Publications by authors named "Peter Tontonoz"

204 Publications

Lysophospholipid acylation modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle.

J Clin Invest 2021 Apr;131(8)

Diabetes and Metabolism Research Center and.

Aberrant lipid metabolism promotes the development of skeletal muscle insulin resistance, but the exact identity of lipid-mediated mechanisms relevant to human obesity remains unclear. A comprehensive lipidomic analysis of primary myocytes from individuals who were insulin-sensitive and lean (LN) or insulin-resistant with obesity (OB) revealed several species of lysophospholipids (lyso-PLs) that were differentially abundant. These changes coincided with greater expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme involved in phospholipid transacylation (Lands cycle). Strikingly, mice with skeletal muscle-specific knockout of LPCAT3 (LPCAT3-MKO) exhibited greater muscle lysophosphatidylcholine/phosphatidylcholine, concomitant with improved skeletal muscle insulin sensitivity. Conversely, skeletal muscle-specific overexpression of LPCAT3 (LPCAT3-MKI) promoted glucose intolerance. The absence of LPCAT3 reduced phospholipid packing of cellular membranes and increased plasma membrane lipid clustering, suggesting that LPCAT3 affects insulin receptor phosphorylation by modulating plasma membrane lipid organization. In conclusion, obesity accelerates the skeletal muscle Lands cycle, whose consequence might induce the disruption of plasma membrane organization that suppresses muscle insulin action.
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http://dx.doi.org/10.1172/JCI135963DOI Listing
April 2021

USP20 links feeding-induced cholesterol synthesis and energy expenditure.

Sci China Life Sci 2021 Feb 6;64(2):337-338. Epub 2021 Jan 6.

Department of Pathology and Laboratory Medicine and Department of Biological Chemistry, University of California, Los Angeles, CA, 90095, USA.

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http://dx.doi.org/10.1007/s11427-020-1867-8DOI Listing
February 2021

Selective Aster inhibitors distinguish vesicular and nonvesicular sterol transport mechanisms.

Proc Natl Acad Sci U S A 2021 Jan;118(2)

Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095;

The Aster proteins (encoded by the genes) contain a ligand-binding fold structurally similar to a START domain and mediate nonvesicular plasma membrane (PM) to endoplasmic reticulum (ER) cholesterol transport. In an effort to develop small molecule modulators of Asters, we identified 20α-hydroxycholesterol (HC) and U18666A as lead compounds. Unfortunately, both 20α-HC and U18666A target other sterol homeostatic proteins, limiting their utility. 20α-HC inhibits sterol regulatory element-binding protein 2 (SREBP2) processing, and U18666A is an inhibitor of the vesicular trafficking protein Niemann-Pick C1 (NPC1). To develop potent and selective Aster inhibitors, we synthesized a series of compounds by modifying 20α-HC and U18666A. Among these, AI (Aster inhibitor)-1l, which has a longer side chain than 20α-HC, selectively bound to Aster-C. The crystal structure of Aster-C in complex with AI-1l suggests that sequence and flexibility differences in the loop that gates the binding cavity may account for the ligand specificity for Aster C. We further identified the U18666A analog AI-3d as a potent inhibitor of all three Aster proteins. AI-3d blocks the ability of Asters to bind and transfer cholesterol in vitro and in cells. Importantly, AI-3d also inhibits the movement of low-density lipoprotein (LDL) cholesterol to the ER, although AI-3d does not block NPC1. This finding positions the nonvesicular Aster pathway downstream of NPC1-dependent vesicular transport in the movement of LDL cholesterol to the ER. Selective Aster inhibitors represent useful chemical tools to distinguish vesicular and nonvesicular sterol transport mechanisms in mammalian cells.
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http://dx.doi.org/10.1073/pnas.2024149118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812747PMC
January 2021

Estrogen receptor α controls metabolism in white and brown adipocytes by regulating and mitochondrial remodeling.

Sci Transl Med 2020 08;12(555)

Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, University of California, Los Angeles, CA 90095, USA.

