scholarly journals Microglial Lipid Biology in the Hypothalamic Regulation of Metabolic Homeostasis

2021 ◽  
Vol 12 ◽  
Author(s):  
Andrew Folick ◽  
Suneil K. Koliwad ◽  
Martin Valdearcos
Keyword(s):  
Metabolic Disease ◽  
Lipid Metabolism ◽  
Myeloid Cells ◽  
Synaptic Organization ◽  
Transcriptional Signature ◽  
Brain Physiology ◽  
Recent Emergence ◽  
Hypothalamic Regulation ◽  
Excessive Consumption ◽  
Health And Disease

In mammals, myeloid cells help maintain the homeostasis of peripheral metabolic tissues, and their immunologic dysregulation contributes to the progression of obesity and associated metabolic disease. There is accumulating evidence that innate immune cells also serve as functional regulators within the mediobasal hypothalamus (MBH), a critical brain region controlling both energy and glucose homeostasis. Specifically, microglia, the resident parenchymal myeloid cells of the CNS, play important roles in brain physiology and pathology. Recent studies have revealed an expanding array of microglial functions beyond their established roles as immune sentinels, including roles in brain development, circuit refinement, and synaptic organization. We showed that microglia modulate MBH function by transmitting information resulting from excess nutrient consumption. For instance, microglia can sense the excessive consumption of saturated fats and instruct neurons within the MBH accordingly, leading to responsive alterations in energy balance. Interestingly, the recent emergence of high-resolution single-cell techniques has enabled specific microglial populations and phenotypes to be profiled in unprecedented detail. Such techniques have highlighted specific subsets of microglia notable for their capacity to regulate the expression of lipid metabolic genes, including lipoprotein lipase (LPL), apolipoprotein E (APOE) and Triggering Receptor Expressed on Myeloid Cells 2 (TREM2). The discovery of this transcriptional signature highlights microglial lipid metabolism as a determinant of brain health and disease pathogenesis, with intriguing implications for the treatment of brain disorders and potentially metabolic disease. Here we review our current understanding of how changes in microglial lipid metabolism could influence the hypothalamic control of systemic metabolism.

scholarly journals Gingival crevicular fluid level of soluble triggering recep-tor expressed on myeloid cells-1(strem-1) in periodontal health and disease: a case-control study

2017 ◽  
Vol 5 (2) ◽  
pp. 83
Author(s):  
Surabhi Gigras ◽  
Sudhir R Patil ◽  
Veena HR ◽  
Sneha Dani
Keyword(s):  
Chronic Periodontitis ◽  
Myeloid Cells ◽  
Cell Surface Receptor ◽  
Periodontal Health ◽  
Group Iii ◽  
Root Planing ◽  
Group I ◽  
Health And Disease ◽  
Group Ii ◽  
Crevicular Fluid

Background: The Triggering Receptor Expressed On Myeloid Cells-1(TREM-1) is a cell-surface receptor of the immunoglobulin superfamily and found to be involved in the amplification of the inflammatory response to various microbial infections, including periodontal diseases.Objectives: The present study was designed to examine gingivalcrevicular fluid(GCF) levels of soluble TREM-1 (sTREM-1) levels in periodontal health and disease as well as evaluate the effect of scaling and/or root planing on the same.Methods: Based on gingival index, probing pocket depth, clinical attachment level, and radiologic parameters (bone loss), 45 subjects were initially divided into three groups- Group, I (Periodontally healthy), Group II (Gingivitis) and Group III (Chronic Periodontitis).From each of the subjects, GCF sample was collected at baseline and scaling and/or root planing was instituted in group II and group III patients. GCF samples were subsequently collected at eight-week interval. Levels of sTREM-1 in collected GCF samples were estimated using enzyme-linked immunosorbent assay.Results: The lowest GCF levels of sTREM-1 were found in periodontal health (69.50±1.8pg/ml) followed by gingivitis (257.17±79pg/ml) and chronic periodontitis (3658.14±55pg/ml) in increasing order, suggesting that levels of sTREM-1 in crevicular fluid increased with the severity of periodontal disease. sTREM-1 levels decreased significantly from baseline to the end of 8 weeks following non-surgical periodontal therapy.Conclusion: Increased GCF levels of sTREM-1 from periodontal health to disease strengthen its association with periodontal status.

