Single cell analysis reveals immune cell–adipocyte crosstalk regulating the transcription of thermogenic adipocytes

Rajbhandari, Prashant; Arneson, Douglas; Hart, Sydney K; Ahn, In Sook; Diamante, Graciel; Santos, Leonardo D.; Zaghari, Nima; Feng, An‐Chieh; Thomas, Brandon J.; Vergnes, Laurent; Lee, Stephen D.; Rajbhandari, Abha K.; Reue, Karen; Smale, Stephen T.; Yang, Xia; Tontonoz, Peter

doi:10.7554/elife.49501

Cited by 131 publications

(114 citation statements)

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“…Expansion of brown adipose tissue (BAT) and increased appearance of beige adipocytes in inguinal white adipose tissue (iWAT) of mice and humans during cold exposure is associated with remodeling of tissue architecture [8][9][10] , and is controlled by activation of local sympathetic nerve fiber (SNF) activity [11][12][13][14] . Single cell RNA transcriptomic analysis has corroborated the extensive cellular heterogeneity of adipose depots and identified various resident immune cells and other cell types that are present [15][16][17][18][19][20] . Moreover, the association between increased abundance of iWAT macrophages with anti-inflammatory, alternatively activated properties and cold-induced adipose remodeling has been demonstrated 15,[21][22][23] .…”

Section: Introductionmentioning

confidence: 94%

“…2) and cell autonomous effects also appear not to play a major role 34 , we hypothesized that other adipose resident cell types may be targets of FASN-deficient adipocyte signals. We therefore applied single cell RNA-seq, a powerful technique to identify cell types and their mRNA expression profiles within complex tissues including adipose tissues from cold exposed mice 15,19,20,50 , to this question. The stromal vascular fractions (SVF) of iWAT from control and iAdFASNKO mice were isolated and subjected to RNA-seq analysis (see single cell RNA-seq workflow for more details related to the protocol in Extended Data Fig.…”

Section: Nrg4 Deficiency Attenuates Cold-induced But Not Iadfasnko-inmentioning

confidence: 99%

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Single Cell RNA Profiling Reveals Adipocyte to Macrophage Signaling Sufficient to Enhance Thermogenesis

Henriques

Bedard

Guilherme

et al. 2020

Preprint

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The "browning" of inguinal white adipose tissue (iWAT) through increased abundance of thermogenic beige/brite adipocytes is induced by cold exposure and many other perturbations in association with beneficial systemic metabolic effects.Adipose browning is reported to require activation of sympathetic nerve fibers (SNF), aided by alternately activated macrophages within iWAT. Here we demonstrate the first example of a non-cell autonomous pathway for iWAT browning that is fully independent of SNF activity. Thus, the strong induction of thermogenic adipocytes prompted by deletion of adipocyte fatty acid synthase (iAdFASNKO mice) was unaffected by denervation or the deletion of SNF modulator Neuregulin-4. However, browning of iWAT in iAdFASNKO mice does require adipocyte cAMP/protein kinase A signaling, as it was blocked in adipocyteselective Fasn/Gsa double KO mice. Single-cell transcriptomic analysis of iAdFASNKO mouse adipose stromal cells revealed increased macrophages displaying gene expression signatures of the alternately activated type.Mechanistically, depletion of such phagocytic immune cells in iAdFASNKO mice fully abrogated appearance of thermogenic adipocytes in iWAT. Altogether, these findings reveal an unexpected pathway of cAMP/PKA-dependent iWAT browning that is initiated by adipocyte signals and caused by macrophage-like cells independent of sympathetic neuron involvement.

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Section: Introductionmentioning

confidence: 94%

Section: Nrg4 Deficiency Attenuates Cold-induced But Not Iadfasnko-inmentioning

confidence: 99%

Single Cell RNA Profiling Reveals Adipocyte to Macrophage Signaling Sufficient to Enhance Thermogenesis

Henriques

Bedard

Guilherme

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…WAT heterogeneity in mice has recently been revealed by scRNA-seq (Burl et al, 2018;Hepler et al, 2018;Schwalie et al, 2018;Cho et al, 2019;Merrick et al, 2019;Rajbhandari et al, 2019). We then profiled the expression of newly-identified white adipocyte progenitor marker genes (Rondini and Granneman, 2020) in human BAT stromal cells.…”

Section: Identification Of Conserved Markers For Brown Adipose Progenmentioning

confidence: 99%

“…Within the adipose tissue, adipocyte stem/progenitor cells and committed preadipocytes reside in the stromal vascular fraction (SVF) and normally express lineage-negative markers including PDGFRα, DLK1, CD34, SCA1, CD29, and CD24 (Rodeheffer et al, 2008;Schulz et al, 2011;Berry and Rodeheffer, 2013). Profiling of the SVF cells from WAT depots at the single-cell level has revealed a developmental hierarchy of white adipocyte precursors (Burl et al, 2018;Hepler et al, 2018;Schwalie et al, 2018;Cho et al, 2019;Merrick et al, 2019;Rajbhandari et al, 2019). However, the cellular heterogeneity and differentiation trajectory of brown adipose precursors have not been defined yet.…”

Section: Introductionmentioning

confidence: 99%

Loss of FSTL1-expressing adipocyte progenitors drives the age-related involution of brown adipose tissue

