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J Clin Endocrinol Metab. May 2010; 95(5): 2476–2485.
Published online Mar 17, 2010. doi:  10.1210/jc.2010-0042
PMCID: PMC2869547

Chemerin, a Novel Adipokine in the Regulation of Angiogenesis

Abstract

Context: Chemerin is a new adipokine associated with obesity and the metabolic syndrome. Gene expression levels of chemerin were elevated in the adipose depots of obese compared with lean animals and was markedly elevated during differentiation of fibroblasts into mature adipocytes.

Objective: The objective of the study was to identify factors that affect the regulation and potential function of chemerin using a genetics approach.

Design, Setting, Patients, and Intervention: Plasma chemerin levels were measured in subjects from the San Antonio Family Heart Study, a large family-based genetic epidemiological study including 1354 Mexican-American individuals. Individuals were randomly sampled without regard to phenotype or disease status.

Main Outcome Measures: A genome-wide association analysis using 542,944 single-nucleotide polymorphisms in a subset of 523 of the same subjects was undertaken. The effect of chemerin on angiogenesis was measured using human endothelial cells and interstitial cells in coculture in a specially formulated medium.

Results: Serum chemerin levels were found to be highly heritable (h2 = 0.25; P = 1.4 × 10−9). The single-nucleotide polymorphism showing strongest evidence of association (rs347344; P = 1.4 × 10−6) was located within the gene encoding epithelial growth factor-like repeats and discoidin I-like domains 3, which has a known role in angiogenesis. Functional angiogenesis assays in human endothelial cells confirmed that chemerin significantly mediated the formation of blood vessels to a similar extent as vascular endothelial growth factor.

Conclusion: Here we demonstrate for the first time that plasma chemerin levels are significantly heritable and identified a novel role for chemerin as a stimulator of angiogenesis.

Chemerin exists as a full-length precursor protein (prochemerin) and is activated by the removal of five to 10 amino acids at the C-terminal end of the precursor protein at sites of injury and inflammation (1,2). The full-length isoform of chemerin (prochemerin) has significantly lower bioactivity compared with the proteolytically processed short form (chemerin). The C terminus of chemerin was identified as important for binding with the seven-transmembrane-spanning G protein-coupled receptor chemokine-like receptor 1 (CMKLR1), and chemotactic activity (1). Binding of CMKLR1 by chemerin is known to stimulate increases in intracellular Ca2+ concentrations and activate nuclear factor-κB and MAPK pathways in monocytes, macrophages, and immature dendritic cells and also induces cell migration (3,4,5). Although chemerin was initially described as a chemoattractant, Cash et al. (6) demonstrated in both in vitro and a mouse model of inflammation (zymosan induced peritoneal inflammation) that picomolar concentrations of a chemerin cleavage product (termed C15′; A140 to A154; AGEDPHGYFLPGQFA) suppresses the production of proinflammatory mediators by activated macrophages. Chemerin’s antiinflammatory effects are dependent on cysteine protease-mediated cleavage of chemerin (6), and in stark contrast to chemerin’s proinflammatory properties, which are produced by serine protease cleavage (2,5). Therefore, depending on the class of protease that cleaves prochemerin to chemerin, the resultant CMKLR1 binding peptides produced can either have pro- or antiinflammatory effects.

Recently we and others have reported that chemerin is a new adipokine elevated in states of obesity and metabolic syndrome. Chemerin gene expression was significantly elevated in the adipose depots of obese compared with lean animals (7,8,9,10) and was predominantly expressed by adipocytes rather than stromal and vascular cells in adipose tissue (7,8,9). In addition, in vitro studies have shown that chemerin expression and secretion was markedly up-regulated during differentiation of fibroblasts to mature adipocytes and was approximately 20-fold higher in fully differentiated adipocytes compared with undifferentiated fibroblasts (7,8,9,10). Furthermore, recombinant chemerin was shown to stimulate 3T3-L1 adipocyte function such as glucose transport (9,10). Plasma chemerin levels were significantly associated with characteristics of the metabolic syndrome, including body mass index, plasma triglycerides, and blood pressure in several independent human populations (7,11,12,13). The influence of genetic factors on circulating chemerin levels is poorly understood, and given its potential importance in disease processes, we sought to identify controlling genetic factors using a large well-characterized human cohort from San Antonio Family Heart Study (SAFHS).

