CCL5 Promotes Macrophage Recruitment and Survival in Human Adipose Tissue
To examine the role of adipose-produced chemokine, chemokine ligand (CCL) 5, on the recruitment and survival of macrophages in human white adipose tissue (WAT).
CCL5 levels measured by enzyme immunoassay in serum and by real-time polymerase chain reaction in WAT were higher in obese compared to lean subjects. CCL5, but not CCL2, secretion was higher in visceral compared to subcutaneous WAT. CCL5 mRNA expression was positively correlated with the inflammatory macrophage markers as CD11b, tumor necrosis factor-alpha, and IL-6 in visceral WAT (n=24 obese subjects), and was higher in macrophages than other WAT cells. We found that CCL5 triggered adhesion and transmigration of blood monocytes to/through endothelial cells of human WAT. Whereas in obese WAT apoptotic macrophages were located around necrotic adipocytes, we demonstrated that CCL5, but not CCL2, protected macrophages from free cholesterol-induced apoptosis via activation of the Akt/Erk pathways.
CCL5 could participate in the inflammation of obese WAT by recruiting blood monocytes and exerting antiapoptotic properties on WAT macrophages. This specific role of CCL5 on macrophage survival with maintenance of their lipid scavenging function should be taken into account for future therapeutic strategies in obesity-related diseases.
Available from: Lisette J A Kogelman
- "It plays a key role in recruiting leukocytes during immune response and plays a role in inducing the activation of Natural Killer cells
. It may also play a role in the inflammation of obese human white adipose tissue
, as it shows up-regulation in obese subjects
. SNX19 (sortin nexin 19) encodes a membrane-associated protein complex which is associated with coronary heart disease and myocardial infarction. "
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Obesity is a complex metabolic condition in strong association with various diseases, like type 2 diabetes, resulting in major public health and economic implications. Obesity is the result of environmental and genetic factors and their interactions, including genome-wide genetic interactions. Identification of co-expressed and regulatory genes in RNA extracted from relevant tissues representing lean and obese individuals provides an entry point for the identification of genes and pathways of importance to the development of obesity. The pig, an omnivorous animal, is an excellent model for human obesity, offering the possibility to study in-depth organ-level transcriptomic regulations of obesity, unfeasible in humans. Our aim was to reveal adipose tissue co-expression networks, pathways and transcriptional regulations of obesity using RNA Sequencing based systems biology approaches in a porcine model.
We selected 36 animals for RNA Sequencing from a previously created F2 pig population representing three extreme groups based on their predicted genetic risks for obesity. We applied Weighted Gene Co-expression Network Analysis (WGCNA) to detect clusters of highly co-expressed genes (modules). Additionally, regulator genes were detected using Lemon-Tree algorithms.
WGCNA revealed five modules which were strongly correlated with at least one obesity-related phenotype (correlations ranging from -0.54 to 0.72, P < 0.001). Functional annotation identified pathways enlightening the association between obesity and other diseases, like osteoporosis (osteoclast differentiation, P = 1.4E-7), and immune-related complications (e.g. Natural killer cell mediated cytotoxity, P = 3.8E-5; B cell receptor signaling pathway, P = 7.2E-5). Lemon-Tree identified three potential regulator genes, using confident scores, for the WGCNA module which was associated with osteoclast differentiation: CCR1, MSR1 and SI1 (probability scores respectively 95.30, 62.28, and 34.58). Moreover, detection of differentially connected genes identified various genes previously identified to be associated with obesity in humans and rodents, e.g. CSF1R and MARC2.
To our knowledge, this is the first study to apply systems biology approaches using porcine adipose tissue RNA-Sequencing data in a genetically characterized porcine model for obesity. We revealed complex networks, pathways, candidate and regulatory genes related to obesity, confirming the complexity of obesity and its association with immune-related disorders and osteoporosis.
