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Cellular Heterogeneity in Brown Adipose Tissue

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Cellular Heterogeneity in Brown Adipose Tissue Cellular heterogeneity in brown adipose tissue Yasuo Oguri, Shingo Kajimura J Clin Invest. 2020;130(1):65-67. https://doi.org/10.1172/JCI133786. Commentary Brown adipose tissue (BAT) contains mitochondria-enriched thermogenic fat cells (brown adipocytes) that play a crucial role in the regulation of energy metabolism and systemic glucose homeostasis. It was presumed that brown adipocytes are composed of a homogeneous cell population. In this issue of the JCI, however, Song and colleagues report a previously uncharacterized subpopulation of brown adipocytes that display distinct characteristics from the conventional brown adipocytes in their molecular signature, regulation, and fuel utilization. The present study provides novel insight into our understanding of cellular heterogeneity in adipose tissues. Find the latest version: https://jci.me/133786/pdf The Journal of Clinical Investigation COMMENTARY Cellular heterogeneity in brown adipose tissue Yasuo Oguri1,2,3 and Shingo Kajimura1,2,3 1UCSF Diabetes Center, San Francisco, California, USA. 2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, San Francisco, California, USA. 3Department of Cell and Tissue Biology, UCSF, San Francisco, California, USA. (scRNA-seq) technology and inducible lin- Brown adipose tissue (BAT) contains mitochondria-enriched thermogenic fat eage-tracing methods, the field has gained cells (brown adipocytes) that play a crucial role in the regulation of energy a momentum to better understand the cel- metabolism and systemic glucose homeostasis. It was presumed that brown lular heterogeneity in adipose tissues. adipocytes are composed of a homogeneous cell population. In this issue of In this issue of the JCI, Song et al. set the JCI, however, Song and colleagues report a previously uncharacterized out to characterize the cellular heterogene- ity in the interscapular BAT (10). First, the subpopulation of brown adipocytes that display distinct characteristics from authors employed the Adipo-Chaser sys- the conventional brown adipocytes in their molecular signature, regulation, tem, an inducible animal model in which and fuel utilization. The present study provides novel insight into our all the differentiated adiponectin-express- understanding of cellular heterogeneity in adipose tissues. ing (Adipoq-expressing) adipocytes were permanently labeled as LacZ+ cells follow- ing doxycycline administration (10, 11). The authors found that LacZ+ brown adipocytes Roles of brown adipose tissue homogeneous adipose cell populations. (Adipoq high-expressing cells) constituted Brown adipose tissue (BAT) contains However, it is becoming clear that each 38% of total brown adipocytes in the BAT numerous brown adipocytes with highly adipose tissue depot contains a variety at room temperature (24°C), whereas only enriched mitochondria and multilocular of fat cells, including brown adipocytes, 6% were LacZ+ cells under a thermoneutral lipid droplets, and possesses the remark- beige adipocytes, and white adipocytes, condition (30°C). Notably, cold exposure able capacity to dissipate energy in the that arise from distinct developmental ori- robustly increased the number of LacZ+ form of heat. Thus, BAT has been viewed gins (6, 7). Even within an adipose tissue cells (76% of total brown adipocytes at merely as a thermogenic organ for a long depot, recent studies indicate the exis- 6°C), although some cells remained LacZ– time; however, emerging evidence sug- tence of heterogeneous cell populations. (Adipoq low-expressing brown adipocytes). gests that the role of BAT is far more than For instance, Chen et al. recently described Further analyses by transmission electron thermogenesis (1). As an example, BAT a previously uncharacterized type of beige microscopy showed that these LacZ+ and functions as a significant metabolic sink adipocyte whose biogenesis is regulated LacZ– brown adipocytes were morphologi- for glucose, fatty acids, and branched- independently from the canonical β3- cally distinct in their lipid droplet size and chain amino acids (BCAAs), such that acti- adrenergic receptor (β3-AR) signaling (8). mitochondrial contents (Figure 1). The vation of BAT leads to a profound improve- This beige fat population stems from a dis- authors next investigated whether the dif- ment in systemic glucose homeostasis, tinct pool of progenitor cells and possesses ferences in the percentage of LacZ+ cells lipid homeostasis, and BCAA clearance a unique fuel utilization (e.g., glycolytic involve de novo adipogenesis or cell death. in rodents and humans (2–4). According- metabolism as opposed to fatty acid oxida- When mature adipocytes were derived ly, BAT biology has become a significant