Obesity is heightened during aging, and although the estrogen receptor α (ERα) has been implicated in the prevention of obesity, its molecular actions in adipocytes remain inadequately understood. Here, we show that adipose tissue expression inversely associated with adiposity and positively associated with genes involved in mitochondrial metabolism and markers of metabolic health in 700 Finnish men and 100 strains of inbred mice from the UCLA Hybrid Mouse Diversity Panel. To determine the anti-obesity actions of ERα in fat, we selectively deleted from white and brown adipocytes in mice. In white adipose tissue, controlled oxidative metabolism by restraining the targeted elimination of mitochondria via the E3 ubiquitin ligase parkin. mtDNA content was elevated, and adipose tissue mass was reduced in adipose-selective parkin knockout mice. In brown fat centrally involved in body temperature maintenance, was requisite for both mitochondrial remodeling by dynamin-related protein 1 (Drp1) and uncoupled respiration thermogenesis by uncoupled protein 1 (Ucp1). In both white and brown fat of female mice and adipocytes in culture, mitochondrial dysfunction in the context of deletion was paralleled by a reduction in the expression of the mtDNA polymerase γ subunit We identified as an ERα target gene by showing that ERα binds the promoter to control its expression in 3T3L1 adipocytes. These findings support strategies leveraging ERα action on mitochondrial function in adipocytes to combat obesity and metabolic dysfunction.
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http://dx.doi.org/10.1126/scitranslmed.aax8096DOI Listing
August 2020

Aster Proteins Regulate the Accessible Cholesterol Pool in the Plasma Membrane.

Mol Cell Biol 2020 09 14;40(19). Epub 2020 Sep 14.

Department of Pathology and Laboratory Medicine and Department of Biological Chemistry, University of California, Los Angeles, California, USA

Recent studies have demonstrated the existence of a discrete pool of cholesterol in the plasma membranes (PM) of mammalian cells-referred to as the accessible cholesterol pool-that can be detected by the binding of modified versions of bacterial cytolysins (e.g., anthrolysin O). When the amount of accessible cholesterol in the PM exceeds a threshold level, the excess cholesterol moves to the endoplasmic reticulum (ER), where it regulates the SREBP2 pathway and undergoes esterification. We reported previously that the Aster/Gramd1 family of sterol transporters mediates nonvesicular movement of cholesterol from the PM to the ER in multiple mammalian cell types. Here, we investigated the PM pool of accessible cholesterol in cholesterol-loaded fibroblasts with a knockdown of Aster-A and in mouse macrophages from Aster-B and Aster-A/B-deficient mice. Nanoscale secondary ion mass spectrometry (NanoSIMS) analyses revealed expansion of the accessible cholesterol pool in cells lacking Aster expression. The increased accessible cholesterol pool in the PM was accompanied by reduced cholesterol movement to the ER, evidenced by increased expression of SREBP2-regulated genes. Cosedimentation experiments with liposomes revealed that the Aster-B GRAM domain binds to membranes in a cholesterol concentration-dependent manner and that the binding is facilitated by the presence of phosphatidylserine. These studies revealed that the Aster-mediated nonvesicular cholesterol transport pathway controls levels of accessible cholesterol in the PM, as well as the activity of the SREBP pathway.
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http://dx.doi.org/10.1128/MCB.00255-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491948PMC
September 2020

Inter-organ cross-talk in metabolic syndrome.

Nat Metab 2019 12 9;1(12):1177-1188. Epub 2019 Dec 9.

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Maintenance of systemic homeostasis and the response to nutritional and environmental challenges require the coordination of multiple organs and tissues. To respond to various metabolic demands, higher organisms have developed a system of inter-organ communication through which one tissue can affect metabolic pathways in a distant tissue. Dysregulation of these lines of communication contributes to human pathologies, including obesity, diabetes, liver disease and atherosclerosis. In recent years, technical advances such as data-driven bioinformatics, proteomics and lipidomics have enabled efforts to understand the complexity of systemic metabolic cross-talk and its underlying mechanisms. Here, we provide an overview of inter-organ signals and their roles in metabolic control, and highlight recent discoveries in the field. We review peptide, small-molecule and lipid mediators secreted by metabolic tissues, as well as the role of the central nervous system in orchestrating peripheral metabolic functions. Finally, we discuss the contributions of inter-organ signalling networks to the features of metabolic syndrome.
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http://dx.doi.org/10.1038/s42255-019-0145-5DOI Listing
December 2019

LDL Receptor Pathway Regulation by miR-224 and miR-520d.

Front Cardiovasc Med 2020 22;7:81. Epub 2020 May 22.

