Low- and high-thermogenic brown adipocyte subpopulations coexist in murine adipose tissue

Song, Anying; Dai, Wenting; Jang, Min Jee; Medrano, Leonard; Li, Zhuo; Zhao, H.; Shao, Mengle; Tan, Jiayi; Li, Aimin; Ning, Tinglu; Miller, Marcia M.; Armstrong, Brian; Huss, Janice M.; Zhu, Yi; Liu, Yong; Gradinaru, Viviana; Wu, Xiwei; Jiang, Lei; Scherer, Philipp E.; Wang, Qiong A.

doi:10.1172/jci129167

Cited by 157 publications

(150 citation statements)

References 47 publications

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“…1A). However, as recently reported (27), immunofluorescence stainings of adult murine interscapular BAT revealed a mosaic of Ucp1 expression throughout the tissue (Fig. 1A).…”

Section: Scrnaseq Reveals Composition and Heterogeneity Within The Stsupporting

confidence: 84%

“…The heterogeneous response of murine BAT in response to changes in ambient temperature further supports functional or developmental heterogeneity among brown adipocytes within one depot. This was recently supported by Song and colleagues, who identified using genetic lineage tracing, scRNAseq and other methods, the presence of Ucp1 low and high murine brown adipocyte subtypes within interscapular brown adipose tissue (27).…”

Section: Introductionmentioning

confidence: 73%

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Identification and characterization of distinct murine brown adipocyte lineages

Karlina

Lutter

Miok

et al. 2020

Preprint

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Brown adipose tissue (BAT) plays an important role in the regulation of body weight and glucose homeostasis. While increasing evidence supports white adipose tissue heterogeneity, little is known about heterogeneity within murine BAT. Using single cell RNA sequencing of the stromal vascular fraction of murine BAT and analysis of 67 brown preadipocyte and adipocyte clones we unravel heterogeneity within brown preadipocytes. Statistical analysis of gene expression profiles from these clones identifies markers distinguishing brown adipocyte lineages. We confirm the presence of distinct brown adipocyte populations in vivo using three identified markers; Eif5, Tcf25, and Bin1. Functionally, we demonstrate that loss of Bin1 enhances UCP1 expression and mitochondrial respiration, suggesting that Bin1 marks a dormant brown adipocyte type. The existence of multiple brown adipocyte lineages suggests distinct functional properties of BAT depending on its cellular composition, with potentially distinct function in thermogenesis and the regulation of whole body energy homeostasis.

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“…1A). However, as recently reported (27), immunofluorescence stainings of adult murine interscapular BAT revealed a mosaic of Ucp1 expression throughout the tissue (Fig. 1A).…”

Section: Scrnaseq Reveals Composition and Heterogeneity Within The Stsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 73%

Identification and characterization of distinct murine brown adipocyte lineages

Karlina

Lutter

Miok

et al. 2020

Preprint

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“…The second type of brown adipocytes is characterized by a high expression of genes related to fatty acid uptake, cell-to-cell trafficking, and UCP1-independent thermogenesis. Moreover, exposure to cold induces interconversion of low-thermogenic brown adipocytes to high-thermogenic, which can be subsequently reversed when thermoneutral conditions are restored [ 6 ].…”

Section: Types Of Adipose Tissue and Their Functionmentioning

confidence: 99%

Induction of Adipose Tissue Browning as a Strategy to Combat Obesity

Kuryłowicz

Puzianowska-Kuźnicka

2020

IJMS

148

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The ongoing obesity pandemic generates a constant need to develop new therapeutic strategies to restore the energy balance. Therefore, the concept of activating brown adipose tissue (BAT) in order to increase energy expenditure has been revived. In mammals, two developmentally distinct types of brown adipocytes exist; the classical or constitutive BAT that arises during embryogenesis, and the beige adipose tissue that is recruited postnatally within white adipose tissue (WAT) in the process called browning. Research of recent years has significantly increased our understanding of the mechanisms involved in BAT activation and WAT browning. They also allowed for the identification of critical molecules and critical steps of both processes and, therefore, many new therapeutic targets. Several non-pharmacological approaches, as well as chemical compounds aiming at the induction of WAT browning and BAT activation, have been tested in vitro as well as in animal models of genetically determined and/or diet-induced obesity. The therapeutic potential of some of these strategies has also been tested in humans. In this review, we summarize present concepts regarding potential therapeutic targets in the process of BAT activation and WAT browning and available strategies aiming at them.

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“…2f), possibly reflecting differences in the metabolic activity of different cell populations in BAT. 19 Although punctate-looking structures remained in the cytoplasm, the number of puncta, size of puncta, largest spot size of puncta, and the average intensity of puncta were reduced compared to cells from saline-injected mice at baseline ( Fig. 2c,e,f).…”

mentioning

confidence: 90%

“…NE, adenylyl cyclase, and PKC were selected for activation as they represent three key control points in the pathway allowing the characterization of all upstream regulators. PKI ([14][15][16][17][18][19][20][21][22], Myristoylated) (Invitrogen, Camarillo, CA), a synthetic peptide inhibitor of PKA, was added to inhibit PKA activation. Atglistatin (Selleckchem, Houston, TX) was used to selectively inhibit the processing of triacylglycerol to fatty acids via the formation of diacylglycerol by ATGL.…”

mentioning

confidence: 99%

Thioesterase Superfamily Member 1 Undergoes Stimulus-coupled Reorganization to Regulate Metabolism

Imai

Goyal

et al. 2020

Preprint

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In brown adipose tissue, cold exposure promotes thermogenesis, in large part by increasing mitochondrial -oxidation of lipid droplet-derived fatty acids. This process is suppressed by thioesterase superfamily member 1 (Them1), a long chain fatty acyl-CoA thioesterase that is highly upregulated by cold ambient temperatures. Them1 reduces fatty acid availability for oxidation in mitochondria and limits thermogenesis by cellular mechanisms that are not well defined. We show that Them1 regulates metabolism by undergoing marked intracellular conformational changes that occur in response to -adrenergic stimulation. Mechanistically, Them1 formed puncta that were localized near LD and mitochondria in an immortalized brown adipose cell line. In response to stimulation by norepinephrine, Them1 was phosphorylated by PKC at S15, which specifically inhibited puncta formation and resulted in a diffuse intracellular localization. This change in Them1 localization also occurred after stimulation in vivo. Puncta formation activated Them1 metabolic activity in vitro, as evidenced by suppression of oxygen consumption following -adrenergic stimulation. We show by correlative light and electron microscopy that puncta are biomolecular condensates (also known as membraneless organelles) that typically form by phase separation. Them1 contains one intrinsically disordered region at the N-terminus with multiple interacting motifs that is frequently observed in phaseseparating proteins. Phosphorylation, which is known to disrupt phase separation and aggregation, results in a diffuse Them1 localization. Our data thus establish that Them1 forms intracellular biomolecular condensates that limit fatty acid oxidation and suppress thermogenesis. During a period of energy demand, the condensates are disrupted by phosphorylation to allow for maximal thermogenesis. The stimulus-coupled reorganization of Them1 thus provides fine-tuning of thermogenesis and energy expenditure.

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Low- and high-thermogenic brown adipocyte subpopulations coexist in murine adipose tissue

Cited by 157 publications

References 47 publications

Identification and characterization of distinct murine brown adipocyte lineages

Identification and characterization of distinct murine brown adipocyte lineages

Induction of Adipose Tissue Browning as a Strategy to Combat Obesity

Thioesterase Superfamily Member 1 Undergoes Stimulus-coupled Reorganization to Regulate Metabolism

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