Chemerin Expression Research Articles

The Impact of Chemokine-Like Receptor 1 Gene Knockout on Lipopolysaccharide-Induced Epididymo-Orchitis in Mice.

This comprehensive study delved into the pivotal function of chemokine-like receptor 1 (CMKLR1) in lipopolysaccharide (LPS)-triggered epididymo-orchitis in mice. Upon LPS exposure, wild-type (WT) mice exhibited marked elevations in serum pro-inflammatory markers, including G-CSF, IL-6, and RANTES, along with heightened levels of TNF-α and IL-6 in testicular and epididymal tissues, which accompanied by pronounced structural damage within the testicular tissue and a concurrent decline in serum testosterone, estradiol (E2) levels, and testicular steroid synthetase expression. Remarkably, Cmklr1 gene ablation intensified the pro-inflammatory response in the serum (especially IFN-γ), testes, and epididymis of epididymo-orchitis models. Furthermore, Cmklr1 deficiency uniquely induced structural alterations within the epididymis, which is absent in the WT model. This genetic manipulation also exacerbated the decline in serum testosterone and E2 levels and testicular steroid synthase activity. While chemerin levels were significantly diminished in WT epididymo-orchitis models, Cmklr1 knockout had no discernible effect on chemerin expression in the model. In addition, a noteworthy observation was the elevation of the serum low density lipoprotein/high density lipoprotein (LDL/HDL) ratio in Cmklr1-deficient mice. Collectively, these findings underscore that the lack of chemerin/CMKLR1 signaling axis could potentially worsen the symptoms during LPS-induced epididymo-orchitis, highlighting its potential as a therapeutic target in related pathologies.

Vascular Chemerin from PVAT contributes to Norepinephrine and Serotonin-Induced Vasoconstriction and Vascular Stiffness in a Sex-Dependent Manner.

The adipokine chemerin supports normal blood pressure and contributes to adiposity-associated hypertension, evidenced by falls in mean arterial pressure in Dahl SS rats given an antisense oligonucleotide against chemerin. In humans, circulating chemerin is positively associated with hypertension and aortic stiffness. Mechanisms of chemerin's influence on vascular health and disease remain unknown. We identified chemerin production in the vasculature-the blood vessel and its perivascular adipose tissue (PVAT). Here, using RNAScope®, QPCR, isometric contractility, high frequency ultrasound imaging, and western blot in the Dahl SS rat, we test the hypothesis that endogenous chemerin amplifies agonist-induced vasoconstriction through Chemerin1 and that chemerin drives aortic stiffness in the thoracic aorta. CMKLR1 (Chemerin1) expression was higher in the media, and Rarres2 (chemerin) expression was higher in the PVAT. Chemerin1 antagonism via selective inhibitor CCX832 reduced maximal contraction to norepinephrine (NE) and serotonin (5-HT), but not angiotensin II, in isolated thoracic aorta (PVAT intact) from male Dahl SS rat. In females, CCX832 did not alter contraction to NE or 5-HT. Male, but not female, genetic chemerin knockout Dahl SS rats had lower aortic arch pulse wave velocity than wild types, indicating chemerin's role in aortic stiffness. Aortic PVAT from females expressed less chemerin protein than males, suggesting PVAT as the primary source of active chemerin. We show that chemerin made by the PVAT amplifies NE and 5-HT-induced contraction and potentially induces aortic stiffening in a sex-dependent manner, highlighting the potential for chemerin to be a key factor in blood pressure control and aortic stiffening.

Expression of chemerin and B7 family proteins in lung adenocarcinoma — pilot study

Expression of chemerin and B7 family proteins in lung adenocarcinoma — pilot study

Chemerin regulates glucose and lipid metabolism by changing mitochondrial structure and function associated with androgen/androgen receptor.