Here we demonstrate for the first time that variation in plasma chemerin levels is significantly heritable, and a number of polymorphisms in candidate genes that may influence plasma chemerin levels are identified. Of particular interest is a gene that has been previously shown to play a role in angiogenesis. Because the expansion of adipose tissue is dependent on the formation of new blood vessels, and given the significant association already established between chemerin and obesity, we explored the effects of chemerin on angiogenesis and found that recombinant chemerin promoted the formation of new blood vessels. These novel data indicate a new role for chemerin in the formation of new blood vessels, and this may be an essential component of adipose tissue expansion.

Materials and Methods

Ethics statement

All study participants provided informed consent. The study and all protocols presented here were approved by the Institutional Review Board at the University of Texas Health Science Centre at San Antonio (San Antonio, TX).

Plasma samples

Plasma and DNA samples were obtained from the SAFHS, a study of risk factors for cardiovascular disease in Mexican-Americans living in and around San Antonio, TX (14,15). The SAFHS is a large family-based genetic epidemiological study including 1431 individuals from 42 extended families at baseline. Individuals from large randomly selected, multigenerational pedigrees were sampled independent of their phenotype or the presence or absence of disease.

Chemerin ELISA

Chemerin levels in 1354 human plasma samples from the SAFHS were determined using a sandwich ELISA developed with commercially available unlabeled and biotinylated polyclonal antihuman chemerin antibodies (R&D Systems, Minneapolis, MN) as previously described (11). The interassay coefficient of variation was less than 10%, and the within-assay coefficient of variation was less than 5%. The sensitivity of the ELISA was 0.5–10 ng/ml, and the midrange of the assay was 5 ng/ml. The lowest detectable concentration of human chemerin was 0.5 ng/ml.

Single-nucleotide polymorphism (SNP) genotyping

The HumanHap550 Genotyping BeadChip (Illumina, San Diego, CA) was used to genotype 542,944 SNPs in 858 individuals in which gene expression data were available using the Infinium II assay (Illumina). This assay combines a single tube whole-genome amplification method with direct array-based capture and enzymatic scoring of the SNP loci. Locus discrimination is provided by a combination of sequence-specific hybridization capture and array-based, single-base primer extensions. A single primer is used to interrogate a SNP locus. The 3′ end of the primer is juxtaposed to the SNP site and extension of the primer incorporates a biotin-labeled nucleotide (C or G) or a dinitrophenyl-labeled nucleotide (A or T). Signal amplification of the incorporated label further improves the overall signal to noise ratio of the assay. The Infinium II genotyping was performed using Illumina’s standard protocols on a Tecan Freedom Evo Robot. After staining, each BeadChip was imaged on the Illumina BeadArray 500GX Reader using Illumina BeadScan image data acquisition software (version 3.2.6). Genotype data were then assessed using the Genotyping Module of Illumina’s BeadStudio software (version 2.0).

Genotype data cleaning

Multivariate methods generally require that individuals with missing data be excluded from the analysis, which can result in a significant decrease in sample size. To minimize this issue, we used likelihood-based imputation with the MERLIN computer package (Centre for Statistical Genetics, University of Michigan, Ann Arbor, MI) as has been previously described (16) to rapidly impute SNP data in pedigrees. For each pedigree, imputation is performed and the posterior genotypic probabilities for each missing genotype are stored. These posterior probabilities are used to construct an appropriately weighted covariate for each SNP that is then used in association analyses.

To eliminate the potential for hidden population stratification that the standard fixed-effect association approach is susceptible to, we also used the Quantitative Trait Disequilibrium Testing approach to association testing implemented in SOLAR (Southwest Foundation for Biomedical Research, San Antonio, TX) (17). Whereas this approach exhibits substantially decreased power than measured genotype analysis (18), it maintains the appropriate significance levels under the null hypothesis, even in the presence of population stratification. However, because of its poor power, we use it only as a check to identify consistency of qualitative inferences drawn from measured genotype analysis.

