snRNA-seq reveals a subpopulation of adipocytes that regulates thermogenesis

Sun, Wenfei; Dong, Hua; Baláž, Miroslav; Slyper, Michal; Drokhlyansky, Eugene; Colleluori, Georgia; Giordano, Antonio; Kovaničová, Zuzana; Štefanička, Patrik; Balážová, Lucia; Ding, Lianggong; Husted, Anna Sofie; Rudofsky, Gottfried; Ukropec, Jozef; Cinti, Saverio; Schwartz, Thue W.; Regev, Aviv; Wolfrum, Christian

doi:10.1038/s41586-020-2856-x

Cited by 233 publications

(176 citation statements)

References 54 publications

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“…In summary, we present a multidimensional reanalysis at a single-nucleus resolution, which allows the recovery of nuclei of cell types in adipose tissue. Using this tool, it was possible to show the plasticity of adipocytes, which corroborates with recent data from AT snRNAseq (Rajbhandari et al, 2019; Sun et al, 2020). In addition to the presence of thermogenic adipocytes subpopulation positive for UCP-1 (Ad1- Ucp1 High ), additional transcriptome analyses allowed us to infer the presence of different secretory functions under thermogenic challenges activated metabolic pathways, especially those related to the futile cycle.…”

Section: Resultssupporting

confidence: 86%

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Multidimensional Single-Nuclei RNA-Seq Reconstruction of Adipose Tissue Reveals Adipocyte Plasticity Underlying Thermogenic Response

Biagi

Cury

Alves

et al. 2021

Preprint

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Adipose tissue has been classified based on its morphology and function as white, brown, or beige / brite. It plays an essential role as a regulator of systemic metabolism through paracrine and endocrine signals. Recently, multiple adipocyte subtypes have been revealed using RNA sequencing technology, going beyond simply defined morphology but by their cellular origin, adaptation to metabolic stress, and plasticity. Here, we performed an in-depth analysis of publicly available single-nuclei RNAseq from adipose tissue and utilized a workflow template to characterize adipocyte plasticity, heterogeneity, and secretome profiles. The reanalyzed dataset led to the identification of different subtypes of adipocytes including three subpopulations of thermogenic adipocytes and provided a characterization of distinct transcriptional profiles along the adipocyte trajectory under thermogenic challenges. This study provides a useful resource for further investigations regarding mechanisms related to adipocyte plasticity and trans-differentiation.

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Section: Resultssupporting

confidence: 86%

“…Recently, snRNA-seq analysis of the WAT identified a rare subpopulation of adipocytes in mice that increase in abundance at higher temperatures. This subpopulation regulates the activity of neighboring adipocytes through acetate-mediated modulation of their thermogenic capacity (Sun et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Multidimensional Single-Nuclei RNA-Seq Reconstruction of Adipose Tissue Reveals Adipocyte Plasticity Underlying Thermogenic Response

Biagi

Cury

Alves

et al. 2021

Preprint

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“…A key element of healthy adipose tissue expansion is de novo differentiation of adipocytes rather than storage of fat in already existing adipocytes 4,5 . However, recent data indicate the existence of multiple white [6][7][8][9] and brown 10,11 adipocyte subtypes that originate from distinct precursor populations. Thus, the type of de novo differentiating adipocytes could strongly affect the metabolic response of the organism to weight gain, as lipid storage capacity, as well as adipokine production differs between white adipocyte subtypes [6][7][8][9] .…”

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confidence: 99%

Asc-1 regulates white versus beige adipocyte fate in a subcutaneous stromal cell population

et al. 2021

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Adipose tissue expansion, as seen in obesity, is often metabolically detrimental causing insulin resistance and the metabolic syndrome. However, white adipose tissue expansion at early ages is essential to establish a functional metabolism. To understand the differences between adolescent and adult adipose tissue expansion, we studied the cellular composition of the stromal vascular fraction of subcutaneous adipose tissue of two and eight weeks old mice using single cell RNA sequencing. We identified a subset of adolescent preadipocytes expressing the mature white adipocyte marker Asc-1 that showed a low ability to differentiate into beige adipocytes compared to Asc-1 negative cells in vitro. Loss of Asc-1 in subcutaneous preadipocytes resulted in spontaneous differentiation of beige adipocytes in vitro and in vivo. Mechanistically, this was mediated by a function of the amino acid transporter ASC-1 specifically in proliferating preadipocytes involving the intracellular accumulation of the ASC-1 cargo D-serine.

