Chemerin Expression Research Articles

Simvastatin inhibits the adipogenesis of bone marrow‑derived mesenchymal stem cells through thedownregulation of chemerin/CMKLR1 signaling.

Simvastatin is effective in the treatment of osteoporosis, partly through the inhibition of the adipogenesis of bone-marrow derived mesenchymal stem cells (BMSCs). The present study focused on the mechanisms responsible for the inhibitory effects of simvastatin on adipogenesis and examined the effects of simvastatin on the expression of peroxisome proliferator-activated receptor γ (PPARγ), chemerin, chemokine-like receptor 1 (CMKLR1), G protein-coupled receptor 1 (GPR1) and the adipocyte marker gene, adiponectin. BMSCs were isolated from 4-week-old female Sprague-Dawley (SD) rats, and adipogenesis was measured by the absorbance values at 490 nm of Oil Red O dye. The expression of each gene was evaluated by western blot analysis or reverse transcription-quantitative PCR (RT-qPCR). The expression of chemerin increased during adipogenesis, while CMKLR1 exhibited a trend towards a decreased expression. On days 7 and 14, the simvastatin-treated cells exhibited a down-regulated expression of chemerin, whereas the upregulated expression of its receptor, CMKLR1 was observed. The results also revealed that CMKLR1 is required for adipogenesis and the simvastatin-mediated inhibitory effect on adipogenesis. Simvastatin regulated adipogenesis by negatively modulating chemerin-CMKLR1 signaling. Importantly, simvastatin stimulation inhibited the upregulation of PPARγ and PPARγ-mediated chemerin expression to prevent adipogenesis. Treatment with the PPARγ agonist, rosiglitazone, partially reversed the negative regulatory effects of simvastatin. On the whole, the findings of the present study demonstrate that simvastatin inhibits the adipogenesis of BMSCs through the downregulation of PPARγ and subsequently prevents the PPARγ-mediated induction of chemerin/CMKLR1 signaling.

Correlation of molecular biomarker concentrations between synovial fluid and saliva of the patients with temporomandibular disorders.

The synovial membrane and fluid are involved in the pathogenesis of temporomandibular joint (TMJ) disorders. This study aims to assess the relationship between matrix metalloproteinase-2 (MMP-2), chemerin and prostaglandin (PGE2) levels in the synovial fluid (SF) and saliva of patients with TMJ disorder regarding their role in inflammation and the value of being a candidate for predictive biomarkers in the disease. Also, it is aimed to find out whether chemerin's main function triggers the formation inflammatory cytokine markers in the associated area. Thirty-two samples of SF and saliva were obtained from patients with disc displacement without reduction with limited opening (DDWORwLO). Mann-Whitney-U test was used for the comparisons of the biomarker levels in SF and saliva. The correlation between chemerin and BMI (Body Mass Index) is analyzed by non-parametric Spearman's rho correlation coefficient. For all of the three biomarkers, statistically significant differences were found between SF and saliva. An unexpectedly high level expression of chemerin was observed in SF. A statistically significant, positive correlation was observed between PGE2 -MMP-2, and chemerin-PGE2 in saliva, chemerin and MMP-2 in SF, respectively (p = 0.031, r = 0.382 / p = 0.039, r = 0.366 / p = 0.032, r = 0.379). A positive correlation was determined between saliva and SF levels of PGE2 (p = 0.016, r = 0.421). Chemerin, MMP-2, and PGE2 can play a role as an inflammatory factor for the development of TMJ disorder. The search for molecular markers in TMJ and the inhibition of the associated molecular signaling mechanism is important to reduce joint inflammation and cartilage degradation.