Leon H. Charney Division of Cardiology, NYU Cardiovascular Research Center, Department of Medicine, New York University School of Medicine, New York, NY, United States.

MicroRNAs (miRNA) have emerged as important post-transcriptional regulators of metabolic pathways that contribute to cellular and systemic lipoprotein homeostasis. Here, we identify two conserved miRNAs, miR-224, and miR-520d, which target gene networks regulating hepatic expression of the low-density lipoprotein (LDL) receptor (LDLR) and LDL clearance. prediction of miR-224 and miR-520d target gene networks showed that they each repress multiple genes impacting the expression of the LDLR, including the chaperone molecules PCSK9 and IDOL that limit LDLR expression at the cell surface and the rate-limiting enzyme for cholesterol synthesis HMGCR, which is the target of LDL-lowering statin drugs. Using gain- and loss-of-function studies, we tested the role of miR-224 and miR-520d in the regulation of those predicted targets and their impact on LDLR expression. We show that overexpression of miR-224 or miR-520d dose-dependently reduced the activity of , and 3'-untranslated region (3'-UTR)-luciferase reporter constructs and that this repression was abrogated by mutation of the putative miR-224 or miR-520d response elements in the , and 3'-UTRs. Compared to a control miRNA, overexpression of miR-224 or miR-520d in hepatocytes inhibited , and mRNA and protein levels and decreased PCSK9 secretion. Furthermore, miR-224 and miR-520d repression of , and was associated with an increase in LDLR protein levels and cell surface expression, as well as enhanced LDL binding. Notably, the effects of miR-224 and miR-520d were additive to the effects of statins in upregulating LDLR expression. Finally, we show that overexpression of miR-224 in the livers of mice using lipid nanoparticle-mediated delivery resulted in a 15% decrease in plasma levels of LDL cholesterol, compared to a control miRNA. Together, these findings identify roles for miR-224 and miR-520d in the posttranscriptional control of LDLR expression and function.
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http://dx.doi.org/10.3389/fcvm.2020.00081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256473PMC
May 2020

Interferon-mediated reprogramming of membrane cholesterol to evade bacterial toxins.

Nat Immunol 2020 07 8;21(7):746-755. Epub 2020 Jun 8.

Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.

Plasma membranes of animal cells are enriched for cholesterol. Cholesterol-dependent cytolysins (CDCs) are pore-forming toxins secreted by bacteria that target membrane cholesterol for their effector function. Phagocytes are essential for clearance of CDC-producing bacteria; however, the mechanisms by which these cells evade the deleterious effects of CDCs are largely unknown. Here, we report that interferon (IFN) signals convey resistance to CDC-induced pores on macrophages and neutrophils. We traced IFN-mediated resistance to CDCs to the rapid modulation of a specific pool of cholesterol in the plasma membrane of macrophages without changes to total cholesterol levels. Resistance to CDC-induced pore formation requires the production of the oxysterol 25-hydroxycholesterol (25HC), inhibition of cholesterol synthesis and redistribution of cholesterol to an esterified cholesterol pool. Accordingly, blocking the ability of IFN to reprogram cholesterol metabolism abrogates cellular protection and renders mice more susceptible to CDC-induced tissue damage. These studies illuminate targeted regulation of membrane cholesterol content as a host defense strategy.
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http://dx.doi.org/10.1038/s41590-020-0695-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778040PMC
July 2020

ABHD12 and LPCAT3 Interplay Regulates a Lyso-phosphatidylserine-C20:4 Phosphatidylserine Lipid Network Implicated in Neurological Disease.

Biochemistry 2020 05 4;59(19):1793-1799. Epub 2020 May 4.

Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States.

PHARC (polyneuropathy, hearing loss, cerebellar ataxia, retinitis pigmentosa, and cataract) is a human neurological disorder caused by deleterious mutations in the gene, which encodes an integral membrane lyso-phosphatidylserine (lyso-PS) lipase. Pharmacological or genetic disruption of ABHD12 leads to higher levels of lyso-PS lipids in human cells and the central nervous system (CNS) of mice. ABHD12 loss also causes rapid rewiring of PS content, resulting in selective increases in the level of arachidonoyl (C20:4) PS and decreases in the levels of other PS species. The biochemical basis for ABHD12-dependent PS remodeling and its pathophysiological significance remain unknown. Here, we show that genetic deletion of the lysophospholipid acyltransferase LPCAT3 blocks accumulation of brain C20:4 PS in mice lacking ABHD12 and concurrently produces hyper-increases in the level of lyso-PS in these animals. These lipid changes correlate with exacerbated auditory dysfunction and brain microgliosis in mice lacking both ABHD12 and LPCAT3. Taken together, our findings reveal that ABHD12 and LPCAT3 coordinately regulate lyso-PS and C20:4 PS content in the CNS and point to lyso-PS lipids as the likely bioactive metabolites contributing to PHARC-related neuropathologies.
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http://dx.doi.org/10.1021/acs.biochem.0c00292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394188PMC
May 2020