Statistical genetic analysis

All statistical analyses on related individuals were performed using variance components-based methodology and software package SOLAR version 4.0 (19). The probabilities of multipoint identity-by-descent allele sharing among pairs of related individuals were computed by the Monte Carlo Markov Chain multipoint approach implemented in software package Loki (University of Washington, Seattle, WA) (20), using the genotypes at all linked markers jointly in the computations. Maximum likelihood marker allele frequencies were calculated using the modified genetic map developed by deCODE genetics (Iceland), as previously described (16). Covariates were included in the variance components framework as linear predictors of phenotype. Measured genotype analysis (21), embedded in a variance components-based linkage model, was used for association testing, assuming an additive model of allelic effect (i.e. the SNP genotypes AA, AB, and BB were coded as −1, 0, and 1, respectively, and used as a linear predictor of phenotype) (17).

To correct for the effect of multiple testing for a given phenotype, we estimated the effective number of SNPs using the method reported elsewhere (22), which uses a modification of an earlier approach by (23). After obtaining the effective number of SNPs, we used a modified Bonferroni procedure to identify a target α-level that would maintain an overall significance level of 0.05 or less.

Heritability analysis

Heritability analysis was performed under the classical approach decomposing the phenotypic variance into independent genetic and environmental components, assuming an additive model of gene action (narrow sense heritability) and expected kinship coefficients based on the observed intrafamilial relationships.

In vitro angiogenesis model

Capillary development was modeled in vitro using the TCS AngioKit model (ZHA-1000; TCS Cell Works Ltd., Buckingham, UK) which accurately reproduces the different phases of the angiogenesis process using a coculture of early passage normal human endothelial cells with early-passage normal human interstitial cells in a specially formulated culture medium. The appropriate controls, including vascular endothelial growth factor (VEGF) as a positive regulator of angiogenesis and the inhibitor suramin (ZHA-1300) as well as a specific endothelium detection marker CD31 [platelet endothelial cell adhesion molecule-1, ZHA-1225] were also purchased from TCS Cell Works. Recombinant human chemerin (2324-CM; R&D Systems) was prepared in sterile PBS containing 0.1% BSA. The specific inhibitor of mitogen-activated protein kinase kinase (MAPKK/MEK) PD98059 (PD; Tocris Bioscience, Bristol, UK) was prepared in 0.1% dimethylsulfoxide (DMSO), a concentration previously reported not to impair capillary formation (24).

Capillary development was followed by fixing the cultures and staining them with an antibody to CD31. Tubule formation was assessed using image analysis according to the manufacturer’s recommendation (TCS Cell Works). Briefly, 0.5 ml of culture medium, or medium including the test compound, was added to each well in the 24-well plate. The treatments included control (C), DMSO 0.1% (DMSO), VEGF 2 ng/ml (VEGF), suramin 20 μm (S), PD98059 25 μm (25,26), and recombinant human chemerin (0.1, 0.3, 1, 3, and 10 ng/ml (Ch) (R&D Systems) in the presence or absence of 25 μm PD, an inhibitor of MAPK-activating kinase/MEK. The media were replenished every 48 h for a period of 8 d, and capillary formation was quantified by immunodetection. Wells were washed with PBS and then fixed with ice-cold 70% ethanol, and the plate was incubated at room temperature for 30 min. After fixation, the cell layer was washed with blocking buffer (1 × Dulbecco’s PBS + 0.1% BSA), and 0.5 ml primary mouse antihuman CD31 antibody was added per well and incubated for 60 min at 37 C. Wells were then washed three times with blocking buffer and incubated with 0.5 ml of secondary antibody and goat antimouse IgG antibody conjugated to alkaline phosphatase for 60 min at 37 C. After this second incubation, the wells were washed three times with 1 ml distilled water.

Staining was visualized after the addition of 0.5 ml 5-bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium chloride substrate solution to each well and incubated for 5–15 min at 37 C until the tubules developed a dark purple coloration. Wells were then washed and the plate was air dried before image analysis. The quantitative measurement of total vessel number, total tubule length, number of junctions, and vessel area were scored using the software package, AngioSys (ZHA-1800) (TCS Cell Works LTD.). Four images were analyzed independently from each of four quadrants from each well. Experiments were carried out in triplicate.