tion), and thus, these cells are termed gly- from prelabeled mice that were main- area of research in the field of metabolic colytic beige fat (or g-beige fat). Relative to tained at 24°C then subsequently pulse- disorders beyond obesity because a better beige adipocytes, brown adipocytes in the chased at 6°C or 30°C, the percentages of understanding of this organ may lead to interscapular BAT region were thought to LacZ+ brown adipocytes were comparable new interventions to improve metabolic be homogeneous, although Cinti’s group with mice that were consistently held at health, such as insulin resistance, dyslipid- has previously reported that BAT con- 24°C. Also, apoptosis signaling remained emia, and type 2 diabetes (5). tained two types of brown adipocytes that unchanged. These data suggest that there expressed high or low levels of uncoupling are two types of brown adipocytes, such Adipose cell heterogeneity — more protein 1 (UCP1) following cold expo- that adiponectin-high and adiponectin-low than brown, beige, and white sure or administration of a β3-AR ago- cells in the BAT are interconvertible with- The adipose tissue was once thought to be nist (CL316,243) (9). Owing to the recent out cell death following acclimation to cold a monolithic organ that was composed of advance in the single-cell RNA sequencing or thermoneutral conditions (10). Related Article: p. 247 Brown adipocytes with high versus low thermogenic Conflict of interest: The authors have declared that no conflict of interest exists. capacities Copyright: © 2020, American Society for Clinical Investigation. Is there any functional difference between Reference information: J Clin Invest. 2020;130(1):65–67. https://doi.org/10.1172/JCI133786. the two forms of brown fat cells? To address jci.org Volume 130 Number 1 January 2020 65 COMMENTARY The Journal of Clinical Investigation recruitment of Adipoq high-expressing brown adipocytes. On the other hand, the number of Adipoq high-expressing brown adipocytes declined gradually in aged mice (below 40% in 30-week-old and 20% in 60-week-old mice) relative to young mice (approximately 70% in 10-week-old mice). These results indicate that the ability of BAT to recruit Adipoq high-expressing cells following cold stim- uli declines with age (10). In conclusion, the present study by Song et al. elegantly demonstrates the existence of two subpopulations of brown adipocytes that possess unique molecular and metabolic features (10). Do they arise from distinct progenitor pools? While embryonic brown adipocytes in the inter- scapular BAT arise from a Myf5+ myogenic lineage (15), it remains unknown whether Myf5+ cells persist as a progenitor source for Adipoq high-expressing and/or low- expressing brown adipocytes in adult BAT. Another key question is: what are the mechanisms by which aging alters the cellular composition of BAT? A recent study reported that mitochondrial lipoy- lation in the BAT declines with age-asso- Figure 1. Two types of brown adipocytes in BAT. A population of brown adipocytes with low ther- ciated impairment in thermogenesis and mogenic activity and adiponectin expression coexists with brown adipocytes with high thermogenic fuel oxidation. Of note, supplementa- activity and adiponectin expression. tion of α-lipoic acids effectively restored BAT function, including thermogenesis and glucose oxidation, in aged mice (14). this question, Song et al. performed roles in the transcriptional regulation of Thus, it would be interesting to test how scRNA-seq in primary brown adipocytes each cell type. Importantly, cell respiration α-lipoic acid supplementation affects the and identified 2352 Adipoq high-expressing was higher in Adipoq high-expressing cells cellular composition of Adipoq high- and cells and 1250 Adipoq low-expressing cells. relative to that in low-expressing cells. low-expressing cells in aged BAT. A better In the Adipoq low-expressing cells, the These data collectively suggest that the understanding of the molecular mecha- authors found lower mRNA expression of two populations of brown adipocytes have nisms that underlie age-associated chang- genes related to oxidative phosphorylation, different cellular functions and metabolic es in BAT may lead to effective prevention β3-adrenergic receptor, lipolysis, glycoly- profiles in that Adipoq high-expressing or therapeutic measures for age-associat- sis, fatty acid oxidation, and the TCA cycle cells possess high thermogenic capacity ed metabolic disorders, including obesity, relative to those of their high-expressing while Adipoq low-expressing cells have low insulin resistance, and type 2 diabetes. counterparts. Similarly, the Adipoq low- thermogenic capacity (10). expressing brown adipocytes expressed Acknowledgments lower levels of genes involved in thermo- Aging affects the cellular We thank
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