The adipokine chemerin contributes to exercise-induced improvements in glucose and lipid metabolism; however, the underlying mechanism remains unclear. We aimed to confirm the impact of reduced chemerin expression on exercise-induced improvement in glycolipid metabolism in male diabetic (DM) mice through exogenous chemerin administration. Furthermore, the underlying mechanism of chemerin involved in changes in muscle mitochondria function mediated by androgen/androgen receptor (AR) was explored by generating adipose-specific and global chemerin knockout (adipo-chemerin-/- and chemerin-/-) mice. DM mice were categorized into the DM, exercised DM (EDM), and EDM + chemerin supplementation groups. Adipo-chemerin-/- and chemerin-/- mice were classified in the sedentary or exercised groups and fed either a normal or high-fat diet. Exercise mice underwent a 6-wk aerobic exercise regimen. The serum testosterone and chemerin levels, glycolipid metabolism indices, mitochondrial function, and protein levels involved in mitochondrial biogenesis and dynamics were measured. Notably, exogenous chemerin reversed exercise-induced improvements in glycolipid metabolism, AR protein levels, mitochondrial biogenesis, and mitochondrial fusion in DM mice. Moreover, adipose-specific chemerin knockout improved glycolipid metabolism, enhanced exercise-induced increases in testosterone and AR levels in exercised mice, and alleviated the detrimental effects of a high-fat diet on mitochondrial morphology, biogenesis, and dynamics. Finally, similar improvements in glucose metabolism (but not lipid metabolism), mitochondrial function, and mitochondrial dynamics were observed in chemerin-/- mice. In conclusion, decreased chemerin levels affect exercise-induced improvements in glycolipid metabolism in male mice by increasing mitochondrial number and function, likely through changes in androgen/AR signaling.NEW & NOTEWORTHY Decreased chemerin levels affect exercise-induced improvements in glycolipid metabolism in male mice by increasing mitochondrial number and function, which is likely mediated by androgen/androgen receptor expression. This study is the first to report the regulatory mechanism of chemerin in muscle mitochondria.

Comparative expression and localization of visfatin, chemerin, and chemerin receptor proteins in a heat-stressed mouse testis

The adipokines, visfatin, chemerin, and its receptor are expressed in the testis. It has also been shown that heat-stress alters the secretion and expression of other adipokines. Testicular heat-stress is now well known to cause the impairment in the testis. It has also been documented that heat-stress changes the expression of genes and proteins in the testis. To the best of our knowledge, the expression and localization of visfatin chemerin and its receptor have not been investigated in the heat-stressed testis. Therefore, the present study has investigated the expression and localization of these proteins in the heat-stressed testis. The expression of visfatin and chemerin and receptor exhibits a differential repossess against the heat stress. Visfatin expression was up-regulated while chemerin and chemerin receptor was down-regulated in the heat-stressed testis as shown by western blot analysis. The immunolocalization of visfatin and chemerin showed increased abundance in the seminiferous tubules of heat-stressed mice testis. Furthermore, abundance of visfatin, chemerin, and its receptor showed a decrease in abundance in the Leydig cells of heat-stressed testis. The decreased abundance of these proteins in the Leydig cells coincides with decreased 3β-HSD immunostaining along with decreased testosterone levels. These results suggest that heat-stress might decrease testosterone secretion by modulating visfatin and chemerin in the Leydig cells. The increased abundance of visfatin and chemerin in the primary spermatocytes, round spermatid, and multinucleated germ cells also coincides with increased immunostaining of active caspase-3. Moreover, expression of Bcl-2 was down-regulated, and expression of active caspase-3 and HSP70 were up-regulated along with increased oxidative stress in the heat-stressed testis, suggesting stimulated apoptosis. In conclusion, our results showed that visfatin, chemerin, and its receptor are differentially expressed in the testis under heat-stress and within the testis also it might differentially regulate testosterone biosynthesis in the Leydig cells and apoptosis in the seminiferous tubules.

Nuclear translocation of metabolic enzyme PKM2 participates in high glucose-promoted HCC metastasis by strengthening immunosuppressive environment

Although some cohort studies have indicated a close association between diabetes and HCC, the underlying mechanism about the contribution of diabetes to HCC progression remains largely unknown. In the study, we applied a novel HCC model in SD rat with diabetes and a series of high glucose-stimulated cell experiments to explore the effect of a high glucose environment on HCC metastasis and its relevant mechanism. Our results uncovered a novel regulatory mechanism by which nuclear translocation of metabolic enzyme PKM2 mediated high glucose-promoted HCC metastasis. Specifically, high glucose-increased PKM2 nuclear translocation downregulates chemerin expression through the redox protein TRX1, and then strengthens immunosuppressive environment to promote HCC metastasis. To the best of our knowledge, this is the first report to elucidate the great contribution of a high glucose environment to HCC metastasis from a new perspective of enhancing the immunosuppressive microenvironment. Simultaneously, this work also highlights a previously unidentified non-metabolic role of PKM2 and opens a novel avenue for cross research and intervention for individuals with HCC and comorbid diabetes.