Huang

Zhang

Heck

et al. 2020

Preprint

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In humans, brown adipose tissue (BAT) undergoes progressive involution or atrophy with increasing age, as manifested by decreased prevalence and mass, transformation to white adipose tissue (WAT), and reduction in thermogenic activity. This involution process cannot be fully recapitulated in rodent models and thus underlying cellular mechanisms are poorly understood. Here, we show that the interscapular BAT (iBAT) in rabbits involutes rapidly in early life, similarly to that in humans. The transcriptomic remodeling and identity switch of mature adipocytes are accompanied with the loss of brown adipogenic competence of their precursor cells. Through single-cell RNA sequencing, we surveyed the heterogenous populations of mesenchymal cells within the stromal vascular fraction of rabbit and human iBAT. An analogous FSTL1 high population of brown adipocyte progenitors exists in both species while gradually disappear during iBAT involution in rabbits. In mice, FSTL1 is highly expressed by adipocyte progenitors in iBAT and genetic deletion of FSTL1 causes defective WNT signaling and iBAT atrophy in neonates. Our results underscore the BAT-intrinsic contribution from FSTL1 high progenitors to age-related tissue involution and point to a potential therapeutic approach for obesity and its comorbidities. HIGHLIGHTS• Rabbit BAT irreversibly transforms to WAT before puberty.• iBAT adipocyte progenitors reprogram transcriptome and lose brown adipogenic ability.• Comparable FSTL1 high brown adipocyte progenitors exist in rabbit and human iBAT.• Loss of FSTL1 in brown adipocyte progenitors causes iBAT atrophy in mice.

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“…68They arise from specific precursor cells, distinct from white adipocytes (Shinoda et al, 2015; Wu et al, 69 2012; Xue et al, 2015), but more recent data demonstrated a continuum in the expression 70 pattern (Altshuler-Keylin et al, 2016;Shao et al, 2019). Additional studies identified four distinct 71 human adipocyte subtypes differentially associated with thermogenesis and/or lipid storage (Min et al, 72 2019), and a recent study demonstrated the presence of brown adipocytes in mice with different 73 thermogenic activities in vivo , while another report showed immune cells and 74 adipocyte interaction via Il-10 using single-nucleus RNA-Seq (snRNA-seq) (Rajbhandari et al, 2019). 75…”

mentioning

confidence: 99%

Single-nucleus RNA-Seq reveals a new type of brown adipocyte regulating thermogenesis

Sun

Dong

Baláž

et al. 2020

Preprint

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31Adipose tissue usually is classified as either white, brown or beige/brite, based on whether it functions 32 as an energy storage or thermogenic organ (Cannon and Nedergaard, 2004; Rosen and Spiegelman, 33 2014). It serves as an important regulator of systemic metabolism, exemplified by the fact that 34 dysfunctional adipose tissue in obesity leads to a host of secondary metabolic complications such as 35 diabetes, cardiovascular diseases and cancer (Hajer et al., 2008;Lauby-Secretan et al., 2016). In addition, 36 adipose tissue is an important endocrine organ, which regulates the function of other metabolic tissues 37 through paracrine and endocrine signals (Scheele and Wolfrum, 2019;Scherer, 2006). Work in recent 38 years has demonstrated that tissue heterogeneity is an important factor regulating the functionality of 39 various organs (Cao et al., 2017;Ginhoux et al., 2016;Park et al., 2018). Here we used single nucleus 40 analysis in mice and men to deconvolute adipocyte heterogeneity. We are able to identify a novel 41 subpopulation of adipocytes whose abundance is low in mice (2-8%) and which is increased under 42 higher ambient temperatures. Interestingly, this population is abundant in humans who live close to 43 thermoneutrality. We demonstrate that this novel adipocyte subtype functions as a paracrine cell 44 regulating the activity of brown adipocytes through acetate-mediated regulation of thermogenesis. These 45 findings could explain, why human brown adipose tissue is substantially less active than mouse tissue 46 and targeting this pathway in humans might be utilized to restore thermogenic activity of this tissue. 47 Main text 49As one of the major endocrine tissues, the adipose organ is organized in different depots across the body 50 and is composed of two different types: brown adipose tissue (BAT) and white adipose tissue (WAT). 51Each is comprised of a heterogeneous cell pool, which can be stratified into two groups. First, the 52 functional cell pool of mature adipocytes, which represent 20 to 50% of the total cell content (Roh et al., 53 2018;Rosenwald et al., 2013), and second, the stromal vascular fraction (SVF), which includes 54 preadipocytes, mesenchymal stem cells, fibroblasts, macrophages, immune cells, endothelial cells and 55 vascular progenitors (Rosenwald and Wolfrum, 2014). 56 57The main parenchymal cells of the adipose organ are adipocytes, which encompass three major cell 58 types. White adipocytes store the energy taken up from the circulation into triacylglycerols. In contrast, 59 brown adipocytes, and a less thermogenic efficient-related population referred to as beige or brite 60 adipocytes, dissipate chemical energy in the form of heat to protect from cold temperature through non-61 shivering thermogenesis. This unique ability is enabled by the specific presence of uncoupling protein 62 1 (UCP1) in mitochondria (Jung et al., 2019). Notably, brown and beige/brite adipocytes share some 63 morphological, biochemical and thermogenic characteristics, such as multiple sma...

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Single cell analysis reveals immune cell–adipocyte crosstalk regulating the transcription of thermogenic adipocytes

Cited by 131 publications

References 52 publications

Single Cell RNA Profiling Reveals Adipocyte to Macrophage Signaling Sufficient to Enhance Thermogenesis

Single Cell RNA Profiling Reveals Adipocyte to Macrophage Signaling Sufficient to Enhance Thermogenesis

Loss of FSTL1-expressing adipocyte progenitors drives the age-related involution of brown adipose tissue

Single-nucleus RNA-Seq reveals a new type of brown adipocyte regulating thermogenesis

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