Role of Chemerin as a Putative Biomarker of Cardiovascular Risk in Metabolic Syndrome: A Brief Review

Cardiovascular disease (CVD) is one of the major alarming causes of morbidity and mortality with widespread prevalence around the world. The major risk factor for cardiovascular disease is metabolic syndrome (MetS) and is most prevalent among obesity-related comorbidities. The main causative factors linking metabolic syndrome and cardiovascular disease are assumed to involve the expansion of adipose tissue and chronic inflammation. In addition to storing surplus fat, adipose tissue also produces adipokines which act through autocrine, paracrine and endocrine functions in the body. Increasing evidence suggests that the altered secretion of adipokines may play a role in the pathogenesis of metabolic syndrome but the mechanisms underlying are not fully known. To date, only leptin and adiponectin are the best-studied adipokines among the variety of adipokines secreted by adipose tissue. However, recent studies have implicated the novel adipokine chemerin as a regulator of adipogenesis, inflammation and glucose metabolism which demonstrates its multifaceted actions. Furthermore, they also found that elevated circulating levels of chemerin in metabolic syndrome acts as a significant risk factor for cardiovascular disease. Chemerin has gained considerable interest due to its role as a pro- or anti-inflammatory mediator is still controversial and the effect of chemerin on glucose metabolism is a matter of debate. Thus, the purpose of this review is to focus primarily on chemerin expression, processing, signaling of receptors, biological actions and pathophysiological implications and the role of chemerin as a biomarker of cardiovascular disease in metabolic syndrome.

Chemerin/CMKLR1 Axis Promotes Inflammation and Pyroptosis by Activating NLRP3 Inflammasome in Diabetic Cardiomyopathy Rat.

Chemerin and its receptor CMKLR1 (a G-protein-coupled receptor) are inducers of inflammation, and play an important role in diabetic cardiomyopathy (DCM). In this study, we investigated the role of the chemerin/CMKLR1 axis in mediating inflammation and cell death in DCM. Sprague–Dawley rats, treated with a high-fat diet and low-dose of streptozotocin, were used as a DCM model. CMKLR1 expression was knocked down by siRNA (CMKLR1-siRNA) to evaluate the role of CMKLR1 in DCM. Chemerin-treated H9c2 cells were used to investigate the factors acting downstream of the chemerin/CMKLR1 axis. LDH release and EthD-III staining were used to measure the ratio of cell death in vitro. CMKLR1-siRNA and siRNA against nucleotide-binding oligomerization domain-like receptors 3 (NLRP3-siRNA) were used to explore the mechanism underlying chemerin-induced inflammation and cell death. The results showed that the expression of chemerin, CMKLR1, NLRP3, pro-caspase-1, activated caspase-1, and mature IL-1β was increased in the DCM model rat. Myocardium of DCM model rats exhibited fibrosis, hypertrophy, a disorganized ultrastructure, and impaired function. Pyroptosis was observed in vivo and in vitro. Silencing of CMKLR1 in vivo attenuated the expression of NLRP3 and activated caspase-1 and IL-1β. CMKLR1-siRNA treatment attenuated cardiac inflammation, fibrosis, hypertrophy, and pyroptosis, and improved cardiac function in vivo. Silencing of either CMKLR1 or NLRP3 suppressed the levels of activated caspase-1, IL-1β, and pyroptosis; however, silencing of both CMKLR1 and NLRP3 further decreased the levels of mature IL-1β and pyroptosis. Overall, the results showed that the chemerin/CMKLR1 axis contributed to the development of DCM and that the NLRP3 inflammasome mediated the chemerin/CMLR1-induced inflammation and pyroptosis. These data indicate that silencing of the CMKLR1 gene might exert a protective effect against DCM.

Chemerin: A Potential Regulator of Inflammation and Metabolism for Chronic Obstructive Pulmonary Disease and Pulmonary Rehabilitation.

Chronic obstructive pulmonary disease (COPD) features chronic inflammatory reactions of both intra- and extrapulmonary nature. Moreover, COPD is associated with abnormal glucose and lipid metabolism in patients, which influences the prognosis and chronicity of this disease. Abnormal glucose and lipid metabolism are also closely related to inflammation processes. Further insights into the interactions of inflammation and glucose and lipid metabolism might therefore inspire novel therapeutic interventions to promote lung rehabilitation. Chemerin, as a recently discovered adipokine, has been shown to play a role in inflammatory response and glucose and lipid metabolism in many diseases (including COPD). Chemerin recruits inflammatory cells to sites of inflammation during the early stages of COPD, leading to endothelial barrier dysfunction, early vascular remodeling, and angiogenesis. Moreover, it supports the recruitment of antigen-presenting cells that guide immune cells as part of the body's inflammatory responses. Chemerin also regulates metabolism via activation of its cognate receptors. Glucose homeostasis is affected via effects on insulin secretion and sensitivity, and lipid metabolism is changed by increased transformation of preadipocytes to mature adipocytes through chemerin-binding receptors. Controlling chemerin signaling may be a promising approach to improve various aspects of COPD-related dysfunction. Importantly, several studies indicate that chemerin expression in vivo is influenced by exercise. Although available evidence is still limited, therapeutic alterations of chemerin activity may be a promising target of therapeutic approaches aimed at the rehabilitation of COPD patients based on exercises. In conclusion, chemerin plays an essential role in COPD, especially in the inflammatory responses and metabolism, and has a potential to become a target for, and a biomarker of, curative mechanisms underlying exercise-mediated lung rehabilitation.