Gualou Xiebai Banxia Decoction treats type 2 diabetes mellitus combined with acute myocardial infarction via chemerin/ CMKLR1/PPARα signaling pathway

This study aims to investigate the effects of Gualou Xiebai Banxia Decoction(GXBD) on type 2 diabetes mellitus(T2DM) combined with acute myocardial infarction(AMI) in rats via chemerin/chemokine-like receptor 1(CMKLR1)/peroxisome proliferator-activated receptor α(PPARα) signaling pathway, and to explore the mechanism of GXBD in alleviating glucose and lipid metabolism disorders. The SD rats were randomized into control, model, positive control, and low-and high-dose GXBD groups. The rat model of T2DM was established by administration with high-fat emulsion(HFE) by gavage and intraperitoneal injection with streptozotocin, and then coronary artery ligation was performed to induce AMI. The control and model groups were administrated with the equal volume of normal saline, and other groups were administrated with corresponding drugs by gavage. Changes in relevant metabolic indicators were assessed by ELISA and biochemical assays, and the protein levels of chemerin, CMKLR1, and PPARα in the liver, abdominal fat, and heart were determined by Western blot. The results showed that GXBD alleviated the myocardial damage and reduced the levels of blood lipids, myocardial enzymes, and inflammatory cytokines, while it did not lead to significant changes in blood glucose. Compared with the model group, GXBD down-regulated the expression of chemerin in peripheral blood and up-regulated the expression of cyclic adenosine monophosphate(cAMP) and protein kinase A(PKA) in the liver. After treatment with GXBD, the protein levels of chemerin and CMKLR1 in the liver, abdominal fat, and heart were down-regulated, while the protein levels of PPARα in the liver and abdominal fat were up-regulated. In conclusion, GXBD significantly ameliorated the disorders of glycolipid metabolism in the T2DM-AMI model by regulating the chemerin/CMKLR1/PPARα signaling pathway to exert a protective effect on the damaged myocardium. This study provides a theoretical basis for further clinical study of GXBD against T2DM-AMI and is a manifestation of TCM treatment of phlegm and turbidity causing obstruction at the protein level.

Progress in the contrary effects of glucagon-like peptide-1 and chemerin on obesity development.

Glucagon-like peptide-1 (GLP-1), secreted by intestinal L-cells, plays a pivotal role in the modulation of β-cell insulin secretion in a glucose-dependent manner, concurrently promoting β-cell survival and β-cell mass. Notably, GLP-1 has emerged as an effective second-line treatment for type 2 diabetes mellitus, gaining further prominence for its pronounced impact on body weight reduction, positioning it as a potent antiobesity agent. However, the mechanism by which GLP-1 improves obesity remains unclear. Some reports suggest that this mechanism may be associated with the regulation of adipokine synthesis within adipose tissue. Chemerin, a multifunctional adipokine and chemokine, has been identified as a pivotal player in adipocyte differentiation and the propagation of systemic inflammation, a hallmark of obesity. This review provides a comprehensive overview of the mechanisms by which GLP-1 and chemerin play crucial roles in obesity and obesity-related diseases. It discusses well-established aspects, such as their effects on food intake and glycolipid metabolism, as well as recent insights, including their influence on macrophage polarization and adipose tissue thermogenesis. GLP-1 has been shown to increase the population of anti-inflammatory M2 macrophages, promote brown adipose tissue thermogenesis, and induce the browning of white adipose tissue. In contrast, chemerin exhibits opposite effects in these processes. In addition, recent research findings have demonstrated the promising potential of GLP-1-based therapies in directly or indirectly regulating chemerin expression. In an intriguing reciprocal relationship, chemerin has also been newly identified as a negative regulator of GLP-1 in vivo. This review delineates the intricate interplay between GLP-1 and chemerin, unraveling their mutual inhibitory interactions. To the best of our knowledge, no previous reviews have focused on this specific topic, making this review particularly valuable in expanding our understanding of the endocrine mechanisms of obesity and providing potential strategies for the treatment of obesity and related diseases.