Statistical analysis

All data were analyzed using GraphPad Prism software version 4.0 (GraphPad, San Diego, CA). Data are expressed as percentages relative to control wells in each case. Effects of recombinant human chemerin, VEGF, and the inhibitor PD were analyzed by one-way ANOVA followed by Dunnett’s or Bonferroni post hoc tests where appropriate. Results are presented as means ± se. Statistical significance for effects in the figures is given (*, P < 0.05; **, P < 0.01; ***, P < 0.001).

Results

Heritability of plasma chemerin levels

Plasma chemerin levels were significantly associated with metabolic syndrome phenotypes in various human populations (7,11,12,13). Significant associations were observed with characteristics of the metabolic syndrome including body mass index (P < 0.0001), triglycerides (P < 0.0001), fasting serum insulin (P < 0.0001), and high-density lipoprotein cholesterol (P < 0.00014) and triglycerides in the SAFHS samples (11). To investigate the functional basis of these associations and determine causality, we studied the genetic factors that influence plasma chemerin levels in 1354 participants of the SAFHS. To confirm that a genetics approach was rational, we first assessed the heritability of plasma chemerin levels. Multivariate variance component analysis implemented in SOLAR was used to estimate the heritability of plasma chemerin levels in the SAFHS samples. The analysis statistically controlled for the effects of age and sex and their interactions. Overall, plasma chemerin levels were higher in females compared with males (188.5 ± 65.3 and 168.2 ± 55.7 ng/ml, respectively; P < 0.0001) and increased with age (P = 0.005). Chemerin levels had a significant heritability estimate of 0.254 (P = 1.4 × 10−9). These data indicate that plasma chemerin levels have a substantial genetic component, with approximately 25% of the variation observed in plasma chemerin levels being due to genetic or other heritable factors.

Genes and genomic regions associated with plasma chemerin levels

Because plasma chemerin levels were significantly heritable, we sought to identify variants associated with plasma chemerin levels by performing a genome-wide association analysis on 542,944 SNP markers present on the Illumina HumanHap550 Genotyping BeadChip. From this analysis, 68 SNPs with a P < 0.0001 were identified as significantly associated with plasma chemerin levels (Table 11).). The variants identified were present in 45 different genes in various genomic regions. The SNP showing strongest evidence of association with plasma chemerin was rs347344 (P = 1.42 × 10−6), which is located within the gene encoding epithelial growth factor-like repeats and discoidin I-like domains 3 (EDIL3). There were three other SNPs within EDIL3 that were associated with plasma chemerin levels (all with a P < 0.0001. Two of these SNPs were in high linkage disequilibrium with rs347344 (r2 > 0.83), whereas the third was in moderate linkage disequilibrium (r2 = 0.67). Taken together, these results suggest that genetic variation within EDIL3 may influence plasma chemerin levels. EDIL3 has been previously reported to play a role in angiogenesis (27,28,29). Because chemerin is increased in states of adiposity, we hypothesized that one function of chemerin may be to promote blood vessel formation in the expanding adipose tissue mass that occurs in obesity. This is further supported by prior work showing that chemerin has chemoattractant properties, albeit in an inflammatory setting (3,5). Furthermore and consistent with this hypothesis, it is known that chemerin binds to the receptor CMKLR1, and that CMKLR1 has been previously shown to promote cell migration (3,5), a key component of the angiogenesis process.

Table 1
Genes within the genome that was associated with plasma chemerin levels

Chemerin promotes angiogenesis in endothelial cells in a dose-dependent manner

Variants in genes involved in angiogenesis were significantly associated with plasma chemerin levels, suggesting a functional link between chemerin and angiogenesis. To test this, we investigated the concentration-dependent response of recombinant chemerin on the formation of endothelial microtubules in a coculture setting. Recombinant human chemerin significantly induced the formation of capillary-like structures by stimulating the total tubule length by 1.34-fold at 0.3 ng/ml (P < 0.05), 1.38-fold by both 1 and 3 ng/ml (P < 0.001), the number of branches as well as the total number of microtubules, in a concentration-dependent manner compared with control (Fig. 11,, A–I). However, the highest concentration of recombinant chemerin (10 ng/ml) did not have an effect on measures of angiogenesis potentially due to toxic and cell/growth inhibitory effects caused by higher doses of recombinant chemerin. As expected, the positive control VEGF (2 ng/ml) induced a significant increase in endothelial capillary formation, whereas suramin (20 μm), a negative control, showed an inhibitory effect when compared with control (Fig. 22,, A–J).

