Single Cell Atlas of Beige Remodeling of White Adipose Tissue Reveals a Myeloid to Lymphoid Shift During Cold Exposure Compared to Beta 3 Adrenergic Stimulation

SUMMARYWhite adipose tissue (WAT) is a dynamic tissue, which responds to environmental stimuli and dietary cues by changing its morphology and metabolic capacity. The ability of WAT to undergo a beige remodeling has become an appealing strategy to combat obesity and its related metabolic complications. Within the cell mixture that constitutes the stromal vascular fraction (SVF), WAT beiging is initiated through expansion and differentiation of adipocytes progenitor cells, however, the extent of the SVF cellular changes is still poorly understood. Additionally, direct beta 3 adrenergic receptor (Adrb3) stimulation has been extensively used to mimic physiological cold- induced beiging, yet it is still unknown whether Adrb3 activation induces the same WAT remodeling as cold exposure. Here, by using single cell RNA sequencing, we provide a comprehensive atlas of the cellular dynamics during beige remodeling within white adipose tissue. We reveal drastic changes both in the overall cellular composition and transcriptional states of individual cell subtypes between Adrb3- and cold-induced beiging. Moreover, we demonstrate that cold exposure induces a myeloid to lymphoid shift of the immune compartment compared to Adrb3 activation. Further analysis, showed that Adrb3 stimulation leads to activation of the interferon/Stat1 pathways favoring infiltration of myeloid immune cells, while repression of this pathway by cold promotes lymphoid immune cells recruitment. These findings provide new insight into the cellular dynamics during WAT beige remodeling and could ultimately lead to novel strategies to identify translationally-relevant drug targets to counteract obesity and T2D.

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Single-cell sequencing of human white adipose tissue identifies new cell states in health and obesity

Nature Immunology ◽

10.1038/s41590-021-00922-4 ◽

2021 ◽

Vol 22 (5) ◽

pp. 639-653

Author(s):

Andrew D. Hildreth ◽

Feiyang Ma ◽

Yung Yu Wong ◽

Ryan Sun ◽

Matteo Pellegrini ◽

...

Keyword(s):

Adipose Tissue ◽

Single Cell ◽

White Adipose Tissue ◽

Single Cell Sequencing

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Chronic β3 adrenergic stimulation induced remodeling of white adipose tissue in mice

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.502.3 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Chris R Lindholm ◽

Jake D. Bauwens ◽

Rebecca L. Ertel ◽

Jake D. Mulligan ◽

Eric G. Schmuck ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Adrenergic Stimulation

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Cold exposure potentiates the effect of insulin on in vivo glucose uptake

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1987.253.2.e179 ◽

1987 ◽

Vol 253 (2) ◽

pp. E179-E186 ◽

Cited By ~ 12

Author(s):

A. L. Vallerand ◽

F. Perusse ◽

L. J. Bukowiecki

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Glucose Uptake ◽

White Adipose Tissue ◽

Cold Exposure ◽

Skeletal Muscles ◽

Insulin Injection ◽

Peripheral Tissues ◽

Brown Adipose ◽

Insulin Responses

The effects of cold exposure (48 h at 4 degrees C) and insulin injection (0.5 U/kg iv) on the rates of net 2-[3H]deoxyglucose uptake (Ki) in peripheral tissues were investigated in warm-acclimated rats (25 degrees C). Cold exposure and insulin treatment independently increased Ki values in skeletal muscles (soleus, extensor digitorum longus, and vastus lateralis), heart, white adipose tissue (subcutaneous, gonadal, and retroperitoneal), and brown adipose tissue (P less than 0.01). The effects of cold exposure were particularly evident in brown adipose tissue where the Ki increased greater than 100 times. When the two treatments were combined (insulin injection in cold-exposed rats), it was found that cold exposure synergistically enhanced the maximal insulin responses for glucose uptake in brown adipose tissue, all white adipose tissue depots, and skeletal muscles investigated. The results indicate that cold exposure induces an "insulin-like" effect on Ki that does not appear to be specifically associated with shivering thermogenesis in skeletal muscles, because that effect was observed in all insulin-sensitive tissues. The data also demonstrate that cold exposure significantly potentiates the maximal insulin responses for glucose uptake in the same tissues. This potentialization may result from an enhanced responsiveness of peripheral tissues to insulin, possibly occurring at metabolic steps lying beyond the insulin receptor and an increased tissue blood flow augmenting glucose and insulin availability and thereby amplifying glucose uptake.

