Defining the lineage of thermogenic perivascular adipose tissue

Angueira, Anthony R.; Sakers, Alexander P.; Holman, Corey D.; Cheng, Lan; Arbocco, Michelangella N.; Shamsi, Farnaz; Lynes, Matthew D.; Shrestha, Rojesh; Okada, Chihiro; Batmanov, Kirill; Suszták, Katalin; Tseng, Yu–Hua; Liaw, Lucy; Seale, Patrick

doi:10.1038/s42255-021-00380-0

Cited by 85 publications

(51 citation statements)

References 60 publications

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“…Discrete thermogenic pathways could segregate inter-or intracellularly. The identi cation of distinct adipocyte subtypes [51][52][53][54][55][56] as well as mitochondrial heterogeneity within thermogenic fat cells 57 supports this idea. Thus, the futile creatine cycle probably operates in conjunction with UCP1-dependent thermogenesis.…”

Section: Discussionmentioning

confidence: 81%

Combined α- and β-adrenergic receptor activation triggers thermogenesis by the futile creatine cycle

Kazak

Rahbani

Scholtes

et al. 2022

Preprint

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Noradrenaline is the primary physiological regulator of adipocyte thermogenesis in response to decreased environmental temperature1. However, the molecular factors and effector pathways that lie downstream of noradrenaline-stimulated thermogenesis are still not fully understood but are purportedly driven by cAMP downstream of β-adrenergic receptor (βAR) activation. Furthermore, while the transcriptional mechanisms regulating Ucp1 are well-characterized2, the transcriptional regulation of UCP1-independent thermogenesis is largely unknown. Here, we show that brown adipose tissue (BAT) is primed to respond to environmental cold by triggering coordinated α-adrenergic receptor (αAR) and βAR signaling to induce the expression of thermogenic genes of the futile creatine cycle3,4. Using fat-specific loss-of-function models, we reveal that EBFs, ERRs, and PGC1α are required for the cold-stimulated transcriptional induction of the futile creatine cycle in vivo. Through the application of chemogenetics, we demonstrate that combined fat-selective Gαs (activated by βARs) and Gαq (activated by αARs) signaling elevates whole-body energy expenditure to a greater extent than either signaling pathway alone in a manner that is dependent on the key effector protein of the futile creatine cycle, CKB3. Moreover, genetic and pharmacological studies reveal that CKB is necessary for nearly all of the α1AR-stimulated component of brown adipocyte-intrinsic respiration and is thus critical for the full activation of noradrenaline-stimulated thermogenesis. Thus, the futile creatine cycle is integrated into facultative and adaptive thermogenesis through coordinated α1AR and β3AR signaling.

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Section: Discussionmentioning

confidence: 81%

Combined α- and β-adrenergic receptor activation triggers thermogenesis by the futile creatine cycle

Kazak

Rahbani

Scholtes

et al. 2022

Preprint

Self Cite

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“…Single-cell techniques have empowered this process by helping draw sophisticated cellular atlas. Some researchers have explored the heterogeneity of PVAT at a single-cell level and uncovered distinct clusters with specific signature markers and signaling pathways ( Angueira et al, 2021 ). Creating a more precise map of such a complex tissue from single-cell sequencing data is, therefore, a challenging task, which on the other hand, opens an opportunity for us to dive into this unknown.…”

Section: Discussionmentioning

confidence: 99%

“…A lineage-tracing study further elaborates that anterior tPVAT adipocytes can be traced to SM22α + progenitors, whereas left lateral tPVAT presents both SM22α + and Myf5 + features (Ye et al, 2019). However, recent cell differentiation assays and genetic fate mapping studies show that fibroblastic progenitor cells but not vascular smooth muscle cells (VSMCs) are responsible for tPVAT adipogenesis (Angueira et al, 2021), which contradicts the previous findings (Chang et al, 2012;Ye et al, 2019). Progenitor cells for tPVAT are from a fibroblastic lineage, including (Pdgfra + ; Ly6a + ; Pparg − ) and preadipocytes (Pdgfra + ; Ly6a − ; Pparg + ).…”