Serum and adipose tissue chemerin is differentially related to insulin sensitivity

ObjectiveThe aim of the study was to assess serum chemerin concentration and s.c. adipose tissue (SAT) chemerin expression in relation to insulin sensitivity and obesity in young healthy subjects.DesignWe performed a cross-sectional study including 128 subjects, 44 with normal weight, 44 with overweight and 40 with obesity.MethodsHyperinsulinemic-euglycemic clamp and SAT biopsy were performed. Next, 30 subjects with obesity underwent 12-week weight-reducing dietary intervention.ResultsSerum chemerin was higher and SAT chemerin expression was lower in subjects with obesity in comparison with other groups. The relationship of serum chemerin with SAT expression and insulin sensitivity were positive in normal weight and overweight individuals, and negative in individuals with obesity. In the entire study population, serum chemerin was also positively related to hsCRP, serum fetuin A and alanine aminotransferase. SAT chemerin was positively related to insulin sensitivity, SAT insulin signaling and adipogenic genes. Weight loss decreased serum chemerin, whereas SAT chemerin increased in subjects with the highest increase in insulin sensitivity.ConclusionsSerum and SAT chemerin is differentially associated with insulin sensitivity and the relationship between serum chemerin and insulin sensitivity depends on adiposity. SAT chemerin is positively associated with insulin sensitivity across a wide range of BMIs and may be proposed as a biomarker of metabolically healthy SAT. Our results suggest that SAT is not the main source of serum chemerin in obesity.

Regulatory effect of chemerin and therapeutic efficacy of chemerin‑9 in pancreatogenic diabetes mellitus.

Chemerin is a novel adipokine that regulates immune responses, adipocyte differentiation, and glucose metabolism. However, the role of chemerin in pancreatogenic diabetes mellitus (PDM) remains unknown. PDM is recognized as DM occurring secondary to chronic pancreatitis or pancreatic resection due to the loss of the loss of islet cell mass. The aim of the present study was to investigate the role of chemerin in PDM by collecting blooding samples from DM patients and establishing in vivo PDM model. The present study demonstrated that chemerin levels are decreased in the serum of patients with PDM and are negatively associated with the insulin resistance (IR) status. Chemerin levels also decreased during the development of PDM in C57BL/6 mice, together with increasing serum levels of interleukin-1 and tumor necrosis factor-α and decreasing mRNA expression levels of glucose transporter 2 (GLUT2) and pancreatic and duodenal homeobox 1 (PDX1). Treatment of PDM model mice with chemerin chemokine-like receptor 1 (CMKLR1) agonist, chemerin-9, elevated the serum levels of chemerin and mRNA expression levels of GLUT2 and PDX1, leading to the alleviation of glucose intolerance and IR in these animals. Together, the accumulated data indicated that chemerin may exert a protective function in PDM, perhaps by regulating perhaps by regulating GLUT2 and PDX1 expression, and that the restoration of the chemerin/CMKLR1 pathway may represent a novel therapeutic strategy for PDM.

