OBJECTIVELeukocyte infiltration of adipose is a critical determinant of obesity-related metabolic diseases. Fractalkine (CX3CL1) and its receptor (CX3CR1) comprise a chemokine system involved in leukocyte recruitment and adhesion in atherosclerosis, but its role in adipose inflammation and type 2 diabetes is unknown.RESEARCH DESIGN AND METHODSCX3CL1 mRNA and protein were quantified in subcutaneous adipose and blood during experimental human endotoxemia and in lean and obese human adipose. CX3CL1 cellular source was probed in human adipocytes, monocytes, and macrophages, and CX3CL1-blocking antibodies were used to assess its role in monocyte-adipocyte adhesion. The association of genetic variation in CX3CR1 with metabolic traits was determined in a community-based sample. Finally, plasma CX3CL1 levels were measured in a case-control study of type 2 diabetes.RESULTSEndotoxemia induced adipose CX3CL1 mRNA (32.7-fold, P < 1 × 10−5) and protein (43-fold, P = 0.006). Obese subjects had higher CX3CL1 levels in subcutaneous adipose compared with lean (0.420 ± 0.387 vs. 0.228 ± 0.187 ng/mL, P = 0.04). CX3CL1 was expressed and secreted by human adipocytes and stromal vascular cells. Inflammatory cytokine induction of CX3CL1 in human adipocytes (27.5-fold mRNA and threefold protein) was completely attenuated by pretreatment with a peroxisome proliferator–activated receptor-γ agonist. A putative functional nonsynonymous single nucleotide polymorphism (rs3732378) in CX3CR1 was associated with adipose and metabolic traits, and plasma CX3CL1 levels were increased in patients with type 2 diabetes vs. nondiabetics (0.506 ± 0.262 vs. 0.422 ± 0.210 ng/mL, P < 0.0001).CONCLUSIONSCX3CL1-CX3CR1 is a novel inflammatory adipose chemokine system that modulates monocyte adhesion to adipocytes and is associated with obesity, insulin resistance, and type 2 diabetes. These data provide support for CX3CL1 as a diagnostic and therapeutic target in cardiometabolic disease.
The association between potential long-term effects of previous schistosome infection (PSI) and the development of metabolic syndrome remains unknown. Therefore, we aimed to evaluate the association between them. Participants were from regions which were all reportedly heavily endemic for S. japonicum in China 40 years ago. One thousand five hundred and ninety-seven men were enrolled. Among these, 465 patients with PSI were selected as study subjects and 1132 subjects served as controls. We found PSI significantly correlated with lower prevalences of metabolic syndrome and its components, including central obesity, hypertriglyceridemia and low high-density lipoprotein cholesterol, which indicates that the potential long-term effects of PSI may reduce the risk of metabolic syndrome. However, further studies are needed to investigate the protective immune effects of PSI.
OBJECTIVEAdipose inflammation plays a central role in obesity-related metabolic and cardiovascular complications. However, few human adipose-secreted proteins are known to mediate these processes. We hypothesized that microarray mRNA profiling of human adipose during evoked inflammation could identify novel adipocytokines.RESEARCH DESIGN AND METHODSHealthy human volunteers (n = 14) were treated with intravenous endotoxin (3 ng/kg lipopolysaccharide [LPS]) and underwent subcutaneous adipose biopsies before and after LPS. On Affymetrix U133Plus 2.0 arrays, adipose mRNAs modulated >1.5-fold (with P < 0.00001) were selected. SignalP 3.0 and SecretomeP 2.0 identified genes predicted to encode secreted proteins. Of these, 86 candidates were chosen for validation in adipose from an independent human endotoxemia protocol (N = 7, with 0.6 ng/kg LPS) and for exploration of cellular origin in primary human adipocytes and macrophages in vitro.RESULTSMicroarray identified 776 adipose genes modulated by LPS; 298 were predicted to be secreted. Of detectable prioritized genes, 82 of 85 (96% [95% CI 90–99]) were upregulated (fold changes >1.0) during the lower-dose (LPS 0.6 ng/kg) validation study and 51 of 85 (59% [49–70]) were induced greater than 1.5-fold. Treatment of primary adipocytes with LPS and macrophage polarization to M1 proinflammatory phenotype increased expression by 1.5-fold for 58 and 73% of detectable genes, respectively.CONCLUSIONSWe demonstrate that evoked inflammation of human adipose in vivo modulated expression of multiple genes likely secreted by adipocytes and monocytes. These included established adipocytokines and chemokines implicated in recruitment and activation of lymphocytes, adhesion molecules, antioxidants, and several novel genes with unknown function. Such candidates may represent biomarkers and therapeutic targets for obesity-related complications.
The American Heart Association aims to improve cardiovascular health by encouraging the general population to meet 7 cardiovascular health behaviors and factors. The atherogenic index of plasma (AIP) is an important index. Our aim is to evaluate the relationship between ideal cardiovascular health and the atherogenic index of plasma (AIP) in middle-aged Chinese men.A cross-sectional study was performed. A total of 27,824 middle-aged Chinese men were enrolled. The association between ideal cardiovascular health behaviors and factors and AIP was determined. The 7 cardiovascular health metrics were scored as follows: 0, poor; 1, general; and 2, ideal. The cardiovascular health status was classified according to the total score, as follows: 0 to 4, inadequate; 5 to 9, average; and 10 to 14, optimum. Analyses assessed the prevalence of 7 cardiovascular health metrics, its association with AIP. Logistic regression models were used to calculate odds ratios (ORs), adjusting for age.All 7 cardiovascular health metrics were shown to correlate with AIP (all P values < 0.05), and the strongest correlation existed between body mass and AIP, followed by total cholesterol and AIP. The mean AIP level increased with the decrease in the score of each of the 7 cardiovascular health metrics (all P values < 0.05). The subjects with poor cardiovascular health status had a 4.982-fold increase in the high risk of developing atherosclerosis, whereas a 1-point increase in the cardiovascular health score resulted a 0.046 reduction in AIP and a 22.3% reduction in the high-risk of developing atherosclerosis (OR = 0.777, 95% CI: 0.768–0.787).The ideal cardiovascular health score correlated significantly with AIP, and a 1-point increase in the cardiovascular health score led to a 0.046 reduction in AIP and a 22.3% reduction in the high risk of developing atherosclerosis. These validated the value of ideal cardiovascular health behaviors and factors in the prediction of high risk of developing cardiovascular diseases. Ideal cardiovascular health metrics are of great realistic significance for the prevention and control of atherosclerosis and cardiovascular diseases.
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