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Interscapular brown adipose tissue denervation does not promote the oxidative activity of inguinal white adipose tissue in male mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00210.2018 ◽

2018 ◽

Vol 315 (5) ◽

pp. E815-E824 ◽

Cited By ~ 6

Author(s):

Sébastien M. Labbé ◽

Alexandre Caron ◽

William T. Festuccia ◽

Roger Lecomte ◽

Denis Richard

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Glucose Uptake ◽

White Adipose Tissue ◽

Oxidative Activity ◽

Substrate Uptake ◽

Adrenergic Stimulation ◽

Brown Adipocytes ◽

Apparent Lack ◽

Brown Adipose

Brown adipose tissue (BAT) thermogenesis is a key controller of energy metabolism. In response to cold or other adrenergic stimuli, brown adipocytes increase their substrate uptake and oxidative activity while uncoupling ATP synthesis from the mitochondrial respiratory chain activity. Brown adipocytes are found in classic depots such as in the interscapular BAT (iBAT). They can also develop in white adipose tissue (WAT), such as in the inguinal WAT (iWAT), where their presence has been associated with metabolic improvements. We previously reported that the induction of oxidative metabolism in iWAT is low compared with that of iBAT, even after sustained adrenergic stimulation. One explanation to this apparent lack of thermogenic ability of iWAT is the presence of an active iBAT, which may prevent the full activation of iWAT. In this study, we evaluated whether iBAT denervation-induced browning of white fat enhanced the thermogenic activity of iWAT following cold acclimation, under beta-3 adrenergic stimulation (CL 316,243). Following a bilateral denervation of iBAT, we assessed energy balance, evaluated the oxidative activity of iBAT and iWAT using 11C-acetate, and quantified the dynamic glucose uptake of those tissues using 2-deoxy-2-[18F]- fluoro-d-glucose. Our results indicate that despite portraying marked browning and mildly enhanced glucose uptake, iWAT of cold-adapted mice does not exhibit significant oxidative activity following beta-3 adrenergic stimulation in the absence of a functional iBAT. The present results suggest that iWAT is not readily recruitable as a thermogenic organ even when functional iBAT is lacking.

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The effects of exercise and cold exposure on mitochondrial biogenesis in skeletal muscle and white adipose tissue

The Journal of Exercise Nutrition and Biochemistry ◽

10.20463/jenb.2017.0020 ◽

2017 ◽

Vol 21 (2) ◽

pp. 39-47 ◽

Cited By ~ 11

Author(s):

Nana Chung ◽

Jonghoon Park ◽

Kiwon Lim

Keyword(s):

Skeletal Muscle ◽

Adipose Tissue ◽

White Adipose Tissue ◽

Mitochondrial Biogenesis ◽

Cold Exposure

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CD137 negatively affects “browning” of white adipose tissue during cold exposure

Journal of Biological Chemistry ◽

10.1074/jbc.ac119.011795 ◽

2020 ◽

Vol 295 (7) ◽

pp. 2034-2042 ◽

Cited By ~ 2

Author(s):

Raj Kamal Srivastava ◽

Annalena Moliner ◽

Ee-Soo Lee ◽

Emily Nickles ◽

Eunice Sim ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Cold Exposure ◽

Uncoupling Protein ◽

Surface Protein ◽

Negative Regulator ◽

Subcutaneous White Adipose Tissue ◽

Brown Adipose ◽

Beige Adipocytes ◽

A Cell

Prolonged cold exposure stimulates the formation of brownlike adipocytes expressing UCP1 (uncoupling-protein-1) in subcutaneous white adipose tissue which, together with classical brown adipose tissue, contributes to maintaining body temperature in mammals through nonshivering thermogenesis. The mechanisms that regulate the formation of these cells, alternatively called beige or brite adipocytes, are incompletely understood. Here we report that mice lacking CD137, a cell surface protein used in several studies as a marker for beige adipocytes, showed elevated levels of thermogenic markers, including UCP1, increased numbers of beige adipocyte precursors, and expanded UCP1-expressing cell clusters in inguinal white adipose tissue after chronic cold exposure. CD137 knockout mice also showed enhanced cold resistance. These results indicate that CD137 functions as a negative regulator of “browning” in white adipose tissue and call into question the use of this protein as a functional marker for beige adipocytes.