Expression of chemerin and its receptors in extra-embryonic annexes and role of chemerin and its GPR1 receptor in embryo development in layer and broiler hens

Intensive genetic selection of broiler breeders and layer hens resulted in differences in the mechanisms of growth and also in cell metabolism during embryogenesis. Previous research has shown that an adipokine named chemerin and one of these receptors, CMKLR1 were potentially involved in broiler embryo development. Here, our objectives were 1. to compare the expression of chemerin and its receptors CMKLR1, GPR1 and CCRL2 and chemerin concentration in extra-embryonic annexes (allantoic and amniotic membranes and fluids and plasma) in broiler and layer fertile eggs during the development (embryonic day (ED) 7, 14 and 18) by RT-qPCR and specific chicken ELISA and 2. to investigate the role of chemerin and one of its receptors GPR1 in embryo development after in ovo injections of neutralizing antibodies against chicken chemerin and GPR1. We found that chemerin expression in amniotic membranes was higher in layer than broiler eggs at ED7 and ED14 whereas the expression of the three receptors was higher in layer than broiler in the allantoic membranes at ED14 and ED18. Chemerin concentration was more important in layer than broiler at ED14 and ED18 in amniotic liquid and at all the studied stages in blood plasma. We also showed positive correlation between amniotic chemerin concentration and chemerin amniotic membrane expression, chemerin plasma concentration and embryo body weight in both breeds. Finally, in ovo injection of chicken chemerin and GPR1 neutralizing antibodies increased embryo mortality in both layer and broiler eggs. Taken together, even if chemerin concentration and chemerin system expression in embryonic membranes are mainly higher expressed in layer than in broiler, chemerin potentially through GPR1 could promote embryo development in both breeds.

Myricetin attenuates hypoxia-induced inflammation in human adipocytes.

Adipose tissue hypoxia plays a crucial role in the development of chronic low-grade systemic inflammation which has been associated with the pathogenesis of obesity-related diseases. Myricetin is a natural compound present in numerous plant-based foods with presumed anti-inflammatory and beneficial health effects. The impact of this flavonoid on hypoxia-induced expression of inflammatory adipokines and hypoxia-regulated pathways is unknown so far and has been addressed in the present study. Differentiated human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were cultured with or without myricetin under normoxic and hypoxic conditions for varying time periods. The effect of hypoxia and myricetin on the expression of the investigated adipokines was measured by real-time RT-PCR. Western blot analysis was used for the detection of transcription factors involved in hypoxia-regulated pathways. Myricetin interfered in the hypoxia-induced regulation of adipokines and the underlying pathways, which are involved in transmitting the inflammatory response. It strongly repressed hypoxia-induced expression of apelin, leptin, chemerin, asprosin, and DPP-4 and HIF-1α accumulation in the nucleus was diminished. Furthermore, the activation of the key regulators in the inflammatory response NF-κB, Akt, and CREB was suppressed by myricetin under hypoxic conditions. Myricetin also decreased hypoxia-induced accumulation of the pro-tumorigenic transcription factors Snail and Slug in the nucleus. Taken together, our results indicated that myricetin regulated hypoxia-induced expression of adipokines and hypoxia-regulated pathways in human adipocytes. Our study therefore provided evidence of the anti-inflammatory effects of myricetin in hypoxia-treated human adipocytes.

Prognostic impact of chemerin expression in colorectal cancer: A detailed analysis based on histological components and meta-analysis

This study aimed to elucidate the clinicopathological significance of chemerin immunohistochemical expression in colorectal cancer (CRC) based on histologic components. Immunohistochemistry was performed to detect chemerin in 266 human CRC tissues. Correlation between chemerin expression, clinicopathological characteristics, and survival in CRC. A meta-analysis was performed to claify the prognostic role of chemerin tissue expression in malignant tumors. Chemerin was expressed in 125 of 266 CRC tissues (47.0 %) and was significantly correlated with distant metastasis (P = 0.012). However, no significant correlation was observed between chemerin expression and other clinicopathological parameters. Subgroup analyses based on histological components showed that chemerin expression was significantly higher in CRCs with the mucinous component than in those without the mucinous component (P 0.001). However, there was no significant correlation between chemerin expression and the micropapillary component. Patients with chemerin expression had worse overall and recurrence-free survival rates (P = 0.017 and P = 0.009, respectively). The prognostic significance of chemerin was found in CRCs without the mucinous component but not in those with the mucinous component. Chemerin expression was significantly correlated with poor survival in breast and ovarian cancers in the meta-analysis. Chemerin expression significantly correlated with distant metastasis and poor survival in CRCs. The predictive role of patient prognosis is useful for CRCs, especially those with no mucinous component.

