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      Single cell analysis reveals immune cell–adipocyte crosstalk regulating the transcription of thermogenic adipocytes

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          Abstract

          Immune cells are vital constituents of the adipose microenvironment that influence both local and systemic lipid metabolism. Mice lacking IL10 have enhanced thermogenesis, but the roles of specific cell types in the metabolic response to IL10 remain to be defined. We demonstrate here that selective loss of IL10 receptor α in adipocytes recapitulates the beneficial effects of global IL10 deletion, and that local crosstalk between IL10-producing immune cells and adipocytes is a determinant of thermogenesis and systemic energy balance. Single Nuclei Adi pocyte RNA -sequencing (SNAP-seq) of subcutaneous adipose tissue defined a metabolically-active mature adipocyte subtype characterized by robust expression of genes involved in thermogenesis whose transcriptome was selectively responsive to IL10Rα deletion. Furthermore, single-cell transcriptomic analysis of adipose stromal populations identified lymphocytes as a key source of IL10 production in response to thermogenic stimuli. These findings implicate adaptive immune cell-adipocyte communication in the maintenance of adipose subtype identity and function.

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          Most cited references29

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          EmptyDrops: distinguishing cells from empty droplets in droplet-based single-cell RNA sequencing data

          Droplet-based single-cell RNA sequencing protocols have dramatically increased the throughput of single-cell transcriptomics studies. A key computational challenge when processing these data is to distinguish libraries for real cells from empty droplets. Here, we describe a new statistical method for calling cells from droplet-based data, based on detecting significant deviations from the expression profile of the ambient solution. Using simulations, we demonstrate that EmptyDrops has greater power than existing approaches while controlling the false discovery rate among detected cells. Our method also retains distinct cell types that would have been discarded by existing methods in several real data sets. Electronic supplementary material The online version of this article (10.1186/s13059-019-1662-y) contains supplementary material, which is available to authorized users.
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            Regulation of lipolysis in adipocytes.

            Lipolysis of white adipose tissue triacylglycerol stores results in the liberation of glycerol and nonesterified fatty acids that are released into the vasculature for use by other organs as energy substrates. In response to changes in nutritional state, lipolysis rates are precisely regulated through hormonal and biochemical signals. These signals modulate the activity of lipolytic enzymes and accessory proteins, allowing for maximal responsiveness of adipose tissue to changes in energy requirements and availability. Recently, a number of novel adipocyte triacylglyceride lipases have been identified, including desnutrin/ATGL, greatly expanding our understanding of adipocyte lipolysis. We have also begun to better appreciate the role of a number of nonenzymatic proteins that are critical to triacylglyceride breakdown. This review provides an overview of key mediators of lipolysis and the regulation of this process by changes in nutritional status and nutrient intakes.
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              Visualizing data using ti-SNE

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                Author and article information

                Contributors
                Role: Reviewing Editor
                Role: Senior Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                23 October 2019
                2019
                : 8
                : e49501
                Affiliations
                [1 ]deptDepartment of Pathology and Laboratory Medicine University of California, Los Angeles Los AngelesUnited States
                [2 ]deptDiabetes, Obesity, and Metabolism Institute Icahn School of Medicine at Mount Sinai New YorkUnited States
                [3 ]deptDepartment of Integrative Biology and Physiology University of California, Los Angeles Los AngelesUnited States
                [4 ]deptBioinformatics Interdepartmental Program University of California, Los Angeles Los AngelesUnited States
                [5 ]deptDepartment of Microbiology, Immunology, and Molecular Genetics University of California, Los Angeles Los AngelesUnited States
                [6 ]deptDepartment of Human Genetics, David Geffen School of Medicine University of California, Los Angeles Los AngelesUnited States
                [7 ]deptDepartment of Psychiatry and Neuroscience Icahn School of Medicine at Mount Sinai New YorkUnited States
                [8 ]deptMolecular Biology Institute University of California, Los Angeles Los AngelesUnited States
                [9 ]deptDepartment of Biological Chemistry University of California, Los Angeles Los AngelesUnited States
                University of Massachusetts Medical School United States
                Genentech United States
                University of Massachusetts Medical School United States
                The University of Texas Southwestern Medical Center United States
                Author notes
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0003-1259-0477
                Article
                49501
                10.7554/eLife.49501
                6837845
                31644425
                ccdb8f8e-9169-41c6-b9cb-308d59725f53
                © 2019, Rajbhandari et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 19 June 2019
                : 22 October 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: K99 DK114571
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: DK063491
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: DK120851
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: HL090533
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: DK104363
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: UK1TR001881
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01GM086372
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Cell Biology
                Human Biology and Medicine
                Custom metadata
                Crosstalk between IL10-producing immune cells and adipocytes within adipose tissue is an important determinant of thermogenesis and systemic energy balance.

                Life sciences
                adipocyte,metabolism,cytokine,mouse
                Life sciences
                adipocyte, metabolism, cytokine, mouse

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