The expression of chemerin and its receptors (CMKLR1, GPR1, CCRL2) in the porcine uterus during the oestrous cycle and early pregnancy and in trophoblasts and conceptuses

Recent research has demonstrated that chemerin may take part in the regulation of reproduction. The aim of this study was to determine the expression of chemerin system – chemerin and its receptors, chemokine-like receptor 1 (CMKLR1), G protein-coupled receptor 1 (GPR1) and C-C chemokine receptor-like 2 (CCRL2) – in the porcine uterus during the oestrous cycle and early pregnancy, and in trophoblasts and conceptuses by real-time PCR and western blotting. Chemerin concentrations in uterine luminal flushings (ULF) were determined using ELISA test. In the endometrium, the highest expression of chemerin and GPR1 proteins was observed during the mid-luteal phase; CMKLR1, during the late luteal phase; and CCRL2, during the follicular phase of the cycle. In the myometrium, chemerin protein expression was enhanced during the early luteal phase, and chemerin receptor proteins were highly expressed during the follicular phase. In the endometrium of pregnant pigs, the highest expression of chemerin and CCRL2 protein was observed during implantation; CMKLR1, during placentation; and GPR1, during embryo migration. In the myometrium, chemerin and CCRL2 protein expression increased at the end of implantation, and the expression of CMKLR1 and GPR1 protein was enhanced during implantation. In the conceptuses and trophoblasts, the highest expression of chemerin system proteins was observed during placentation, with the exception of GPR1 protein in the trophoblasts. The highest concentrations of the analysed adipokine were observed in ULF during the luteal phase of the cycle and during maternal recognition of pregnancy. This is the first study to demonstrate that the expression of the chemerin system in the porcine uterus, conceptuses and trophoblasts, and chemerin concentrations in ULF are influenced by the hormonal milieu in different stages of the oestrous cycle and in early pregnancy. The present results also suggest that chemerin is implicated in the regulation of reproductive functions in pigs.

Alpha-syntrophin deficiency protects against non-alcoholic steatohepatitis associated increase of macrophages, CD8+ T-cells and galectin-3 in the liver

Non-alcoholic steatohepatitis (NASH) is characterized by immune cell infiltration. Loss of the scaffold protein alpha-syntrophin (SNTA) protected mice from hepatic inflammation in the methionine-choline-deficient (MCD) diet model. Here, we determined increased numbers of macrophages and CD8+ T-cells in MCD diet induced NASH liver of wild type mice. In the mutant animals these NASH associated changes in immune cell composition were less pronounced. Further, there were more γδ T-cells in the NASH liver of the null mice. Galectin-3 protein in the hepatic non-parenchymal cell fraction was strongly induced in MCD diet fed wild type but not mutant mice. Antioxidant enzymes declined in NASH liver with no differences between the genotypes. To identify the target cells responsive to SNTA loss in-vitro experiments were performed. In the human hepatic stellate cell line LX-2, SNTA did not regulate pro-fibrotic or antioxidant proteins like alpha-smooth muscle actin or catalase. Soluble galectin-3 was, however, reduced upon SNTA knock-down and increased upon SNTA overexpression. SNTA deficiency neither affected cell proliferation nor cell death of LX-2 cells. In the macrophage cell line RAW264.7 low SNTA indeed caused higher galectin-3 production whereas release of TNF and cell viability were normal. Moreover, SNTA had no effect on hepatocyte chemerin and CCL2 expression. Overall, SNTA loss improved NASH without causing major effects in macrophage, hepatocyte and hepatic stellate cell lines. SNTA null mice fed the MCD diet had less body weight loss and this seems to contribute to improved liver health of the mutant mice.

Renal Chemerin Expression is Induced in Models of Hypertensive Nephropathy and Glomerulonephritis and Correlates with Markers of Inflammation and Fibrosis.

Chemerin and its receptor, chemokine-like receptor 1 (CmklR1), are associated with chemotaxis, inflammation, and endothelial function, especially in metabolic syndrome, coronary heart disease, and hypertension. In humans, circulating chemerin levels and renal function show an inverse relation. So far, little is known about the potential role of chemerin in hypertensive nephropathy and renal inflammation. Therefore, we determined systemic and renal chemerin levels in 2-kidney-1-clip (2k1c) hypertensive and Thy1.1 nephritic rats, respectively, to explore the correlation between chemerin and markers of renal inflammation and fibrosis. Immunohistochemistry revealed a model-specific induction of chemerin expression at the corresponding site of renal damage (tubular vs. glomerular). In both models, renal expression of chemerin (RT-PCR, Western blot) was increased and correlated positively with markers of inflammation and fibrosis. In contrast, circulating chemerin levels remained unchanged. Taken together, these findings demonstrate that renal chemerin expression is associated with processes of inflammation and fibrosis-related to renal damage. However, its use as circulating biomarker of renal inflammation seems to be limited in our rat models.

