scholarly journals Role of Tim4 in the regulation of ABCA1+ adipose tissue macrophages and post-prandial cholesterol levels

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
M. S. Magalhaes ◽  
P. Smith ◽  
J. R. Portman ◽  
L. H. Jackson-Jones ◽  
C. C. Bain ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Transcriptional Activation ◽  
Density Lipoprotein ◽  
Cholesterol Transport ◽  
Tissue Macrophage ◽  
Phosphatidylserine Receptor ◽  
Adipose Tissue Macrophages ◽  
Main Driver ◽  
New Treatments ◽  
Bone Marrow Chimeras

AbstractDyslipidemia is a main driver of cardiovascular diseases. The ability of macrophages to scavenge excess lipids implicate them as mediators in this process and understanding the mechanisms underlying macrophage lipid metabolism is key to the development of new treatments. Here, we investigated how adipose tissue macrophages regulate post-prandial cholesterol transport. Single-cell RNA sequencing and protected bone marrow chimeras demonstrated that ingestion of lipids led to specific transcriptional activation of a population of resident macrophages expressing Lyve1, Tim4, and ABCA1. Blocking the phosphatidylserine receptor Tim4 inhibited lysosomal activation and the release of post-prandial high density lipoprotein cholesterol following a high fat meal. Both effects were recapitulated by chloroquine, an inhibitor of lysosomal function. Moreover, clodronate-mediated cell-depletion implicated Tim4+ resident adipose tissue macrophages in this process. Thus, these data indicate that Tim4 is a key regulator of post-prandial cholesterol transport and adipose tissue macrophage function and may represent a novel pathway to treat dyslipidemia.

scholarly journals Adipose Tissue Immunometabolism and Apoptotic Cell Clearance

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2288
Author(s):  
Tamás Röszer
Keyword(s):  
Adipose Tissue ◽  
Metabolic Diseases ◽  
Apoptotic Cell ◽  
Apoptotic Cells ◽  
Immune Functions ◽  
Tissue Macrophage ◽  
Sequence Of Events ◽  
Cell Clearance ◽  
Adipose Tissue Macrophages ◽  
Dying Cells

The safe removal of apoptotic debris by macrophages—often referred to as efferocytosis—is crucial for maintaining tissue integrity and preventing self-immunity or tissue damaging inflammation. Macrophages clear tissues of hazardous materials from dying cells and ultimately adopt a pro-resolving activation state. However, adipocyte apoptosis is an inflammation-generating process, and the removal of apoptotic adipocytes by so-called adipose tissue macrophages triggers a sequence of events that lead to meta-inflammation and obesity-associated metabolic diseases. Signals that allow apoptotic cells to control macrophage immune functions are complex and involve metabolites released by the apoptotic cells and also metabolites produced by the macrophages during the digestion of apoptotic cell contents. This review provides a concise summary of the adipocyte-derived metabolites that potentially control adipose tissue macrophage immune functions and, hence, may induce or alleviate adipose tissue inflammation.

scholarly journals AP2-NR4A3 transgenic mice display reduced serum epinephrine because of increased catecholamine catabolism in adipose tissue

2016 ◽  
Vol 311 (1) ◽  
pp. E69-E81 ◽  
Author(s):  
R. Grace Walton ◽  
Xiaolin Zhu ◽  
Ling Tian ◽  
Elizabeth B. Heywood ◽  
Jian Liu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Tolerance ◽  
Monoamine Oxidase ◽  
Transgenic Mice ◽  
Transcriptional Activation ◽  
Density Lipoprotein ◽  
Monoamine Oxidase A ◽  
Orphan Nuclear Receptors ◽  
Fatty Acid Binding

The NR4A orphan nuclear receptors function as early response genes to numerous stimuli. Our laboratory has previously demonstrated that overexpression of NR4A3 (NOR-1, MINOR) in 3T3-L1 adipocytes enhances insulin-stimulated glucose uptake. To assess the in vivo effect of NR4A3 on adipocytes, we generated transgenic mice with NR4A3 overexpression driven by the adipocyte fatty acid-binding protein (AP2) promoter (AP2-NR4A3 mice). We hypothesized that AP2-NR4A3 mice would display enhanced glucose tolerance and insulin sensitivity. However, AP2-NR4A3 mice exhibit metabolic impairment, including increased fasting glucose and insulin, impaired glucose tolerance, insulin resistance, decreased serum free fatty acids, and increased low-density lipoprotein-cholesterol. AP2-NR4A3 mice also display a significant reduction in serum epinephrine due to increased expression of catecholamine-catabolizing enzymes in adipose tissue, including monoamine oxidase-A. Furthermore, enhanced expression of monoamine oxidase-A is due to direct transcriptional activation by NR4A3. Finally, AP2-NR4A3 mice display cardiac and behavioral alterations consistent with chronically low circulating epinephrine levels. In conclusion, overexpression of NR4A3 in adipocytes produces a complex phenotype characterized by impaired glucose metabolism and low serum catecholamines due to enhanced degradation by adipose tissue.