Figure 1
Effect of recombinant chemerin concentration on blood vessel formation by endothelial cells in a coculture system. A coculture of endothelial cells and fibroblasts was used to study the tube formation by endothelial cells. The AngioKit was seeded with ...
Figure 2
The effect of PD, a MEK1 inhibitor, on the angiogenic properties of chemerin in endothelial cells in a coculture system. The coculture of endothelial cells and fibroblasts (AngioKit) was used to study the formation of new blood vessels. The AngioKit was ...

Chemerin’s angiogenic effect on endothelial cells is dependent on MEK1 activity

Chemerin has previously been shown to activate ERK1 and ERK2 (p42/44) of the MAPK pathway, after binding to its receptor, CMKLR1 (5). Therefore, we hypothesized that the angiogenic effects of chemerin are dependent on the p42/44 MAPK pathway. To test this, we used an angiogenesis assay in which cells were treated with recombinant chemerin (3 ng/ml) and 25 μm of the MEK1 inhibitor PD, which is known to exert antiangiogenic effects through inhibition of the p42/44 MAPK pathway (25,26). PD binds to the inactive forms of MEK1 and prevents activation by upstream activators such as c-Raf (30). MEK1 is upstream of p42/44, and therefore, suppressing MEK1 would suppress downstream events. As expected, 3 ng/ml of recombinant human chemerin significantly induced the number of junctions by 2.93-fold (P < 0.001), the number of tubules by 1.49-fold (P < 0.05), the total tubule length by 1.63-fold (P < 0.05), and total tubule area by 2.3-fold (P < 0.01) compared with control. PD, on the other hand, significantly inhibited the microtubule formation by 0.64-fold compared with control; however, we found that treatment of the human endothelial cells with PD and 3 ng/ml of recombinant chemerin substantially reduced the chemerin-induced effect on angiogenesis by reducing the length, number of branches, and total number of microtubules by 0.64-fold compared with control (Fig. 22,, A–J). These observations suggest that chemerin’s angiogenic effects are dependent on p42/44 MEK activation.

Discussion

Obesity is a metabolic disorder commonly associated with type 2 diabetes, cancer, hypertension, dyslipidemia, and coronary heart disease and has become a problem of epidemic proportions worldwide (31,32). Adipose tissue is a highly vascularized organ, and consequently, the expansion of adipose tissue that occurs during the development of obesity is dependent on angiogenesis. Previously we and others have shown that chemerin is an adipokine (7,8,9,10) and that plasma chemerin levels were significantly associated with obesity measures in human plasma samples (7,11,12,13). Here we show for the first time that plasma chemerin levels are significantly heritable with approximately 25% of variation being influenced by heritable factors. Using genome-wide association data, we explored the mechanism underlying variation in plasma chemerin levels. We observed strong evidence for contribution of genetic variation within EDIL3 (a gene involved in angiogenesis) and chemerin plasma levels. Although the mechanism by which the observed polymorphisms influence chemerin levels is unclear (and currently under investigation), these observations prompted us to investigate a potential role for chemerin in angiogenesis. Here we report for the first time that chemerin may exhibit proangiogenic activity.