Correlation between adiponectin, chemerin, vascular endothelial growth factor and epicardial fat volume in patients with coronary artery disease.

Epicardial fat, a local visceral fat depot surrounded by visceral pericardial sac, surrounds the coronary arteries for most of their course and may contribute to the development of coronary atherosclerosis by local production of inflammatory cytokines. Some studies on non-invasive measurement of epicardial fat mass have shown that epicardial fat mass is associated with the increased incidence of coronary artery disease (CAD), onset and progression of coronary plaque, mainly including major adverse cardiovascular events, myocardial ischemia, and atrial fibrillation. In the present study the correlation of adiponectin, chemerin, and vascular endothelial growth factor (VEGF) with the epicardial fat volume in patients with coronary artery disease was explored, and the risk factors for vascular remodeling of CAD patients were analyzed. A total of 50 CAD patients, treated in Chongzuo People's Hospital from August 2017 to September 2018, were enrolled as the observation group, and further 50 healthy individuals, who underwent physical examinations in the hospital at the same period, were enrolled as the control group. RT-qPCR was adopted to detect the expression levels of adiponectin, chemerin and VEGF in the two groups, a 64-slice dual-source CT to detect epicardial fat volume, and Pearson's correlation to analyze adiponectin, chemerin, VEGF and epicardial fat volume. Logistic regression analysis was performed to analyze the risk factors for vascular remodeling in CAD patients, and a receiver operating characteristic (ROC) curve analysis was used to analyze the value of indexes with multifactorial significance in vascular remodeling. The observation group showed obviously larger epicardial fat volume than the control group (P<0.001), lower adiponectin expression than the control group (P<0.001), and higher chemerin and VEGF expression than the control group (P<0.001). In the observation group, adiponectin expression decreased with the increase of epicardial fat volume (P<0.001), while the expression of chemerin and VEGF increased with the increase of epicardial fat volume (P<0.001). Remodeling occurred in 27 of the 50 patients. ROC curve analysis showed that the areas under the curves of adiponectin, chemerin, VEGF and epicardial fat volume were 0.697, 0.652, 0.696 and 0.689, respectively. Epicardial fat volume, adiponectin, chemerin and VEGF are independent risk factors for vascular remodeling and the expression of adiponectin, chemerin and VEGF can reflect epicardial fat volume.

Expression and correlation of Chemerin and FABP4 in peripheral blood of gestational diabetes mellitus patients.

Expression and correlation of Chemerin and fatty acid-binding protein 4 (FABP4) in peripheral blood of gestational diabetes mellitus (GDM) patients were investigated. Sixty patients with GDM from March 2018 to March 2019 in the People's Hospital of Zhangqiu Area were selected as the study group (SG) and another 50 healthy pregnant women corresponding to their age and pregnancy were selected as the control group (CG). Enzyme linked immunosorbent assay (ELISA) was used to detect the expression of Chemerin and FABP4 in serum. Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of Chemerin and FABP4 in peripheral blood for GDM patients. Pearson's correlation coefficient was used to analyze the correlation between Chemerin and FABP4 and the correlation between Chemerin and inflammatory factors such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Expression of Chemerin and FABP4 in peripheral blood of GDM patients were significantly higher than those in CG. The AUC of GDM patients diagnosed with Chemerin and FABP4 in peripheral blood was 0.820 and 0.814, while the AUC of GDM patients diagnosed with Chemerin combined with FABP4 in peripheral blood was 0.904. Expression of inflammatory factors IL-6 and TNF-α in the SG were significantly higher than those in the CG. Chemerin in the SG was positively correlated with FABP4 and positively correlated with inflammatory factors IL-6 and TNF-α. Patients with advanced age (≥35 years), family history of diabetes, hyperlipidemia, high pre-pregnancy BMI, high fasting blood glucose, high Chemerin and high FABP4 expression have high risk of GDM. In conclusion, Chemerin and FABP4 were upregulated in the peripheral blood of GDM patients. There was a positive correlation between the two and a positive correlation with the inflammatory factors IL-6 and TNF-α.

Expression of Bioactive Chemerin by Keratinocytes Inhibits Late Stages of Tumor Development in a Chemical Model of Skin Carcinogenesis.