scholarly journals Vasculature-associated adipose tissue macrophages dynamically adapt to inflammatory and metabolic challenges

2018 ◽  
Author(s):  
Hernandez Moura Silva ◽  
André Báfica ◽  
Gabriela Flavia Rodrigues-Luiz ◽  
Jingyi Chi ◽  
Patricia d’Emery Alves Santos ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Immune Cell ◽  
Metabolic Stress ◽  
Double Positive ◽  
Immune Cell Population ◽  
Inflammatory Stress ◽  
Tissue Macrophage ◽  
Adipose Tissue Macrophage ◽  
Adipose Tissue Macrophages ◽  
Macrophage Populations

AbstractTissue-resident macrophages comprise the most abundant immune cell population in healthy adipose tissue. Adipose tissue macrophage populations change during metabolic stress and ageing, and are thought to contribute to the pathogenesis of obesity. Here, we studied adipose tissue macrophage subpopulations in the steady state, and in response to nutritional and infectious challenges.Using comprehensive cell-surface-based and gene expression analyses, we found that tissue-resident macrophages from healthy epididymal white adipose tissue (eWAT) tightly associate with blood vessels, displaying a very high endocytic capacity. We refer to these cells as Vasculature-associated Adipose tissue Macrophages (VAMs). Chronic high fat diet (HFD) feeding results in the accumulation of a monocyte-derived CD11c+CD64+double positive (DP) macrophage eWAT population with a predominant anti-inflammatory gene profile, but reduced endocytic function. In contrast, fasting rapidly and reversibly leads to VAM depletion, while acute inflammatory stress induced by pathogens transiently depletes VAMs and simultaneously boosts DP macrophage accumulation. Our results indicate that adipose tissue macrophage populations adapt to metabolic stress and inflammation, suggesting an important role for these cells in restoring homeostasis.

2029-P: Role of Adipose Tissue Macrophage–Derived F13A1 in Regulating Preadipocyte Hyperplasia during Obesity

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 2029-P
Author(s):  
DIANA M. ELIZONDO ◽  
LYNN M. GELETKA ◽  
CARMEN G. FLESHER ◽  
CAREY N. LUMENG
Keyword(s):  
Adipose Tissue ◽  
Tissue Macrophage ◽  
Adipose Tissue Macrophage

Structure and Function of Proprotein Convertase Subtilisin/kexin Type 9 (PCSK9) in Hyperlipidemia and Atherosclerosis

2019 ◽  
Vol 20 (10) ◽  
pp. 1029-1040 ◽  
Author(s):  
Xinjie Lu
Keyword(s):  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Structure And Function ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Proprotein Convertase ◽  
Novel Target ◽  
New Treatments ◽  
And Function

Background:One of the important factors in Low-Density Lipoprotein (LDL) metabolism is the LDL receptor (LDLR) by its capacity to bind and subsequently clear cholesterol derived from LDL (LDL-C) in the circulation. Proprotein Convertase Subtilisin-like Kexin type 9 (PCSK9) is a newly discovered serine protease that destroys LDLR in the liver and thereby controls the levels of LDL in plasma. Inhibition of PCSK9-mediated degradation of LDLR has, therefore, become a novel target for lipid-lowering therapy.Methods:We review the current understanding of the structure and function of PCSK9 as well as its implications for the treatment of hyperlipidemia and atherosclerosis.Results:New treatments such as monoclonal antibodies against PCSK9 may be useful agents to lower plasma levels of LDL and hence prevent atherosclerosis.Conclusion:PCSK9's mechanism of action is not yet fully clarified. However, treatments that target PCSK9 have shown striking early efficacy and promise to improve the lives of countless patients with hyperlipidemia and atherosclerosis.

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