Cultured macrophages transfer surplus cholesterol into adjacent cells in the absence of serum or high-density lipoproteins.

Proc Natl Acad Sci U S A 2020 05 30;117(19):10476-10483. Epub 2020 Apr 30.

Department of Medicine, University of California, Los Angeles, CA 90095;

Cholesterol-laden macrophage foam cells are a hallmark of atherosclerosis. For that reason, cholesterol metabolism in macrophages has attracted considerable scrutiny, particularly the mechanisms by which macrophages unload surplus cholesterol (a process referred to as "cholesterol efflux"). Many studies of cholesterol efflux in macrophages have focused on the role of ABC transporters in moving cholesterol onto high-density lipoproteins (HDLs), but other mechanisms for cholesterol efflux likely exist. We hypothesized that macrophages have the capacity to unload cholesterol directly onto adjacent cells. To test this hypothesis, we used methyl-β-cyclodextrin (MβCD) to load mouse peritoneal macrophages with [C]cholesterol. We then plated the macrophages (in the absence of serum or HDL) onto smooth muscle cells (SMCs) that had been metabolically labeled with [N]choline. After incubating the cells overnight in the absence of HDL or serum, we visualized C and N distribution by nanoscale secondary ion mass spectrometry (NanoSIMS). We observed substantial C enrichment in SMCs that were adjacent to [C]cholesterol-loaded macrophages-including in cytosolic lipid droplets of SMCs. In follow-up studies, we depleted "accessible cholesterol" from the plasma membrane of [C]cholesterol-loaded macrophages with MβCD before plating the macrophages onto the SMCs. After an overnight incubation, we again observed substantial C enrichment in the SMCs adjacent to macrophages. Thus, macrophages transfer cholesterol to adjacent cells in the absence of serum or HDL. We suspect that macrophages within tissues transfer cholesterol to adjacent cells, thereby contributing to the ability to unload surplus cholesterol.
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http://dx.doi.org/10.1073/pnas.1922879117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229689PMC
May 2020

Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis.

Cell Metab 2020 May 6;31(5):969-986.e7. Epub 2020 Apr 6.

Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address:

Incomplete understanding of how hepatosteatosis transitions to fibrotic non-alcoholic steatohepatitis (NASH) has limited therapeutic options. Two molecules that are elevated in hepatocytes in human NASH liver are cholesterol, whose mechanistic link to NASH remains incompletely understood, and TAZ, a transcriptional regulator that promotes fibrosis but whose mechanism of increase in NASH is unknown. We now show that increased hepatocyte cholesterol upregulates TAZ and promotes fibrotic NASH. ASTER-B/C-mediated internalization of plasma membrane cholesterol activates soluble adenylyl cyclase (sAC; ADCY10), triggering a calcium-RhoA-mediated pathway that suppresses β-TrCP/proteasome-mediated TAZ degradation. In mice fed with a cholesterol-rich NASH-inducing diet, hepatocyte-specific silencing of ASTER-B/C, sAC, or RhoA decreased TAZ and ameliorated fibrotic NASH. The cholesterol-TAZ pathway is present in primary human hepatocytes, and associations among liver cholesterol, TAZ, and RhoA in human NASH liver are consistent with the pathway. Thus, hepatocyte cholesterol contributes to fibrotic NASH by increasing TAZ, suggesting new targets for therapeutic intervention.
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http://dx.doi.org/10.1016/j.cmet.2020.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313619PMC
May 2020

IDOL regulates systemic energy balance through control of neuronal VLDLR expression.

Nat Metab 2019 11 28;1(11):1089-1100. Epub 2019 Oct 28.