Chemerin is a multifunctional protein acting mainly through the G protein-coupled receptor ChemR23/CMKLR1/Chemerin1. Its expression is frequently downregulated in human tumors, including in melanoma and squamous cell carcinoma of the skin and anti-tumoral properties of chemerin were reported in mouse tumor graft models. In the present study, we report the development of spontaneous skin tumors in aged ChemR23-deficient mice. In order to test the potential therapeutic benefit of chemerin analogs, a transgenic model in which bioactive chemerin is over-expressed by basal keratinocytes was generated. These animals are characterized by increased levels of chemerin immunoreactivity and bioactivity in the skin and the circulation. In a chemical carcinogenesis model, papillomas developed later, were less numerous, and their progression to carcinomas was delayed. Temporal control of chemerin expression by doxycycline allowed to attribute its effects to late stages of carcinogenesis. The protective effects of chemerin were partly abrogated by ChemR23 invalidation. These results demonstrate that chemerin is able to delay very significantly tumor progression in a model that recapitulates closely the evolution of solid cancer types in human and suggest that the chemerin-ChemR23 system might constitute an interesting target for therapeutic intervention in the cancer field.

Chemerin-9, a potent agonist of chemerin receptor (ChemR23), prevents atherogenesis.

Plasma levels of chemerin, an adipocytokine produced from the adipose tissues and liver, are associated with metabolic syndrome and coronary artery disease (CAD). Chemerin and its analog, chemerin-9, are known to bind to their receptor, ChemR23. However, whether chemerin and chemerin-9 affect atherogenesis remains to be elucidated. We investigated the expression of chemerin and ChemR23 in human coronary arteries and cultured human vascular cells. The effects of chemerin and chemerin-9 on atheroprone phenomena were assessed in human THP1 monocytes, human umbilical vein endothelial cells (HUVECs), and human aortic smooth muscle cells (HASMCs) and aortic lesions in Apoe-/- mice. In patients with CAD, a small amount of ChemR23, but not chemerin, was expressed within atheromatous plaques in coronary arteries. Chemerin and ChemR23 were expressed at high levels in THP1 monocytes, THP1-derived macrophages, and HUVECs; however, their expression in HASMCs was weak. Chemerin and chemerin-9 significantly suppressed the tumor necrosis factor-α (TNF-α)-induced mRNA expression of adhesion and pro-inflammatory molecules in HUVECs. Chemerin and chemerin-9 significantly attenuated the TNF-α-induced adhesion of THP1 monocytes to HUVECs and macrophage inflammatory phenotype. Chemerin and chemerin-9 suppressed oxidized low-density lipoprotein (oxLDL)-induced macrophage foam cell formation associated with down-regulation of CD36 and up-regulation of ATP-binding cassette transporter A1 (ABCA1). In HASMCs, chemerin and chemerin-9 significantly suppressed migration and proliferation without inducing apoptosis. In the Apoe-/- mice, a 4-week infusion of chemerin-9 significantly decreased the areas of aortic atherosclerotic lesions by reducing intraplaque macrophage and SMC contents. Our results indicate that chemerin-9 prevents atherosclerosis. Therefore, the development of chemerin analogs/ChemR23 agonists may serve as a novel therapeutic target for atherosclerotic diseases.

Expression of Chemerin and Its Receptors in the Porcine Hypothalamus and Plasma Chemerin Levels during the Oestrous Cycle and Early Pregnancy.

Chemerin (CHEM) may act as an important link integrating energy homeostasis and reproductive functions of females, and its actions are mediated by three receptors: chemokine-like receptor 1 (CMKLR1), G protein-coupled receptor 1 (GPR1), and C-C motif chemokine receptor-like 2 (CCRL2). The aim of the current study was to compare the expression of CHEM and its receptor (CHEM system) mRNAs (quantitative real-time PCR) and proteins (Western blotting and fluorescent immunohistochemistry) in the selected areas of the porcine hypothalamus responsible for gonadotropin-releasing hormone production and secretion: the mediobasal hypothalamus, preoptic area and stalk median eminence during the oestrous cycle and early pregnancy. Moreover, plasma CHEM concentrations were determined using ELISA. The expression of CHEM system has been demonstrated in the porcine hypothalamus throughout the luteal phase and follicular phase of the oestrous cycle, and during early pregnancy from days 10 to 28. Plasma CHEM levels and concentrations of transcripts and proteins of CHEM system components in the hypothalamus fluctuated throughout pregnancy and the oestrous cycle. Our study was the first experiment to demonstrate the presence of CHEM system mRNAs and proteins in the porcine hypothalamus and the correlations between the expression levels and physiological hormonal milieu related to the oestrous cycle and early pregnancy.