Chemerin triggers migration of a CD8 T cell subset with natural killer cell functions

The recruitment of cells with effector functions into the tumor microenvironment holds potential for delaying cancer progression. We show that subsets of human CD28-effector CD8 Tcells, CCR7- CD45RO+ effector memory, and CCR7- CD45RO- effector memory RA phenotypes, express the chemerin receptor CMKLR1 and bind chemerin via the receptor. CMKLR1-expressing human CD8 effector memory Tcells present gene, protein, and cytotoxic features of NK cells. Active chemerin promotes chemotaxis of CMKLR1-expressing CD8 effector memory cells and triggers activation of the α4β1 integrin. In an experimental prostate tumor mouse model, chemerin expression is downregulated in the tumor microenvironment, which is associated with few tumor-infiltrating CD8+ Tcells, while forced overexpression of chemerin by mouse prostate cancer cells leads to an accumulation of intra-tumor CD8+ Tcells. Furthermore, α4 integrin blockade abrogated the chemerin-dependent recruitment of CD8+ T effector memory cells into implanted prostate tumors invivo. The results identify a role for chemerin:CMKLR1 in defining a specialized NK-like CD8 Tcell, and suggest the use of chemerin-dependent modalities to target effector CMKLR1-expressing Tcells to the tumor microenvironment for immunotherapeutic purposes.

Expression and protective effect of chemerin in idiopathic pulmonary fibrosis

Objective: To explore the expression and the role of chemerin in idiopathic pulmonary fibrosis (IPF). Methods: Quantitative PCR and Western blotting were used to determine the mRNA and protein levels of chemerin in lung tissues from IPF patients and the controls. Clinical serum level of chemerin was analyzed by enzyme-linked immunosorbent assay. The mouse lung fibroblasts isolated and cultured in vitro were divided into the control, TGF-β, TGF-β+chemerin and chemerin groups. Immunofluorescence staining was used to observe the expression of α-smooth muscle actin (α-SMA). C57BL/6 mice were randomly divided into the control, bleomycin, bleomycin+chemerin, and chemerin groups. Masson and immunohistochemical staining were performed to evaluate the severity of pulmonary fibrosis. Expression of epithelial to mesenchymal transition (EMT) markers was detected by quantitative PCR and immunohistochemical staining in the in vitro and in vivo models of pulmonary fibrosis, respectively. Results: Compared with the control group, the expression of chemerin was downregulated in both the lung tissue and the serum of IPF patients. Immunofluorescence showed that treatment of fibroblasts with TGF-β alone resulted in a robust expression of α-SMA, whereas treatment with TGF-β and chemerin together exhibited the similar expression levels of α-SMA as the control group. Masson staining indicated that the bleomycin-induced pulmonary fibrosis model was constructed successfully, while treatment of chemerin partially alleviated the damage of lung tissue. Immunohistochemical staining showed that the expression of chemerin in the lung tissue was significantly decreased in the bleomycin group. Quantitative PCR and immunohistochemistry showed that chemerin attenuated EMT induced by TGF-β and bleomycin both in vitro and in vivo. Conclusions: The expression of chemerin was reduced in patients with IPF. Chemerin may play a protective role in the development of IPF by regulating EMT, providing a new idea for the clinical treatment of IPF.

