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. 2008 Jun;22(6):1416-26.
doi: 10.1210/me.2007-0420. Epub 2008 Feb 21.

The role of lipocalin 2 in the regulation of inflammation in adipocytes and macrophages (VSports)

Jinhui Zhang  1 , Yingjie Wu, Yuanyuan Zhang, Derek Leroith, David A Bernlohr, Xiaoli Chen
Affiliations

The role of lipocalin 2 in the regulation of inflammation in adipocytes and macrophages

Jinhui Zhang et al. Mol Endocrinol. 2008 Jun.

Abstract

Adipose tissue-derived cytokines (adipokines) are associated with the development of inflammation and insulin resistance. However, which adipokine(s) mediate this linkage and the mechanisms involved during obesity is poorly understood. Through proteomics and microarray screening, we recently identified lipocalin 2 (LCN 2) as an adipokine that potentially connects obesity and its related adipose inflammation VSports手机版. Herein we show that the levels of LCN2 mRNA are dramatically increased in adipose tissue and liver of ob/ob mice and primary adipose cells isolated from Zucker obese rats, and thiazolidinedione administration reduces LCN2 expression. Interestingly, addition of LCN2 induces mRNA levels of peroxisome proliferator-activated receptor-gamma (PPARgamma) and adiponectin. Reducing LCN2 gene expression causes decreased expression of PPARgamma and adiponectin, slightly reducing insulin-stimulated Akt2 phosphorylation at Serine 473 in 3T3-L1 adipocytes. LCN2 administration to 3T3-L1 cells attenuated TNFalpha-effect on glucose uptake, expression of PPARgamma, insulin receptor substrate-1, and glucose transporter 4, and secretion of adiponectin and leptin. When added to macrophages, LCN2 suppressed lipopolysaccharide-induced cytokine production. Our data suggest that LCN2, as a novel autocrine and paracrine adipokine, acts as an antagonist to the effect of inflammatory molecules on inflammation and secretion of adipokines. .

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Figures

Figure 1
Figure 1
Adipose Expression of LCN2 in Obesity and Insulin Resistance LCN2 mRNA levels in cultured primary rat adipose cells after 24 h in culture (A), 3T3-L1 adipocytes during differentiation (B), and epididymal adipose tissue and liver of ob/ob and their control C57BL/6J mice (C) and isolated primary adipose cells of Zucker obese rats with or without TZD treatment (D). Levels of LCN2 mRNA were detected by real-time RT-PCR. The expression levels in each sample in panels A, C, and D were normalized to the level in 0 h or lean control and shown as fold changes. The results are presented as mean ± se. The statistical P value and sample size are as indicated in Results.
Figure 2
Figure 2
LCN2 Enhances Expression of PPARγ and PPARγ Target Genes and Attenuates TNFα effect on Glucose Uptake and Expression of PPARγ and PPARγ Target Genes in 3T3-L1 Adipocytes 3T3-L1 adipocytes at d 8 of differentiation were treated with 0.5% FBS and 1 mg/ml glucose for 24 h, followed by various treatments as described in Materials and Methods. Cells with 24 h LCN2 treatment were harvested for immunoblotting of anti-PPARγ and tubulin (A). Day 9 differentiated serum-starved 3T3-L1 adipocytes with various treatments of LCN2, TNFα, or combined LCN2 and TNFα for 24 h were incubated with [3H] 2-deoxy-d-glucose in the absence and presence of 100 nmol/liter insulin as described in Materials and Methods and glucose influx was determined (B). The results represent three to four independent experiments of mean ± se. The statistical information is as indicated in the figures and Results. In addition, cells were harvested for gene expression of PPARγ, adiponectin, leptin, FASN, and LPL (C), and immunoblotting of anti-PPARγ (D), and GLUT4 and IRS-1 (E). Note: the values for leptin expression was scaled down 10-fold.
Figure 3
Figure 3
Alterations in Gene Expression and Insulin Signal Transduction in LCN2 Knockdown Adipocytes LCN2 shRNA lentivirus-infected 3T3-L1 fibroblasts were induced to differentiate into adipocytes. At d 8 of differentiation, cells were examined for determining transfection efficiency using fluorescent microscopy (A); the mRNA levels of LCN2 and adiponectin (B) were determined by real-time RT-PCR as well as lipid accumulation by Oil-red O staining (H). Cells were harvested for detecting protein levels of IRS-1, GLUT4, and PPARγ by Western blotting (C and D), insulin-stimulated Akt2 phosphorylation at Serine 473 (E and F), and mRNA levels of PPARγ, adiponectin, leptin, FASN, and LPL (G). At d 0, d 2, and d 6 of differentiation, cells were harvested for detecting mRNA levels of FASN and LPL gene expression (I). The results are presented as mean ± se (B, G, and I), and the statistical information is as indicated in Results.
Figure 4
Figure 4
LPS Induction of LCN2 Expression and LCN2 Induction of PPARγ Expression in Macrophages RAW 264.7 cells were treated with or without LPS for 4 h or LCN2 (500 ng/ml) for 24 h. At the end of experiments, cells were harvested for mRNA extraction and LCN2 (A) and PPARγ(B) gene expression by real-time RT-PCR.
Figure 5
Figure 5
The Time Course of TNFα Effect on Expression of LCN2 Gene and Genes Involved in Metabolism and Insulin Resistance in 3T3-L1 Adipocytes 3T3-L1 adipocytes at d 8 of differentiation were treated with 0.5% FBS and 1 mg/ml glucose for 24 h, followed by TNFα treatment. At the indicated time points, total RNAs were extracted for determining the mRNA levels of LCN2, PPARγ, adiponectin, and GLUT4 by real-time RT-PCR. The results represent three independent experiments of mean ± se. The statistical information is as described in Results.
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