Chemerin levels in metabolic syndrome: a promising biomarker

Metabolic Syndrome (MetS) is a serious and prevalent global problem. It comprises a cardio-metabolic cluster consisting of central adiposity, hypertriglyceridaemia (HTG), low levels of high density lipoprotein-cholesterol (HDL-C), hypertension and increased fasting glucose levels. The diagnosis of MetS requires 3 of the following 5 features according to the global harmonised definition and Adult Treatment Panel (ATP): waist circumference (WC) using population and country specific cut points, hypertension (≥130/85 mm Hg), fasting plasma glucose ≥5.6 mmol/L, HTG ≥1.7 mmol/L, HDL-C levels <1.0 mmol/L in males and <1.3 mmol/L in females (Grundy et al. 2005, Alberti et al. 2009). MetS is a harbinger of both type 2 diabetes mellitus (T2DM) and premature atherosclerotic cardiovascular diseases (ASCVD).

A recent report using the National Health and Nutrition Examination Survey (NHANES) data suggests that the prevalence of MetS is 34.7% in American Adults and 50% in those over 60 years old (Aguilar et al. 2015). With respect to its pathophysiology both insulin resistance and inflammation appear to be pivotal (Samson and Garber 2014, Jialal and Devaraj 2018). In this perspective we attempt to bring a clearer focus on this important chemoattractant, Chemerin, given the confusing literature with respect to MetS and chemerin, largely due to most authors not adhering to the above definition of 3 of 5 cardio-metabolic features to diagnose MetS. We briefly review the biochemistry, physiology and biological effects of chemerin and then discuss chemerin in MetS and suggest future directions.

Numerous groups have detailed the biochemistry, physiology and biological effects of chemerin in cell culture and animal models (Ernst and Sinal 2010, Rourke et al. 2013, Fatima et al. 2014, Helfer and Wu 2018, Buechler et al. 2019). Hence, we will only discuss aspects germane to chemerin and MetS and refer the readers to this list of comprehensive reviews for other aspects. Chemerin is also referred to as retinoic acid receptor responder protein 2(RARRES2) and tazarotene-induced gene 2 protein (TIG2). It is produced as preprochemerin and following cleavage of the N terminal signal sequence, prochemerin is released into the circulation. Chemerin appears to have 3 receptors, of which 2 are involved in transducing biological activity. Chemerin was described as the natural ligand for the G protein coupled receptor (GPCR), chemokine-like receptor1 (CMKLR1). It also binds another GPCR known as G protein coupled receptor1 (GPR1). In 2007, 2 seminal studies reported that chemerin and the CMKLR1 receptor were expressed in mice and human white adipose tissue and that chemerin levels were increased in both obese rodents and humans (Bozaoglu et al. 2007, Goralski et al. 2007). The animal model used was Psammomys obesus (Bozaoglu et al. 2007). These studies ushered in a series of reports supporting elevated levels of chemerin in obesity as discussed in the above reviews (Ernst and Sinal 2010, Rourke et al. 2013, Fatima et al. 2014, Li et al. 2014, Buechler et al. 2019). Chemerin appears to be present most abundantly in adipose tissue (produced by adipocytes) and liver, but is also present in multiple tissues. Prochemerin (Chem-163) is the dominant form in the circulation but appears to be largely devoid of biological activity. The C-terminus of prochemerin is acted on by multiple proteases to produce both active isoforms (Chem-157, Chem-156) and inactive isoforms (Chem-155, Chem-154). Chemerin levels assayed in most human studies report on total immunoreactive chemerin. None of the vendors appear to have investigated whether their assays detect the biologically active isoforms. However, assays for biological activity are now available such as the Tango Bioassay that quantifies beta–arrestin2 activation. Chemerin is best characterised as a chemoattractant for dendritic cells and macrophages. However, studies in animal models and cell culture suggest important roles in adipogenesis, inflammation, glucose metabolism and angiogenesis, all of which are pivotal in cardio-metabolic disorders. As pointed out in the above reviews, the findings especially with respect to inflammation and glucose metabolism have been contradictory. This might be dependent on the doses used, different animal models and cell types, mode and duration of therapy etc. Also, the dominant isoforms present could dictate biological effects.