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Lipid Profiling Reveals Browning Heterogeneity of White Adipose Tissue by Β3-Adrenergic Stimulation

Biomolecules ◽

10.3390/biom9090444 ◽

2019 ◽

Vol 9 (9) ◽

pp. 444 ◽

Cited By ~ 4

Author(s):

Ping He ◽

Biyu Hou ◽

Yanliang Li ◽

Chunyang Xu ◽

Peng Ma ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Metabolic Diseases ◽

Multiple Reaction Monitoring ◽

Adrenergic Stimulation ◽

Lipid Profiling ◽

High Coverage ◽

Beneficial Effects ◽

Visceral Adipose ◽

Subcutaneous Adipose

Background: White adipose tissue (WAT) browning confers beneficial effects on metabolic diseases. However, visceral adipose tissue (VAT) is not as susceptible to browning as subcutaneous adipose tissue (SAT). Aim: Interpreting the heterogeneity of VAT and SAT in brown remodeling and provide promising lipid targets to promote WAT browning. Methods: We first investigated the effects of β3-adrenergic stimulation by CL316,243 on systemic metabolism. Then, high-coverage targeted lipidomics approach with multiple reaction monitoring (MRM) was utilized to provide extensive detection of lipid metabolites in VAT and SAT. Results: CL316,243 notably ameliorated the systemic metabolism and induced brown remodeling of SAT but browning resistance of VAT. Comprehensive lipidomics analysis revealed browning heterogeneity of VAT and SAT with more dramatic alteration of lipid classes and species in VAT rather than SAT, though VAT is resistant to browning. Adrenergic stimulation differentially affected glycerides content in VAT and SAT and boosted the abundance of more glycerophospholipids species in VAT than in SAT. Besides, CL316,243 increased sphingolipids in VAT without changes in SAT, meanwhile, elevated cardiolipin species more prominently in VAT than in SAT. Conclusions: We demonstrated the browning heterogeneity of WAT and identified potential lipid biomarkers which may provide lipid targets for overcoming VAT browning resistance.

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Cold-induced lipid dynamics and transcriptional programs in white adipose tissue

BMC Biology ◽

10.1186/s12915-019-0693-x ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 9

Author(s):

Ziye Xu ◽

Wenjing You ◽

Yanbing Zhou ◽

Wentao Chen ◽

Yizhen Wang ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Fatty Acid ◽

White Adipose Tissue ◽

Cold Exposure ◽

Fatty Acid Elongation ◽

Rna Seq ◽

Short Term ◽

Lipid Dynamics ◽

Expression Of Genes

Abstract Background In mammals, cold exposure induces browning of white adipose tissue (WAT) and alters WAT gene expression and lipid metabolism to boost adaptive thermogenesis and maintain body temperature. Understanding the lipidomic and transcriptomic profiles of WAT upon cold exposure provides insights into the adaptive changes associated with this process. Results Here, we applied mass spectrometry and RNA sequencing (RNA-seq) to provide a comprehensive resource for describing the lipidomic or transcriptome profiles in cold-induced inguinal WAT (iWAT). We showed that short-term (3-day) cold exposure induces browning of iWAT, increases energy expenditure, and results in loss of body weight and fat mass. Lipidomic analysis shows that short-term cold exposure leads to dramatic changes of the overall composition of lipid classes WAT. Notably, cold exposure induces significant changes in the acyl-chain composition of triacylglycerols (TAGs), as well as the levels of glycerophospholipids and sphingolipids in iWAT. RNA-seq and qPCR analysis suggests that short-term cold exposure alters the expression of genes and pathways involved in fatty acid elongation, and the synthesis of TAGs, sphingolipids, and glycerophospholipids. Furthermore, the cold-induced lipid dynamics and gene expression pathways in iWAT are contrary to those previously observed in metabolic syndrome, neurodegenerative disorders, and aging, suggesting beneficial effects of cold-induced WAT browning on health and lifespan. Conclusion We described the significant alterations in the composition of glyphospholipids, glycerolipids, and sphingolipids and expression of genes involved in thermogenesis, fatty acid elongation, and fatty acid metabolism during the response of iWAT to short-term cold exposure. We also found that some changes in the levels of specific lipid species happening after cold treatment of iWAT are negatively correlated to metabolic diseases, including obesity and T2D.

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