Obesity is associated with a substantial modulation of adipose tissue structure including adipocyte hyperplasia (the differentiation and proliferation of preadipocytes), adipocyte hypertrophy (an increase in triglyceride storage and dilation), and recruitment of activated macrophages. In addition, the blood supply for adipose depots is increased via dilation of existing capillary networks and the formation of new blood vessels via angiogenesis. The formation of these new blood vessels is essential for the enlargement of adipose tissue depots because inhibition of angiogenesis prevents adipose tissue development (33,34), and inadequate blood supply leads to hypoxia and the development of systemic inflammation. Adipose tissue from obese animals and humans produce elevated levels of soluble factors (adipokines) that promote angiogenesis, e.g. VEGF, TNF-α, plasminogen activator inhibitor-1, and angiopoïetin-2 (35,36). It was of interest that our genetic analysis identified variants in EDLI3, which is an integrin ligand (27,28,29) known to promote migration and adhesion of endothelial cells to the extracellular matrix and regulates vascular morphogenesis in embryonic development (29). These observations led us to functionally explore a role of chemerin in angiogenesis and new blood vessel formation. Using in vitro angiogenesis assays, chemerin significantly induced the formation of capillary-like structures, increased the total tubule length, and the number of branches as well as total number of microtubules in these cultures. Furthermore, the ability of chemerin to promote vascularization of endothelial cells was abolished by a MEK1 inhibitor, which suggests that chemerin’s angiogenic effects are dependent on the p42/44 MAPK pathway. These results are consistent with those described in the very recent publication by Kaur et al. (37), in which it was demonstrated that recombinant chemerin significantly induced tube formation in endothelial cells using a Matrigel. The phosphorylation of ERK1/2 and p38 MAPK in lysates derived from endothelial cells treated with chemerin was also measured by Western blot analysis and demonstrated that chemerin induced significant changes in the phosphorylation of ERK1/2 and p38MAPK at lower doses (0.01–1 nm) (37). These findings suggest that chemerin has angiogenic properties and functions through the MAPK pathway, and hence, further characterization of chemerin in obesity-associated angiogenesis in adipose tissue is warranted.

Vascular remodeling in expanding adipose tissue may also be driven by hypoxia, which is a potent inducer of angiogenesis (38). It has also been proposed that inflammation in adipose tissue during states of obesity may be in response to hypoxia in adipocytes that become distant from the vasculature as the adipose tissue expands (39). Hypoxia is an important factor for vascular growth and remodeling in rapidly expanding adipose tissue and can induce the expression of inflammatory genes in adipose tissue including, PAI-1, monocyte chemoattractant protein-1, IL-6, and TNFα as well as angiogenic genes hypoxia-inducible factor-1α and VEGF, which assist in the regulation of vascularogenesis and angiogenesis (40,41,42). Although we have no data to support a relationship between hypoxia and chemerin, it is plausible that hypoxia may also induce chemerin. Consistent with this, induction of EDIL3 expression after ischemia has been previously reported in muscle tissue (28). Further studies would be required to determine whether hypoxia can induce chemerin expression, like VEGF and hypoxia-inducible factor-1α, and contribute to vasculogenesis in expanding adipose tissue or whether there is an independent mechanism controlling angiogenesis.

In broader terms, obesity is a well-established risk factor for the development of cancer including breast cancer (43). Experimentally it has been demonstrated that adipose-derived angiogenic factors promote tumor growth (43,44). We speculate that elevated levels of chemerin as a result of obesity may be a further contributory factor to this risk as result of chemerin’s angiogenic properties. Clearly, however, further work would be required to address this potential contribution to cancer risk.

In summary, these novel data demonstrate that plasma chemerin levels are significantly heritable and may be a stimulator of angiogenesis. This newly described function of chemerin suggests a role in the development of obesity through promotion of angiogenesis within the expanding adipose tissue mass.

Acknowledgments

The authors gratefully acknowledge Kelly Windmill for her technical assistance and the participants in the San Antonio Family Heart Study.

Footnotes

This work was supported by a Diabetes Research Australia Trust grant and a National Institutes of Health grant.

Disclosure Summary: The authors of this manuscript have nothing to declare.

First Published Online March 17, 2010

Abbreviations: CMKLR1, Chemokine-like receptor 1; DMSO, dimethylsulfoxide; EDIL3, epithelial growth factor-like repeats and discoidin I-like domains 3; MAPKK/MEK, mitogen-activated protein kinase kinase; PD, PD98059; SAFHS, San Antonio Family Heart Study; SNP, single-nucleotide polymorphism; VEGF, vascular endothelial growth factor.

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