Multiple studies from the original report of Bozaoglu et al. have shown that chemerin levels are uniformly increased in animal models and humans with obesity (Bozaoglu et al. 2007).

With respect to MetS there is much confusion since most authors did not adhere to the recommended criteria of 3/5 features but instead used their own terminology such as MetS phenotype/MetS features/MetS characteristics, a trend started by Bozaoglu et al. and perpetuated in the literature including the above reviews (Bozaoglu et al. 2009). Most surprising in a meta-analysis, the authors again failed to use the defined criteria or check on the studies they cite adding to this confusion (Li et al. 2014). Our review of the PubMed literature base identifies 5 good studies that have adhered to the recommended definition of 3 of 5 cardio-metabolic features. These studies are summarised in Table 1.

Table 1. Chemerin levels in metabolic syndrome.

Authors/Country	Mets criteria	Chemerin (ug/L)	Pertinent comments
1. Stejskal et al. 2008 Czech Republic	+ Males and females n = 59 with MetS	285 ± 80.1 vs. 228.9 ± 41.1 (p < .01)	Correlations with glucose, BP, TG, HDL-C but not with HOMA-IR and WC CRP not reported
2. Dong et al. 2011 China	+ Males and females n = 46 with MetS	111.6 ± 37.3 vs. 95.1 ± 29.7 p = .01	Also showed chemerin higher in MetS with CAD Correlations with BMI, BP, TG, CRP but not with HDL-C and HOMA-IR
3. Jialal et al. 2013 USA	+ Males and females n = 45 with MetS	366 ± 64 vs. 271 ± 53 p < .0001	Also showed increased SAT secreted chemerin Correlations with TG, BP, HDL-C, CRP, HOMA-IR
4. Wang et al. 2013 China	+ Males and females n = 30 with MetS	97.6 ± 6.5 vs. 70.3 ± 7.0 p < .05	Significant correlations with WC, BP, BG, HBAIC, Insulin and HDL-C
5. Aksan, et al. 2014 Turkey	+ Males and females n = 41 with MetS	115.7 ± 15.2 vs. 90.4 ± 11.4 p < .17	Also showed chemerin higher in MetS with CAD Correlations with BMI, BP, TG, BG, HDL-C. Both CRP and HOMA-IR not reported. 54% smokers

BP: blood pressure; TG: triglycerides; HDL-C: high density lipoprotein-cholesterol; BMI: body mass index; WC: waist circumference; BG: blood glucose; CRP: C-reactive protein; HBA1c: glycated haemoglobin; HOMA-IR: homeostasis model of assessment of insulin resistance.

All 5 studies included males and females and showed significant increases in circulating chemerin levels in patients with MetS. The size of the cohorts with MetS were small and the number of patients ranged from 30–58 . Since obesity increases chemerin levels it is important to point out that following adjustment for WC or BMI that the significant increases persisted. In one of the studies the authors used patients with nascent MetS since they excluded diabetes, smoking, ASCVD, lipid therapy and macro-inflammation (CRP < 10 mg/L). They also showed an increase in subcutaneous adipose tissue (SAT) secreted chemerin which correlated significantly with the increased plasma chemerin (r = 0.44) (Jialal et al. 2013). Also 2 of the 5 studies showed a significant correlation between chemerin with insulin resistance measures. In the one study in which they did not show a correlation they failed to show, like the other groups, differences in both homeostasis model of assessment of insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI) accepted surrogates of insulin resistance despite a median BMI of 31.2 kg/m² in MetS patients (Stejskal et al. 2008). Since some of their patients appeared to have diabetes this could have contributed to this null effect. In the other study they showed a significant increase in HOMA-IR in MetS versus controls but no correlation with chemerin levels (Dong et al. 2011). They also showed that chemerin was significantly higher in patients with MetS with coronary artery disease (CAD) versus MetS patients without CAD (Dong et al. 2011). The final study essentially confirmed the findings of Dong et al. in a Turkish population: elevated chemerin levels in MetS with significantly higher levels in patients with both MetS and CAD (Aksan et al. 2014).