Section: Origin Of Thoracic Periaortic Adipose Tissuementioning

confidence: 97%

“…Progenitor cells for tPVAT are from a fibroblastic lineage, including (Pdgfra + ; Ly6a + ; Pparg − ) and preadipocytes (Pdgfra + ; Ly6a − ; Pparg + ). Bona fide VSMCs were not found to contribute to adipocyte formation in tPVAT (Angueira et al, 2021). Single-cell transcriptomic analyses both at embryonic (E18) and perinatal (P3, after birth) stages identified transcription factor early B cell factor-2 (EBF2) as a critical modulator of BAT (Angueira et al, 2020) and tPVAT development (Angueira et al, 2021).…”

Section: Origin Of Thoracic Periaortic Adipose Tissuementioning

confidence: 99%

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Regional Heterogeneity of Perivascular Adipose Tissue: Morphology, Origin, and Secretome

Zhu

2021

Front. Pharmacol.

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Perivascular adipose tissue (PVAT) is a unique fat depot with local and systemic impacts. PVATs are anatomically, developmentally, and functionally different from classical adipose tissues and they are also different from each other. PVAT adipocytes originate from different progenitors and precursors. They can produce and secrete a wide range of autocrine and paracrine factors, many of which are vasoactive modulators. In the context of obesity-associated low-grade inflammation, these phenotypic and functional differences become more evident. In this review, we focus on the recent findings of PVAT’s heterogeneity by comparing commonly studied adipose tissues around the thoracic aorta (tPVAT), abdominal aorta (aPVAT), and mesenteric artery (mPVAT). Distinct origins and developmental trajectory of PVAT adipocyte potentially contribute to regional heterogeneity. Regional differences also exist in ways how PVAT communicates with its neighboring vasculature by producing specific adipokines, vascular tone regulators, and extracellular vesicles in a given microenvironment. These insights may inspire new therapeutic strategies targeting the PVAT.

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“…More importantly, CD81 + cells respond to the cold challenge by giving rise to new brite/beige positive adipocytes in the inguinal adipose tissue, while the loss of CD81 causes diet-induced obesity and other complications [ 26 ]. In the newest study, Angueira et al reported three brown adipogenic populations by applying scRNAseq and linage tracing to perivascular adipose tissue, comprising progenitors (Pdgfra + ; Ly6a + ; Pparg-), preadipocytes (Pdgfra + ; Ly6a-; Pparg +) [ 27 ], and a novel subpopulation of smooth muscle cells (Myh11 + ; Pdgfra − ; Pparg +) within the aortic adventitia of adult mice. These three populations of cells possess the capacity to generate adipocytes in vitro and in vivo and give rise to brown adipocytes in perivascular adipose tissue.…”

Section: Heterogeneity Of Vascular Mural Apcsmentioning

confidence: 99%

Novel insights into adipose tissue heterogeneity

Wang

Sharma

Wolfrum

2021

Rev Endocr Metab Disord

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When normalized to volume, adipose tissue is comprised mainly of large lipid metabolizing and storing cells called adipocytes. Strikingly, the numerical representation of non-adipocytes, composed of a wide variety of cell types found in the so-called stromal vascular fraction (SVF), outnumber adipocytes by far. Besides its function in energy storage, adipose tissue has emerged as a versatile organ that regulates systemic metabolism and has therefore constituted an attractive target for the treatment of metabolic diseases. Recent high-resolution single cells/nucleus RNA seq data exemplify an intriguingly profound diversity of both adipocytes and SVF cells in all adipose depots, and the current data, while limited, demonstrate the significance of the intra-tissue cell composition in shaping the overall functionality of this tissue. Due to the complexity of adipose tissue, our understanding of the biological relevance of this heterogeneity and plasticity is fractional. Therefore, establishing atlases of adipose tissue cell heterogeneity is the first step towards generating an understanding of these functionalities. In this review, we will describe the current knowledge on adipose tissue cell composition and the heterogeneity of single-cell RNA sequencing, including the technical limitations.

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Defining the lineage of thermogenic perivascular adipose tissue

Cited by 85 publications

References 60 publications

Combined α- and β-adrenergic receptor activation triggers thermogenesis by the futile creatine cycle

Combined α- and β-adrenergic receptor activation triggers thermogenesis by the futile creatine cycle

Regional Heterogeneity of Perivascular Adipose Tissue: Morphology, Origin, and Secretome

Novel insights into adipose tissue heterogeneity

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