Deconstructing Adipogenesis Induced by β3-Adrenergic Receptor Activation with Single-Cell Expression Profiling

Burl, Rayanne B.; Ramseyer, Vanesa D.; Rondini, Elizabeth A.; Piqué-Regi, Roger; Lee, Yun Hee; Granneman, James G.

doi:10.1016/j.cmet.2018.05.025

Cited by 279 publications

(345 citation statements)

References 39 publications

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“…Another way to model the negative energy balance associated with weight loss is via activating lipolysis. Dr Granneman et al per-formed scRNA-seq on over 33 000 cells from the stromal vascular fraction of epididymal and inguinal AT in lean mice with or without β-adrenergic stimulation 86. The purpose of this study was to evaluate the recruitment of brown/beige adipocytes during lipolytic stimulation, and they indeed found that they could classify a proliferating population of cells that would differentiate into brown/ beige adipocytes.…”

mentioning

confidence: 93%

Adipose tissue macrophages: Unique polarization and bioenergetics in obesity

Caslin

Bhanot

Bolus

et al. 2020

Immunological Reviews

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Macrophages comprise a majority of the resident immune cells in adipose tissue (AT) and regulate both tissue homeostasis in the lean state and metabolic dysregulation in obesity. Since the AT environment rapidly changes based upon systemic energy status, AT macrophages (ATMs) must adapt phenotypically and metabolically. There is a distinct dichotomy in the polarization and bioenergetics of in vitro models, with M2 macrophages utilizing oxidative phosphorylation (OX PHOS) and M1 macrophages utilizing glycolysis. Early studies suggested differential polarization of ATMs, with M2‐like macrophages predominant in lean AT and M1‐like macrophages in obese AT. However, recent studies show that the phenotypic plasticity of ATMs is far more complicated, which is also reflected in their bioenergetics. Multiple ATM populations exist along the M2 to M1 continuum and appear to utilize both glycolysis and OX PHOS in obesity. The significance of the dual fuel bioenergetics is unclear and may be related to an intermediate polarization, their buffering capacity, or the result of a mixed population of distinct polarized ATMs. Recent evidence also suggests that ATMs of lean mice serve as a substrate buffer or reservoir to modulate lipid, catecholamine, and iron availability. Furthermore, recent models of weight loss and weight cycling reveal additional roles for ATMs in systemic metabolism. Evaluating ATM phenotype and intracellular metabolism together may more accurately illuminate the consequences of ATM accumulation in obese AT, lending further insight into obesity‐related comorbidities in humans.

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confidence: 93%

Adipose tissue macrophages: Unique polarization and bioenergetics in obesity

Caslin

Bhanot

Bolus

et al. 2020

Immunological Reviews

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“…Recent advances in the ability to study single-cell transcriptomes can be leveraged to better understand the cellular composition of adipose tissue [11][12][13]. Single-cell transcriptomics of nonmature adipocytes in mouse fat has revealed specific populations of adipocyte stem cells primed to expand in response to adrenergic stimulation [13], stromal cells capable of inhibiting adipogenesis [11], and cells with enhanced adipogenic or fibro-inflammatory properties [14]. The use of single-cell transcriptomics to define mature adipocyte subtypes is complicated by the large size and high buoyancy of these cells, and the fact that the extensive proteolytic digestion required to isolate them from the adipose tissue compromises their viability and alters their phenotype [15].…”

Section: Introductionmentioning

confidence: 99%

“Multiple human adipocyte subtypes and mechanisms of their development”

Desai

Yang

et al. 2019

Preprint

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Human adipose tissue depots perform numerous diverse physiological functions, and are differentially linked to metabolic disease risk, yet only two major human adipocyte subtypes have been described, white and "brown/brite/beige." The diversity and lineages of adipocyte classes have been studied in mice using genetic methods that cannot be applied in humans. Here we circumvent this problem by studying the fate of single mesenchymal progenitor cells obtained from human adipose tissue. We report that a minimum of four human adipocyte subtypes can be distinguished by transcriptomic analysis, specialized for functionally distinct processes such as adipokine secretion and thermogenesis. Evidence for the presence of these adipocytes subtypes in adult humans is evidenced by differential expression of key adipokines leptin and adiponectin in isolated mature adipocytes. The human adipocytes most similar to the mouse "brite/beige" adipocytes are enriched in mechanisms that promote iron accumulation and protect from oxidative stress, and are derived from progenitors that express high levels of cytokines such as IL1B, IL8, IL11 and the IL6 family cytokine LIF, and low levels of the transcriptional repressors ID1 and ID3. Our finding of this adipocyte repertoire and its developmental mechanisms provides a high-resolution framework to analyze human adipose tissue architecture and its role in systemic metabolism and metabolic disease.