The Myeloid-Kidney Interface in Health and Disease

2021 ◽  
pp. CJN.04120321
Author(s):  
Caitlyn Vlasschaert ◽  
Sarah Moran ◽  
Michael Rauh
Keyword(s):  
Structural Damage ◽  
Functional Decline ◽  
Myeloid Cells ◽  
Kidney Injury ◽  
Myeloid Cell ◽  
Surveillance Network ◽  
Targeted Treatments ◽  
Myeloid Leukemias ◽  
Integral Role ◽  
Health And Disease

Kidney homeostasis is highly dependent upon the correct functioning of myeloid cells. These cells form a distributed surveillance network throughout the kidney, where they play an integral role in the response to organ threat. Dysregulation of resident pro-inflammatory and pro-fibrotic macrophages leads to kidney structural damage and scarring following kidney injury. Fibrosis throughout the kidney parenchyma contributes to the progressive functional decline observed in chronic kidney disease (CKD), independent of the etiology. Circulating myeloid cells bearing intrinsic defects also affect the kidney substructures, such as neutrophils activated by autoantibodies that cause glomerulonephritis in ANCA-associated vasculitis. The kidney can also be affected by disorders of myelopoiesis, including myeloid leukemias (AML, CML) and myelodysplastic syndromes (MDS). Clonal hematopoiesis of indeterminate potential (CHIP) is a common, newly recognized pre-malignant clinical entity characterized by clonal expansion of hyper-inflammatory myeloid lineage cells that may have significant kidney sequelae. A number of existing therapies in CKD target myeloid cells and inflammation, including glucocorticoid receptor agonists and mineralocorticoid receptor antagonists. The therapeutic indications for these and other myeloid cell-targeted treatments is poised to expand as our understanding of the myeloid-kidney interface evolves.

scholarly journals miR-125a-5p: a novel regulator of SLC26A6 expression in intestinal epithelial cells

2019 ◽  
Vol 317 (2) ◽  
pp. C200-C208 ◽  
Author(s):  
Arivarasu N. Anbazhagan ◽  
Shubha Priyamvada ◽  
Alip Borthakur ◽  
Seema Saksena ◽  
Ravinder K. Gill ◽  
...  
Keyword(s):  
Untranslated Region ◽  
In Silico Analysis ◽  
Luciferase Reporter ◽  
Intestinal Epithelial ◽  
Protein Levels ◽  
Anion Transporter ◽  
Oxalate Secretion ◽  
Recent Emergence ◽  
Health And Disease ◽  
And Function

Putative anion transporter 1 (PAT1, SLC26A6), an intestinal epithelial Cl−/[Formula: see text] exchanger, also plays a key role in oxalate homeostasis via mediating intestinal oxalate secretion. Indeed, Slc26a6-null mice showed defect in intestinal oxalate secretion and high incidence of kidney stones. Recent emergence of PAT-1 as a novel therapeutic target for nephrolithiasis warrants detailed understanding of the mechanisms of PAT-1 regulation in health and disease. Therefore, we investigated the regulation of PAT-1 expression by microRNAs (miRNA), as they have been shown to play key role in modulating expression of other ion transporters. In silico analysis of PAT-1 3′-untranslated region (UTR) revealed potential binding sites for several miRNAs, suggesting the role of miRNAs in modulating PAT1 expression. miRNAs showing highest context scores (125a-5p, 339-5p, 423-5p, 485-5p, and 501-3p) were selected as candidates for their effects on the activity of a 263-bp PAT-1 3′-untranslated region (UTR) fragment cloned into pmirGLO vector upstream of luciferase. The 3′-UTR activity was measured by dual luciferase reporter assay in Caco-2, T-84, HT-29, and SK-CO15 cells. Transient transfection of PAT-1 3′-UTR significantly decreased the relative luciferase activity compared with the empty vector suggesting binding of potential miRNA(s) to the PAT-1 3′-UTR. Among all the selected candidates, cotransfection with miRNA mimics 125a-5p and 423-5p further decreased PAT-1 3′-UTR activity. Furthermore, increasing miR-125a-5p abundance via mimic transfection in Caco-2 cells decreased both mRNA and protein levels of PAT-1. Our results demonstrate a novel regulatory mechanism of intestinal PAT-1 expression via miR-125a-5p that could be of therapeutic importance in disorders associated with decreased PAT-1 expression and function.