GPR1 Promotes Breast Cancer Tumorigenesis and Metastasis via PI3K/Akt Pathway

Background: Obesity has been shown to be highly correlated with breast cancer risk and therapy resistance. However, the underlying mechanism has yet been undetermined. The adipokine chemerin was shown to be associated with the prognosis of breast cancer and downregulated in patients. A survey of public whole genome expression datasets found that the receptor GPR1 is upregulated in breast cancers as well as in other human tumors. Moreover, high chemerin expression in tumors was correlated with adverse outcomes in breast cancer. Methods: GPR1 expression was ablated in human breast cancer cell line (MDA-MB-231) by shRNA. Tumor cell line proliferation, migration, colony formation, cell cycle and apoptosis was monitored in MDA-MB-231 cell line, and then the xenograft beared on nude mice was measured. Findings: Here, we report that disruption of GPR1, through shRNA in breast cancer cell MDA-MB-231, significantly inhibited tumor cell growth and invasion in vitro and tumor xenograft in vivo. This inhibition was involved in the suppression of phosphorylation of the PI3K/Akt signaling pathway. Interpretation: These results show that GPR1, as the receptor of adipokine chemerin, can promote the tumor growth and invasion through AKT/PI3K signaling, suggesting that obesity-derived chemerin may have a role in tumor genesis and invasion. Funding Statement: This work was partially supported by National Key Research and Development Program of China (2018YFC1003703), the National Major Basic Research Program of China (2013CB945503 ), NSFC grant (81830041, 81830041, 31671562), China Postdoctoral Science Foundation Funded Project (2018M640843 ), Guangdong grant (2018A030310058), and Shenzhen grant (JCYJ20170815090309586, JCYJ20170412140326739, JCYJ20170817143406822). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All procedures related to animal were carried out according to the guidelines of the Committee on the Use of Live Animals for Teaching and Research, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences.

Ovarian Expression of Adipokines in Polycystic Ovary Syndrome: A Role for Chemerin, Omentin, and Apelin in Follicular Growth Arrest and Ovulatory Dysfunction?

Adipokines are a potential link between reproduction and energy metabolism and could partly explain some infertilities related to some pathophysiology, such as polycystic ovary syndrome (PCOS). However, adipokines were predominantly assessed in blood samples, while very little is known concerning their variations in follicular fluid (FF) and ovarian granulosa cells (GCs) of PCOS women. Thus, the objectives of our study were to investigate adiponectin, chemerin, resistin, visfatin, omentin, and apelin ovarian expression in PCOS women in comparison with controls and women with only a polycystic ovary morphology. In total, 78 women undergoing an in vitro fertilization procedure were divided into three groups: 23 PCOS women, 28 women presenting only ≥12 follicles per ovary (ECHO group), and 27 control women. Each group almost equally included normal weight and obese women. Follicular fluid (FF) concentration and granulosa cells (GCs) mRNA expression of adipokines and their receptors were assessed by ELISA and RT-qPCR, respectively. Omentin levels in FF and GC were higher in PCOS than in ECHO and control women, while apelin expression was increased in both PCOS and ECHO groups. FF chemerin concentration was predominant in normal-weight PCOS women compared to BMI (Body Mass Index)-matched ECHO and control women, while GC mRNA levels were higher in the obese PCOS group than in the ECHO one. Compared to PCOS, ECHO women had increased FF adiponectin concentrations and lower plasma AMH levels. The FF concentration of all adipokines was higher in obese subjects except for adiponectin, predominant in normal-weight women. In conclusion, women with PCOS expressed higher GC chemerin and omentin, whereas the ECHO group presented higher levels of FF adiponectin and apelin and lower plasma AMH and LH concentrations. Chemerin, omentin, and apelin expression was differently regulated in women with PCOS, suggesting their possible role in follicular growth arrest and ovulatory dysfunction characterizing PCOS pathogenesis.