Adipokines expression in reproductive tract, egg white and embryonic annexes in hen

In mammals, molecules mainly secreted by white adipose tissue named adipokines are also synthetized locally in the reproductive tract and are able to influence reproductive functions. In avian species, previous studies indicated that the adipokine chemerin is highly abundant in the albumen, compared to the yolk and this was associated to high chemerin expression in the magnum. In addition, the authors observed that chemerin and its receptors are expressed by allantoic and amniotic membranes and chemerin is present in fluids during the embryo development. Here, we studied other adipokines, including adiponectin, visfatin, apelin, and adipolin in egg white and their known receptors in the active (egg-laying hen) and regressed (hen not laying) oviduct and embryonic annexes during embryo development. By using Western blot, RT-qPCR analysis and immunohistochemistry, we demonstrated the expression of different adipokines in the egg albumen (visfatin) and the reproductive tract (adiponectin, visfatin, apelin, adipolin, and their cognate receptors) according the position of egg in the oviduct. We showed that the expression of adipokines and adipokines receptors was strongly reduced in the regressed oviducts (arrested laying hen). Results indicated that visfatin and adiponectin appeared at ED11 to 14 and increased until ED18 in amniotic fluid whereas it was found from ED7 and was unchanged during embryo development in allantoic fluid. Taken together, adipokines and their receptors are expressed in the egg white, the reproductive tract and the embryonic annexes. Data obtained suggest important functions of theses metabolic hormones during the chicken embryo development. Thus, adipokines could be potential biomarkers to improve the embryo development.

Abstract 5139: Chemerin suppresses prostate tumor growth by modulating the recruitment of NK and CD8+ T-cells to tumor microenvironment

Abstract Infiltration of immune cells into the tumor microenvironment (TME) can regulate growth and survival of malignant cells, thereby affecting tumorigenesis and tumor progression. While immune checkpoint inhibitors and agonism of costimulatory molecules can act to stimulate leukocytes, the lack of adequate recruitment of effector cells into TME often results in suboptimal immune responses. Chemerin (retinoic acid receptor responder 2, RARRES2) is an endogenous chemoattractant that is widely expressed by many tissues and recruits innate leukocytes through its receptor, CMKLR1 which is expressed on NK cells, some dendritic cells, and macrophages. Previous studies show that RARRES2 is downregulated across multiple tumor types including prostate cancer. Here, using a syngeneic transgenic adenocarcinoma mouse prostate (TRAMP-C1) model, we show that forced overexpression of RARRES2 by tumor cells results in significant tumor suppression and recruitment of NK and CD8+ T-cells within the TME. Male C57/BL/6 mice were inoculated with either RARRES2-overexpressing, vector control (VC) or mixed (50:50; VC: RARRES2) TRAMP-C1 cells. Chemerin overexpression in TRAMP-C1 cells did not alter their phenotypic behavior in vitro, but significantly suppressed tumor growth in vivo in mice. Furthermore, we observed a significantly higher influx of NK (CD3-CD19-NK1.1+) and CD8+ T-cells (CD3+CD8+) in tumor-infiltrating leukocytes (TILs) from mice with mixed tumors compared with VC tumors. Depletion of NK cells, CD4+, or CD8+ T cells showed that NK cells and CD8+ T-cells, but not CD4+ T-cells, were required for chemerin-dependent suppression of TRAMP-C1 tumor growth. We found significant increases in splenic NK and CD8 T cells, and a concomitant significant decrease in splenic G-MDSC in mice with chemerin-expressing tumors compared to controls, suggesting chemerin expression within the TME has an effect on systemic immune responses. Treatment of control tumors with anti-PD1 checkpoint inhibition did not result in significant tumor suppression, while anti-PD1 treatment of chemerin-expressing tumors significantly reduced tumor growth, doubling the complete response rate in these unresponsive tumors. Thus, for the first time we have demonstrated that increasing chemerin expression within the prostate TME can suppress growth by augmenting recruitment of NK and CD8+ T-cells and has the potential to be combined with checkpoint inhibitors in order to improve response rates in non-responsive tumors. Overall, these data suggest that a tumor-targeted chemerin therapeutic may have potential to treat human prostate cancers. Citation Format: Muhammad A. Saeed, Kevin Kim, Russell K. Pachynski. Chemerin suppresses prostate tumor growth by modulating the recruitment of NK and CD8+ T-cells to tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5139.

Chemerin and Chemokine-like Receptor 1 Expression Are Associated with Hepatocellular Carcinoma Progression in European Patients.