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“…Suppression of certain brown or white pathway genes (indirect regulation of thermogenesis by getting rid of interfering proteins) may result in more decisive physiological consequences in contrast to differentially upregulating processes. For example, a recent study using single nucleus RNA sequencing was able to identify a rare population of cells in brown and white adipose tissues that express the enzyme that negatively regulates thermogenesis, and it suggests that downregulation of ALDH1A1 is required for heat-producing adipocyte phenotype (38). Taken together, most of the well-known brown marker-genes that seems to be required for the thermogenic brown adipocyte state may be essential for proper differentiation too, although, at a moderate level, which fits well with the previously demonstrated phenomenon that the cafeteria diet induces adipocyte thermogenesis in addition to differentiation (39)Their amount may affect browning capacity and promote hyperplasia, while a bit paradoxically, the thermogenic state may be induced through broad gene repression processes.…”

Section: Discussionmentioning

confidence: 99%

“…By network analyses we can explore the biological processes, signaling pathways and key proteins that may become important in thermogenesis from a different perspective. Growing evidence indicates that mouse and adult human BAT (Brown Adipose Tissue) have high heterogeneity (8,38,40) and plasticity (41-43) as a response to external cues that makes characterization a challenge, and may give contradictory results (10,11). Generally, the presence of proteins and their interaction in cells is highly dynamic and with the expanded gene set we can explore all possible interactions of the protein network and identify molecular signatures and pathways that potentially play a role in thermogenesis, but otherwise conditional dependent and therefore hard to catch.…”

Section: Discussionmentioning

confidence: 99%

Regulatory Modules of Human Thermogenic Adipocytes: Functional Genomics of Meta-Analyses Derived Marker-Genes

Barta

Fésüs

2021

Preprint

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SummaryRecently, ProFAT and BATLAS scores have been offered to determine thermogenic status of adipocytes using expression pattern of brown and white marker-genes. In this work, we investigated the functional context of these genes. Although the two meta-analyses based marker-gene lists have little overlap, their enriched pathways show strong coincides suggesting they may better characterize adipocytes. We demonstrate that functional genomics of the annotated genes in common pathways enables an extended analysis of thermogenesis regulation, generates testable hypotheses supported by experimental results in human adipocytes with different browning potential and may lead to more global conclusions than single-state studies. Our results imply that different biological processes shape brown and white adipocytes with presumed transitional states. We propose that the thermogenic adipocyte phenotype require both repression of whitening and induction of browning. These simultaneous actions and hitherto unnoticed regulatory modules, such as the exemplified HIF1A that may directly act at UCP1 promoter, can set new direction in obesity research.HighlightsIntegrated pathways better characterize brown adipocytes than marker-genesDifferent processes shape the brown and white adipocyte phenotypesThermogenic phenotype may require simultaneous repression of whitening and induction of browningProtein network analyses reveals unnoticed regulatory modules of adipocyte phenotypeHIF1A may regulate thermogenesis by direct control of UCP1 gene-expressionGraphical Abstract

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snRNA-seq reveals a subpopulation of adipocytes that regulates thermogenesis

Cited by 233 publications

References 54 publications

Multidimensional Single-Nuclei RNA-Seq Reconstruction of Adipose Tissue Reveals Adipocyte Plasticity Underlying Thermogenic Response

Multidimensional Single-Nuclei RNA-Seq Reconstruction of Adipose Tissue Reveals Adipocyte Plasticity Underlying Thermogenic Response

Asc-1 regulates white versus beige adipocyte fate in a subcutaneous stromal cell population

Regulatory Modules of Human Thermogenic Adipocytes: Functional Genomics of Meta-Analyses Derived Marker-Genes

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