Circadian Rhythm of Lipid Metabolism in Health and Disease

Small Methods ◽  
2020 ◽  
Vol 4 (7) ◽  
pp. 1900601 ◽  
Author(s):  
Zhihui Zhang ◽  
Haoran Xin ◽  
Min‐Dian Li
Keyword(s):  
Circadian Rhythm ◽  
Lipid Metabolism ◽  
Health And Disease

scholarly journals Integrative transcriptome and chromatin landscape analysis reveals distinct epigenetic regulations in human memory B cells

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Justin B. Moroney ◽  
Anusha Vasudev ◽  
Alexander Pertsemlidis ◽  
Hong Zan ◽  
Paolo Casali
Keyword(s):  
B Cells ◽  
Target Genes ◽  
Human Memory ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Memory B Cells ◽  
Transcriptional Signature ◽  
Integrative Analyses ◽  
Health And Disease ◽  
Variable Gene

Abstract Memory B cells (MBCs) are long-lived and produce high-affinity, generally, class-switched antibodies. Here, we use a multiparameter approach involving CD27 to segregate naïve B cells (NBC), IgD+ unswitched (unsw)MBCs and IgG+ or IgA+ class-switched (sw)MBCs from humans of different age, sex and race. Conserved antibody variable gene expression indicates that MBCs emerge through unbiased selection from NBCs. Integrative analyses of mRNAs, miRNAs, lncRNAs, chromatin accessibility and cis-regulatory elements uncover a core mRNA-ncRNA transcriptional signature shared by IgG+ and IgA+ swMBCs and distinct from NBCs, while unswMBCs display a transitional transcriptome. Some swMBC transcriptional signature loci are accessible but not expressed in NBCs. Profiling miRNAs reveals downregulated MIR181, and concomitantly upregulated MIR181 target genes such as RASSF6, TOX, TRERF1, TRPV3 and RORα, in swMBCs. Finally, lncRNAs differentially expressed in swMBCs cluster proximal to the IgH chain locus on chromosome 14. Our findings thus provide new insights into MBC transcriptional programs and epigenetic regulation, opening new investigative avenues on these critical cell elements in human health and disease.

scholarly journals OR04-04 Identification of a Novel Transcriptional Regulator of Metabolic Disease in Circulating and Central Myeloid Cells

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
David R Sweet ◽  
Neelakantan T Vasudevan ◽  
Liyan Fan ◽  
Chloe E Booth ◽  
Komal S Keerthy ◽  
...  
Keyword(s):  
Metabolic Disease ◽  
Immune Cells ◽  
Therapeutic Option ◽  
Myeloid Cells ◽  
Metabolic Stress ◽  
Myeloid Cell ◽  
Metabolic Phenotype ◽  
Adipose Tissue Macrophages ◽  
Improved Outcomes ◽  
Peripheral Immune Cells

Abstract Derangement in systemic metabolic homeostasis is tightly associated with widespread activation of resident and circulating immune cells, a phenomenon known as ‘metaflammation’. Numerous studies have explored the role of tissue resident and circulating macrophages in contributing to metaflammation, obesity, and their sequelae; however, there is a dearth of information regarding targetable transcriptional regulators of the genesis and persistence of metabolic disease. Here, we identify myeloid Krüppel-like factor 2 (KLF2) as a novel regulator of metabolic disease. Previous reports demonstrate that KLF2 serves as a critical regulator of myeloid cell quiescence and is downregulated in numerous acute and chronic inflammatory states. Specifically in the context of chronic metaflammation, we note that KLF2 expression is decreased in circulating immune cells of obese patients and in adipose tissue macrophages of high fat diet (HFD) fed mice, which is consistent with the hypothesis that KLF2 regulates metaflammation. To explore this further, we utilized mice with myeloid cell-specific deletion of KLF2 (K2KO) which exhibit accelerated obesity and insulin resistance. K2KO mice have widespread central (i.e. CNS) and peripheral metaflammation both in the basal and HFD-stimulated states. To discern whether the effect of myeloid deletion of KLF2 on metabolism is due to deletion in microglia in the feeding centers of the hypothalamus or in peripheral immune cells, bone marrow chimeras with head shielding were created. 50% reconstitution of circulating immune cells with K2KO cells in wildtype (WT) mice was sufficient to maintain the metabolic disease phenotype, while mice with K2KO microglia + WT circulating cells had only slightly improved outcomes compared to K2KO mice. Conversely, ablation of microglia in K2KO mice using PLX5622 formulated in HFD also successfully attenuated the aberrant feeding behavior, weight gain, and glucose dyshomeostasis seen in K2KO mice. Together, these data demonstrate a role for loss of KLF2 in hematopoietic and CNS resident cells in causing metabolic disease. Given that myeloid KLF2 expression decreases under metabolic stress in WT mice and humans, we sought to explore whether maintenance of KLF2 expression in these cells would be protective against diet-induced metabolic disease. Indeed, mice with myeloid-specific overexpression of KLF2 demonstrated a markedly improved metabolic phenotype when challenged with HFD, providing evidence that targeting KLF2 expression in myeloid cells may prove to be a therapeutic option against metaflammation.

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