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“…PGT mRNA in iWAT is expressed in an adipocyte precursor population 63 . This cell specificity would position PGT for paracrine control 7 of white or beige adipogenesis.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting the prostaglandin transporter PGT induces non-canonical thermogenesis at thermoneutrality

Pai

et al. 2019

Preprint

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1Prostaglandins play fundamental roles in adipose tissue function. While prostaglandin 2 F 2α inhibits adipogenesis, prostaglandin E 2 promotes adipose beiging. PGF 2α and 3 PGE 2 are both inactivated through uptake by the plasma membrane transporter (PGT). 4We hypothesized that inhibiting PGT would increase PGF 2α and PGE 2 levels, thereby 5 reducing white fat expansion and inducing beiging. Consistent with this hypothesis, 6inhibiting PGT in mice on high fat diet via genetic knockout or pharmacological blockade 7 reduced body fat stores and induced thermogenesis at thermoneutrality. Inguinal white 8 adipose tissue (iWAT) of these mice exhibited robust UCP1-independent thermogenesis 9 characterized by mitochondrial expansion, coupling of O 2 consumption to ATP 10 synthesis, and induction of the creatine pathway. Enhanced coupled respiration 11 persisted in PGT-KO iWAT adipocytes in a creatine shuttle-dependent manner. Thus, 12inhibiting PGT increases mitochondrial biogenesis and coupled respiration-each 13 supported by the creatine pathway in a system lacking UCP1 expression-revealing 14PGT as a promising drug target against obesity. 15 16 RESULTS 48 PGT global knockout mice (PGT-KO mice) exhibit a lean phenotype. 49Results from both male and female KO mice are presented without stratification 50 by sex because mice of both sexes exhibited the same metabolic phenotype. PGT-KO 51 mice had elevated urinary PGE 2 and PGF 2α excretion rates, indicating impaired 52 systemic prostaglandin metabolism ( Figure 1A). PGT-KO mice exhibited reductions in 53 waist circumference (Figure 1 B-D), subcutaneous white adipose tissue (WAT) (Figure 1 54 E-F), visceral (gonadal) white adipose tissue (gWAT) (Figure 1 G-I), dermal fat (Figure 1 55 J-L), liver steatosis (Figure 1 M,N), and whole-body fat by echo-MRI composition 56 analysis (Figure 1 O). PGT was differentially expressed in gWAT, iWAT, and 57 interscapular brown adipose tissue (iBAT); compared to WT mice, the masses of these 58 three fat depots in PGT-KO mice were reduced proportional to PGT expression 59 ( Supplementary Figure 1). PGT-KO mice displayed improved glucose tolerance 60 compared to controls ( Figures 1P and Supplementary Figure 1). WAT leptin gene 61 expression, fasting serum leptin, and fasting serum free fatty acids were reduced in 62 PGT-KO mice, whereas fasting serum adiponectin and insulin concentrations were 63 unchanged ( Supplementary Figure 1). Histology revealed that adipocytes of PGT-KO 64 iWAT and iBAT depots were smaller than those of WT mice, and that PGT-KO iWAT 65 contained multilocular adipocytes ( Supplementary Figure 1). 66 PGT-KO mice display increased energy expenditure due to beige induction in the 67iWAT depot. 68Although PGT-KO mice exhibited a 2-fold increase in food intake (Figures 2A 69 and Supplementary Figure 2), there was no difference in stool weight, stool fatty acids, 70

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Deconstructing Adipogenesis Induced by β3-Adrenergic Receptor Activation with Single-Cell Expression Profiling

Cited by 279 publications

References 39 publications

Adipose tissue macrophages: Unique polarization and bioenergetics in obesity

Adipose tissue macrophages: Unique polarization and bioenergetics in obesity

“Multiple human adipocyte subtypes and mechanisms of their development”

Inhibiting the prostaglandin transporter PGT induces non-canonical thermogenesis at thermoneutrality

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