BMC Medical Genomics 09/2014; 7(1):57. DOI:10.1186/1755-8794-7-57 · 2.87 Impact Factor
Available from: Kelly S Swanson
- "CCL2 expression is positively correlated with macrophage accumulation in adipose tissue, with overexpression being associated with obesity and insulin resistance [66-68]. CCL5 functions similarly by recruiting macrophages into adipose tissue and activating nuclear factor-kappa-B (NFκB) signaling [69,70]. PAI1 is a protease inhibitor that facilitates blood clotting. "
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Photoperiod is known to cause physiological changes in seasonal mammals, including changes in body weight, physical activity, reproductive status, and adipose tissue gene expression in several species. The objective of this study was to determine the effects of day length on the adipose transcriptome of cats as assessed by RNA sequencing. Ten healthy adult neutered male domestic shorthair cats were used in a randomized crossover design study. During two 12-wk periods, cats were exposed to either short days (8 hr light:16 hr dark) or long days (16 hr light:8 hr dark). Cats were fed a commercial diet to maintain baseline body weight to avoid weight-related bias. Subcutaneous adipose biopsies were collected at wk 12 of each period for RNA isolation and sequencing.
A total of 578 million sequences (28.9 million/sample) were generated by Illumina sequencing. A total of 170 mRNA transcripts were differentially expressed between short day- and long day-housed cats. 89 annotated transcripts were up-regulated by short days, while 24 annotated transcripts were down-regulated by short days. Another 57 un-annotated transcripts were also different between groups. Adipose tissue of short day-housed cats had greater expression of genes involved with cell growth and differentiation (e.g., myostatin; frizzled-related protein), cell development and structure (e.g., cytokeratins), and protein processing and ubiquitination (e.g., kelch-like proteins). In contrast, short day-housed cats had decreased expression of genes involved with immune function (e.g., plasminogen activator inhibitor 1; chemokine (C-C motif) ligand 2; C-C motif chemokine 5; T-cell activators), and altered expression of genes associated with carbohydrate and lipid metabolism.
Collectively, these gene expression changes suggest that short day housing may promote adipogenesis, minimize inflammation and oxidative stress, and alter nutrient metabolism in feline adipose tissue, even when fed to maintain body weight. Although this study has highlighted molecular mechanisms contributing to the seasonal metabolic changes observed in cats, future research that specifically targets and studies these biological pathways, and the physiological outcomes that are affected by them, is justified.
BMC Veterinary Research 07/2014; 10(1):146. DOI:10.1186/1746-6148-10-146 · 1.78 Impact Factor
Available from: Said Dermime
- "Regulated upon Activation Normal T cells Expressed and Secreted (RANTES or CCL5) is a powerful proinflammatory mediator of the CC chemokine family that regulates the mobilization and, in certain cases, promotes survival of immune inflammatory cells from the bloodstream into tissues and other areas of injury and infection   . Although the chemotactic activity of RANTES on immune cells to injured and infected areas is beneficial, sustained production of RANTES is associated with several detrimental effects such as atherosclerosis  , arthritis rheumatoid , liver disease  , and viral infection  that share in common chronic inflammatory response. "
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ABSTRACT: RANTES and its CCR5 receptor trigger inflammation and its progression to insulin resistance in obese. In the present study, we investigated for the first time the effect of physical exercise on the expression of RANTES and CCR5 in obese humans. Fifty-seven adult nondiabetic subjects (17 lean and 40 obese) were enrolled in a 3-month supervised physical exercise. RANTES and CCR5 expressions were measured in PBMCs and subcutaneous adipose tissue before and after exercise. Circulating plasma levels of RANTES were also investigated. There was a significant increase in RANTES and CCR5 expression in the subcutaneous adipose tissue of obese compared to lean. In PBMCs, however, while the levels of RANTES mRNA and protein were comparable between both groups, CCR5 mRNA was downregulated in obese subjects (P < 0.05). Physical exercise significantly reduced the expression of both RANTES and CCR5 (P < 0.05) in the adipose tissue of obese individuals with a concomitant decrease in the levels of the inflammatory markers TNF- α , IL-6, and P-JNK. Circulating RANTES correlated negatively with anti-inflammatory IL-1ra (P = 0.001) and positively with proinflammatory IP-10 and TBARS levels (P < 0.05). Therefore, physical exercise may provide an effective approach for combating the deleterious effects associated with obesity through RANTES signaling in the adipose tissue.
Mediators of Inflammation 04/2014; 2014(6). DOI:10.1155/2014/627150 · 3.24 Impact Factor
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