Department of Pathology and Laboratory Medicine, Department of Biological Chemistry, and Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Liver X receptors limit cellular lipid uptake by stimulating the transcription of Inducible Degrader of the LDL Receptor (IDOL), an E3 ubiquitin ligase that targets lipoprotein receptors for degradation. The function of IDOL in systemic metabolism is incompletely understood. Here we show that loss of IDOL in mice protects against the development of diet-induced obesity and metabolic dysfunction by altering food intake and thermogenesis. Unexpectedly, analysis of tissue-specific knockout mice revealed that IDOL affects energy balance, not through its actions in peripheral metabolic tissues (liver, adipose, endothelium, intestine, skeletal muscle), but by controlling lipoprotein receptor abundance in neurons. Single-cell RNA sequencing of the hypothalamus demonstrated that IDOL deletion altered gene expression linked to control of metabolism. Finally, we identify VLDLR rather than LDLR as the primary mediator of IDOL effects on energy balance. These studies identify a role for the neuronal IDOL-VLDLR pathway in metabolic homeostasis and diet-induced obesity.
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http://dx.doi.org/10.1038/s42255-019-0127-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028310PMC
November 2019

Therapeutic IDOL Reduction Ameliorates Amyloidosis and Improves Cognitive Function in APP/PS1 Mice.

Mol Cell Biol 2020 03 30;40(8). Epub 2020 Mar 30.

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, USA

Brain lipoprotein receptors have been shown to regulate the metabolism of ApoE and β-amyloid (Aβ) and are potential therapeutic targets for Alzheimer's disease (AD). Previously, we identified E3 ubiquitin ligase IDOL as a negative regulator of brain lipoprotein receptors. Genetic ablation of increases low-density lipoprotein receptor protein levels, which facilitates Aβ uptake and clearance by microglia. In this study, we utilized an antisense oligonucleotide (ASO) to reduce IDOL expression therapeutically in the brains of APP/PS1 male mice. ASO treatment led to decreased Aβ pathology and improved spatial learning and memory. Single-cell transcriptomic analysis of hippocampus revealed that IDOL inhibition upregulated lysosomal/phagocytic genes in microglia. Furthermore, clustering of microglia revealed that IDOL-ASO treatment shifted the composition of the microglia population by increasing the prevalence of disease-associated microglia. Our results suggest that reducing IDOL expression in the adult brain promotes the phagocytic clearance of Aβ and ameliorates Aβ-dependent pathology. Pharmacological inhibition of IDOL activity in the brain may represent a therapeutic strategy for the treatment of AD.
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http://dx.doi.org/10.1128/MCB.00518-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108818PMC
March 2020

LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target.

JCI Insight 2020 01 16;5(1). Epub 2020 Jan 16.

Duke Eye Center, Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina, USA.

Effective treatments and animal models for the most prevalent neurodegenerative form of blindness in elderly people, called age-related macular degeneration (AMD), are lacking. Genome-wide association studies have identified lipid metabolism and inflammation as AMD-associated pathogenic pathways. Given liver X receptors (LXRs), encoded by the nuclear receptor subfamily 1 group H members 2 and 3 (NR1H3 and NR1H2), are master regulators of these pathways, herein we investigated the role of LXR in human and mouse eyes as a function of age and disease and tested the therapeutic potential of targeting LXR. We identified immunopositive LXR fragments in human extracellular early dry AMD lesions and a decrease in LXR expression within the retinal pigment epithelium (RPE) as a function of age. Aged mice lacking LXR presented with isoform-dependent ocular pathologies. Specifically, loss of the Nr1h3 isoform resulted in pathobiologies aligned with AMD, supported by compromised visual function, accumulation of native and oxidized lipids in the outer retina, and upregulation of ocular inflammatory cytokines, while absence of Nr1h2 was associated with ocular lipoidal degeneration. LXR activation not only ameliorated lipid accumulation and oxidant-induced injury in RPE cells but also decreased ocular inflammatory markers and lipid deposition in a mouse model, thereby providing translational support for pursuing LXR-active pharmaceuticals as potential therapies for dry AMD.
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http://dx.doi.org/10.1172/jci.insight.131928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7030875PMC
January 2020

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

Elife 2019 10 23;8. Epub 2019 Oct 23.

Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, United States.

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. ingle uclei diocyte RNAuencing (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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http://dx.doi.org/10.7554/eLife.49501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6837845PMC
October 2019