In the 2 studies that reported on inflammatory biomarkers they showed significant correlations. Chu et al. in a study of Korean patients with MetS, suggested that high chemerin and low adiponectin conferred and increase risk for MetS with an odds ratio of 5.8 (Chu et al. 2012). However, they did not have a control group without MetS to show that indeed chemerin was increased with MetS nor did not provide absolute levels defining high chemerin or low adiponectin. In a recent report we showed that whilst the chemerin: HDL-C ratio was a superior biomarker of MetS than CRP the chemerin: adiponectin ratio was not significant following adjustment for WC (Shafer-Eggleton et al. 2020).

Since the ADA funded our study to investigate adipose tissue dysregulation we also reported an increase in adipose tissue insulin resistance (Adipo-IR), increased angiogenesis in SAT, increase density of pro-inflammatory mast cells and pro-inflammatory eosinophils in SAT and an increase in SAT Inflammasome activity evidenced by elevated caspase1 activity in MetS versus controls (Adams-Huet et al. 2014; Jialal et al. 2017; Gurung et al. 2019; Moussa et al. 2019, Pahwa et al. 2021). In all these studies we reported significant correlations with chemerin levels:

r = 0.55, p = .0008 with Adipo-IR; r = 0.66, p = 0.0001 with endotoxin , r = 0.56, p = .008 and r = 0.60, p = .006 with CD31 and VEGF respectively; r = 0.61, p = .007 with mast cell density; r = 0.57, p = .01 with eosinophil density, r = 0.64, p = .003 with caspase1 activity.

Thus our studies in patients with nascent MetS support a role of chemerin in both insulin resistance and inflammation. Furthermore, we support the studies suggesting chemerin promotes angiogenesis (Kaur et al. 2018).

A polymorphism in the chemerin gene (rs17173608) confers an increased risk for MetS in 151 Iranian patients with MetS (Hashemi et al. 2012). This was also recently confirmed in a study of 100 Egyptian women with MetS (Mehanna et al. 2016). Sadly, neither study reported on chemerin levels. Collectively, both studies add to the body of data suggesting an important role of chemerin the pathogenesis of MetS.

In conclusion, chemerin is emerging as a very important protein in the pathogenesis of MetS. Since this predicate is based on cross–sectional studies, prospective studies examining chemerin and its polymorphism in the subsequent development of MetS are urgently needed and could prove very instructive in unravelling the role of chemerin in MetS. In this regard it is important to point out that Bobbert et al. showed that chemerin levels prospectively predicted T2DM over a mean follow-up of 5.3 years (Bobbert et al. 2015). Also, it is encouraging that both weight loss and exercise can favourably modulate chemerin levels and could thus serve as a therapeutic strategies if prospective studies define a clear role for chemerin (Chakaroun et al. 2012, Ashtary-Larky et al. 2021). However future studies should adhere to the recommended criteria to diagnose MetS and ideally also use an assay of the most bioactive chemerin isoforms to quantify chemerin status.

Acknowledgements

We thank the American Diabetes Association for partial funding of some of the earlier cited studies. We also thank the patients for their participation and Jeanita Jialal BA for manuscript preparation.

Disclosure Statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data cited by the author in this Editorial are published in various manuscripts as referenced. However, the data from the author’s studies are available on request from the author, Professor I. Jialal and not in the public domain to respect confidentiality and protect participant privacy.