KD evoked a major change in alternative splicing patterns of many genes involved in adipogenesis, lipid metabolism, mitochondrial function, and splicing, beyond the above‐described splice events (Fig 6Z). Roughly one third of the differentially spliced genes were identified as candidates for browning regulation in our previous study (Li et al, 2019a).…”

Section: Resultsmentioning

confidence: 99%

“…Primary preadipocytes and differentiated adipocytes ((w/o) rosiglitazone), isolated from inguinal white adipose tissue (iWAT) of five inbred mouse strains of varying browning propensity (evaluated based on Ucp1 transcript levels in RPKM (reads per kilobase per million mapped reads)). Mean values ± SD, n = 3 (biological replicates) (Data ref: Array Express E‐MTAB‐8344, 2019) (Data ref: Li et al, 2019b) were subjected to RNA sequencing to identify regulated long noncoding (lnc) RNAs. BPrincipal component analysis (PCA) of undifferentiated and differentiated adipocyte samples, n = 3 (biological replicates). CHierarchical clustering of the long noncoding transcriptome of undifferentiated and differentiated adipocyte samples, n = 3 (biological replicates), Euclidean distance. DHeatmap, displaying row‐wise centered log2 normalized counts. E, FVenn diagrams of positively and negatively regulated lncRNAs selected according to correlation with Ucp1 , regulation during differentiation and regulation by rosiglitazone treatment, n = 3 (biological replicates). GGO term analysis of different mRNA clusters derived from lncRNA–mRNA coexpression network (according to Bai et al, 2017) that point toward lncRNA‐associated cellular processes, hypergeometric test.…”

Section: Resultsmentioning

confidence: 99%

“…Adipose tissue‐specific ectopic expression and knockout of Prdm16 demonstrate that it is sufficient and required for browning of WAT with impact on whole body metabolism (Seale et al, 2011; Cohen et al, 2014). These core transcription factors, however, sketch only a rough frame of the regulatory network in brite adipogenesis that needs to be further specified in more depth (Li et al, 2019a).…”

Section: Introductionmentioning

confidence: 99%

“…To this end, comparative studies between mouse strains with naturally varying browning propensities provide a fruitful approach that allows to fade out general noise unveiling the key factors that determine the capacity for WAT browning (Li et al, 2019a). Different inbred mouse strains possess diverging capacities to recruit brite adipocytes in WAT in response to cold or β‐adrenergic receptor stimulation (Koza et al, 2000; Xue et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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LncRNA Ctcflos orchestrates transcription and alternative splicing in thermogenic adipogenesis

et al. 2021

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The recruitment of thermogenic brite adipocytes within white adipose tissue attenuates obesity and metabolic comorbidities, arousing interest in understanding the underlying regulatory mechanisms. The molecular network of brite adipogenesis, however, remains largely unresolved. In this light, long noncoding RNAs (lncRNAs) emerged as a versatile class of modulators that control many steps within the differentiation machinery. Leveraging the naturally varying propensities of different inbred mouse strains for white adipose tissue browning, we identify the nuclear lncRNA Ctcflos as a pivotal orchestrator of thermogenic gene expression during brite adipocyte differentiation. Mechanistically, Ctcflos acts as a pleiotropic regulator, being essential for the transcriptional recruitment of the early core thermogenic regulatory program and the modulation of alternative splicing to drive brite adipogenesis. This is showcased by Ctcflos-regulated gene transcription and splicing of the key browning factor Prdm16 toward the isoform that is specific for the thermogenic gene program. Conclusively, our findings emphasize the mechanistic versatility of lncRNAs acting at several independent levels of gene expression for effective regulation of key differentiation factors to direct cell fate and function.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

LncRNA Ctcflos orchestrates transcription and alternative splicing in thermogenic adipogenesis

et al. 2021

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“…For example, a muscle-specific promoter containing clusters of transcription factor binding sites resulted in a 400-fold increase in muscle-specific gene transcription, better than the ubiquitous promoter CMV. 99 Future studies can test the strategy of incorporating adipose-specific CRMs 100 to enhance transgene expression in adipose tissue.…”

Section: Main Textmentioning

confidence: 99%

Adipose Tissue: An Emerging Target for Adeno-associated Viral Vectors

Bates

Huang

Cao

2020

Molecular Therapy - Methods & Clinical Development

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Adipose tissue is one of the largest organs, playing important roles in physiology and pathologies of multiple diseases. However, research related to adeno-associated virus (AAV) targeting adipose tissue has been left far behind studies carried out in the liver, brain, heart, and muscle. Despite initial reports indicating poor performance, AAV-mediated gene delivery to adipose tissue has continued to rise during the past two decades. AAV8 and a novel engineered hybrid serotype, Rec2, have been shown to transduce adipose tissue more efficiently than other serotypes so far tested and have been applied in most of the in vivo studies. The Rec2 serotype displays high efficacy of gene transfer to both brown and white fat via local and systemic administration. This review summarizes the advances in developing AAV vectors with enhanced adipose tropism and restricting off-target transgene expression. We discuss the challenges and strategies to search for and generate novel serotypes with tropism tailoring for adipose tissue and develop AAV vector systems to improve adipose transgene expression for basic research and translational studies.

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6‐Gingerol induces browning of white adipose tissue to improve obesity through PI3K/AKT‐RPS6‐mediated thermogenesis pathway

Alhamoud

Ahmad

et al. 2023

Food Frontiers

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The browning of white fat has become a hot topic as it could help to lose weight and improve metabolic health. Therefore, this study aims to explore the in vivo browning or thermogenesis effect of 6‐gingerol (6G), a natural bioactive compound of ginger, and to clarify the underlying mechanism. The results showed that 6G limited weight gain, improved cold tolerance, and increased energy expenditure in high‐fat diet‐induced obese mice. Moreover, histological and immunohistochemical analysis revealed that 6G activated brown adipose tissue (BAT) and induced more beige cells in epididymal adipose tissue (eWAT). Meanwhile, eWAT browning was marked by appearance of multilocular lipid droplets, a higher level of uncoupling protein 1 (UCP1), and increased mitochondrial content. The potential molecular mechanism of eWAT browning was further investigated by RNA‐seq, qPCR, and western blot assays. Results indicated that 6G significantly induced the expression of beige and thermogenesis‐specific markers in eWAT and triggers thermogenesis mainly through a phosphoinositide 3‐kinase (PI3K) / protein kinase B (AKT)‐ribosomal protein S6 (RPS6) axis. Consistently, in vitro, data showed that pretreatment of primary white adipocytes with PI3K/AKT pathway inhibitor significantly counteracted the 6G‐induced effects. This study reveals, for the first time, that 6G induces browning in adipose tissue by modulating the PI3K/AKT‐RPS6 and thermogenesis pathways, thereby alleviating obesity.

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Systems-Genetics-Based Inference of a Core Regulatory Network Underlying White Fat Browning

Cited by 11 publications

References 70 publications

LncRNA Ctcflos orchestrates transcription and alternative splicing in thermogenic adipogenesis

LncRNA Ctcflos orchestrates transcription and alternative splicing in thermogenic adipogenesis

Adipose Tissue: An Emerging Target for Adeno-associated Viral Vectors

6‐Gingerol induces browning of white adipose tissue to improve obesity through PI3K/AKT‐RPS6‐mediated thermogenesis pathway

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