Chemerin and Cancer.

Chemerin is a multifunctional adipokine with established roles in inflammation, adipogenesis and glucose homeostasis. Increasing evidence suggest an important function of chemerin in cancer. Chemerin’s main cellular receptors, chemokine-like receptor 1 (CMKLR1), G-protein coupled receptor 1 (GPR1) and C-C chemokine receptor-like 2 (CCRL2) are expressed in most normal and tumor tissues. Chemerin’s role in cancer is considered controversial, since it is able to exert both anti-tumoral and tumor-promoting effects, which are mediated by different mechanisms like recruiting innate immune defenses or activation of endothelial angiogenesis. For this review article, original research articles on the role of chemerin and its receptors in cancer were considered, which are listed in the PubMed database. Additionally, we included meta-analyses of publicly accessible DNA microarray data to elucidate the association of expression of chemerin and its receptors in tumor tissues with patients’ survival.

Elevated chemerin induces insulin resistance in human granulosa-lutein cells from polycystic ovary syndrome patients.

The insulin resistance (IR) of ovarian granulosa cells from polycystic ovary syndrome (PCOS) aggravates the abnormalities in steroidogenesis and anovulation, and chemerin is an adipokine involved in regulating adipogenesis and glucose homeostasis. The role and underlying mechanism of chemerin in developing IR of the granulosa cells from PCOS remain unclear. Plasma, follicular fluid, and human granulosa-lutein cells (hGLs) were collected from non-PCOS and patients with PCOS with or without IR. The chemerin levels were elevated in both follicular fluid and hGL samples from patients with PCOS with IR, and the hGLs from patients with PCOS with IR showed decreased insulin sensitivity and impaired glucose uptake capacity. Moreover, treatment of chemerin attenuated insulin-stimulated glucose uptake by decreasing phosphorylation of insulin receptor substrate (IRS)1/2 Tyr612, phosphorylation of protein kinase B Ser473, and membrane translocation of glucose transporter type 4 through increasing Ser307 phosphorylation of IRS1 in cultured hGLs. These effects could be abolished by small interfering RNA-mediated knockdown of chemokine-like receptor 1. Furthermore, insulin induced the expression of chemerin in hGLs. Our findings demonstrate a novel role of chemerin in the metabolic dysfunction of PCOS, which suggested that chemerin and its receptor can be further implicated as potential therapeutic targets in the future treatment of PCOS.-Li, X., Zhu, Q., Wang, W., Qi, J., He, Y., Wang, Y., Lu, Y., Wu, H., Ding, Y., Sun, Y. Elevated chemerin induces insulin resistance in human granulosa-lutein cells from polycystic ovary syndrome patients.

Hydrogen-Rich Saline Attenuates Acute Lung Injury Induced by Limb Ischemia/Reperfusion via Down-Regulating Chemerin and NLRP3 in Rats.

Limb ischemia/reperfusion (LI/R) injury is associated with high morbidity and mortality. The hypothesis of this study is that hydrogen-rich solution could attenuateacute lung injury and improve mortality via chemerin and NLRP3 after LI/R in rats. A rat model of LI/R was performed by clamping the bilateral femoral arteries for 3 h followed by reperfusion. Hydrogen-rich saline (HRS) was administered intraperitoneally (10 mL/kg or 2.5 mL/kg) when the atraumatic micro clips were released. The rats were euthanized at 2 h after reperfusion and then the arterial blood and lung specimens were harvested for further analyses. Meanwhile, survival rate was observed. The results showed that HRS improved the survival rate and attenuated pulmonary edema, injury, and apoptosis. HRS also decreased the levels of tumor necrosis factor-α, interleukin-6, myeloperoxidase and malondialdehyde, and increased the activity of superoxide dismutase in serum and lung after the LI/R event. HRS downregulated the expression of chemerin and NLRP3 in lung. The study demonstrated that chemerin and NLRP3 could serve as important response factors that were involved in the lung injury following LI/R. HRS could significantly attenuate LI/R-mediated acute lung injury, at least in part, by inhibiting the activated chemerin/NLRP3 signaling pathway.