Unraveling the Developmental Roadmap toward Human Brown AdiposeTissue

Carobbio, Stefania; Guénantin, Anne-Claire; Bahri, Myriam; Rodríguez-Fdez, Sonia; Honig, Floris; Kamzolas, Ioannis; Samuelson, Isabella; Long, Kathleen; Awad, Sherine; Lukovic, Dunja; Erceg, Slaven; Bassett, Andrew; Mendjan, Sasha; Vallier, Ludovic; Rosen, Barry; Chiarugi, Davide; Vidal-Puig, António

doi:10.1016/j.stemcr.2021.03.009

Cited by 6 publications

(6 citation statements)

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“…This agrees with previous reports indicating that PCK1 mRNA is preferentially expressed in BAT versus WAT 24 and an early induced gene in human brown adipogenic differentiation. 25 The previous findings in brown/beige adipocytes and their precursors are therefore consistent with the present transcriptomics analysis on adipose tissue from pheochromocytoma patients.…”

Section: Resultssupporting

confidence: 92%

“… 35 We also assessed the time courses of transcriptomic changes during the brown adipogenic differentiation of human embryonic stem cells and inducible pluripotent stem cells. 25 This multi-omics comparison revealed that transcripts encoding components involved in forming pre-mRNP and spliceosomal complexes A, B, C, and E, as well as parts of the exon inclusion/exclusion machinery, were generally down-regulated during the in vitro differentiation of human cells into brown/beige adipocytes ( Figure 5 A). There was also a converse upregulation of some components involved in splicing regulation and the mRNA stabilization machinery (e.g., ELAVL3 and ELAVL4 ) across brown/beige differentiation in the studied cell culture models.…”

Section: Resultsmentioning

confidence: 94%

“… 35 GEO: GSE123385 Raw RNA-Sequencing data – H9 hESC and KOLF2-C1 iPS Carobbio et al. 25 GEO: GSE168387 Experimental models: Cell lines Human: Simpson-Golabi-Behmel syndrome (SGBS) cells ATCC RRID: CVCL_GS28; Cat#ATCC® PCS-210-010 Oligonucleotides TaqMan™ gene expression probes (see Table S7 for a complete list) Thermo Fisher Scientific See Table S7 Software and algorithms FastQC v0.11.8 Babraham Bioinformatics RRID: SCR_01458 ; https://www.bioinformatics.babraham.ac.uk/projects/fastqc/ Salmon v1.1.0 Patro et al. 60 RRID: SCR_017036 ; https://combine-lab.github.io/salmon/ DESeq2 v1.24.0 Love et al.…”

Section: Methodsmentioning

confidence: 99%

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Adipose tissue plasticity in pheochromocytoma patients suggests a role of the splicing machinery in human adipose browning

et al. 2023

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

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Adipose tissue plasticity in pheochromocytoma patients suggests a role of the splicing machinery in human adipose browning

et al. 2023

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“…5F-H ). Furthermore, the analysis of datasets on human stem cells differentiated into mature brown adipocytes[62] showed that the expression of Sema4B is regulated during adipogenesis ( Fig. 5I ), and that the treatment of adipocytes differentiated from human subclavicular BAT or abdominal subcutaneous WAT with NE[63] downregulates the expression of Sema4b ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The data in Figures 5I and J were replotted from publicly available data. The data for Figure 5I were replotted from data from an experiment in which two human pluripotent stem cell lines (H9 and KOLF2-C1) were differentiated into brown adipocytes [62]. The data in Figure 5J were obtained from a study in which human adipocytes were differentiated from SVF obtained from subcutaneous WAT and subclavicular BAT from human subjects [63].…”

Section: Methodsmentioning

confidence: 99%

Semaphorin 4B is an ADAM17-cleaved inhibitor of adipocyte thermogenesis

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et al. 2022

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Objective: The metalloprotease ADAM17 (also called TACE) plays fundamental roles in homeostasis by shedding key signaling molecules from the cell surface. Although its importance for the immune system and epithelial tissues is well-documented, little is known about the role of ADAM17 in metabolic homeostasis. The purpose of this study was to determine the impact of ADAM17 expression, specifically in adipose tissues, on metabolic homeostasis. Methods: We used histopathology, molecular, proteomic, transcriptomic, in vivo integrative physiological and ex vivo biochemical approaches to determine the impact of adipose tissue-specific deletion of ADAM17 upon adipocyte and whole organism metabolic physiology. Results: ADAM17adipoq-creΔ/Δ mice exhibited a hypermetabolic phenotype characterized by elevated energy consumption and increased levels of adipocyte thermogenic gene expression. On a high fat diet, these mice were more thermogenic, while exhibiting elevated expression levels of genes associated with lipid oxidation and lipolysis. This hypermetabolic phenotype protected mutant mice from obesogenic challenge, limiting weight gain, hepatosteatosis and insulin resistance. Activation of beta-adrenoceptors by the neurotransmitter norepinephrine, a key regulator of adipocyte physiology, triggered the shedding of ADAM17 substrates, and regulated ADAM17 expression at the mRNA and protein levels, hence identifying a functional connection between thermogenic licensing and the regulation of ADAM17. Proteomic studies identified Semaphorin 4B (SEMA4B), as a novel ADAM17-shed adipokine, whose expression is regulated by physiological thermogenic cues that acts to dampen thermogenic responses in adipocytes. Transcriptomic data showed that cleaved SEMA4B acts in an autocrine manner in brown adipocytes to dampen the expression of genes involved in thermogenesis, adipogenesis, lipid uptake, storage and catabolism. Conclusion: Our findings identify a novel ADAM17-dependent axis, regulated by beta-adrenoceptors and mediated by the ADAM17-cleaved form of SEMA4B, that may act to limit uncontrolled energy depletion during thermogenesis.

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