The chemoattractant protein chemerin is protective in experimental hepatocellular carcinoma (HCC), and high expression in HCC tissues of Asian patients was related to a favorable prognosis. Studies from Asia found reduced expression of chemerin in HCC compared to para-tumor tissues while our previous analysis observed the opposite. Aim of this study was to correlate chemerin expression in HCC tissues with disease severity of European patients Hepatocyte chemerin protein expression was assessed by immunohistochemistry in HCC tissue of 383 patients, and was low in 24%, moderate in 49% and high in 27%. High chemerin protein in the HCC tissues was related to the T stage, vessel invasion, histologic grade, Union for International Cancer Control (UICC) stage and tumor size. Chemokine-like receptor 1 (CMKLR1) is a functional chemerin receptor. CMKLR1 protein in hepatocytes was low expressed in HCC tissues of 36%, moderate in tissues of 32% and high in 32% of the HCCs. Tumor CMKLR1 was associated with the T stage, vessel invasion, histologic grade and UICC stage. Notably, sex-specific analysis revealed that associations of chemerin and CMKLR1 expression with HCC progression were significant in males but not in females. The tumor chemerin and CMKLR1 protein expression were not related to steatosis, inflammation and fibrosis grades. In summary, chemerin as well as CMKLR1 protein were related to disease severity of European HCC patients, and this was significant in males. This observation is in contrast to Asian patients where higher chemerin in the tumors was protective. Current analysis provides evidence for ethnicity and sex-related differences of tumor expressed chemerin and HCC severity.

Concentration of Polycyclic Aromatic Hydrocarbons (PAHs) in Human Serum and Adipose Tissues and Stimulatory Effect of Naphthalene in Adipogenesis in 3T3-L1 Cells.

Polycyclic aromatic hydrocarbons (PAHs) are one of the most prevalent classes of environmental pollutants. Some evidence shows that PAHs could be involved in human obesity. However, little is known about the distribution patterns of PAHs in human adipose tissue (AT) and the role of PAHs on adipogenesis/lipogenesis. The aims of this pilot study were to determine concentrations of 16 PAHs defined as high-priority pollutants in the plasma and adipose tissue of French and Polish bariatric patients, as well as their correlation with body mass index (BMI), plasma and AT adipokines expression levels. We finally investigated the role of naphthalene on cell proliferation, viability, and differentiation in 3T3-L1 preadipocytes. The concentration of most PAHs was similar in the three types of AT and it was significantly higher in AT as compared to plasma, suggesting bioaccumulation. Polish patients had higher PAH levels in AT than French ones. Only the concentration of naphthalene in AT was positively correlated with the BMI and serum or adipose chemerin, adiponectin and resistin expression, in French but not in Polish patients, who had significantly higher BMIs. Moreover, naphthalene exposure increased the cell proliferation of 3T3-L1 preadipocytes and lipogenesis, and increased the expression of genes involved in adipogenesis after cell differentiation. Taken together, PAHs and more particularly naphthalene could be an obesogenic molecule and increase the risk of obesity.

Intrauterine androgen exposure impairs gonadal adipose tissue functions of adult female rats

Prenatal androgen exposure induces fetal programming leading to alterations in offspring health and phenotypes that resemble those seen in women with Polycystic Ovary Syndrome. It has been described that prenatal androgenization affects the reproductive axis and leads to metabolic and endocrine disorders. Adipose tissue plays a crucial role in all these functions and is susceptible to programming effects. Particularly, gonadal adipose tissue is involved in reproductive functions, so dysfunctions in this tissue could be related to fertility alterations. We aimed to investigate the extent to which prenatal hyperandrogenization is able to alter the functionality of gonadal adipose tissue in female adult rats, including lipid metabolism, adipokines expression, and de novo synthesis of steroids. Pregnant rats were treated with 1 mg of testosterone from day 16 to day 19 of pregnancy, and female offspring were followed until 90 days of age, when they were euthanized. The prenatally hyperandrogenized (PH) female offspring displayed two phenotypes: irregular ovulatory (PHiov) and anovulatory (PHanov). Regarding lipid metabolism, both PH groups displayed disruptions in the main lipid pathways with altered levels of triglyceride and increased lipid peroxidation levels. In addition, we found that Peroxisome Proliferator-Activated Receptors (PPARs) alpha protein expression was decreased in both PH phenotypes (p < 0.05), but no changes were found in PPARγ protein levels. Furthermore, regarding adipokines, no changes were found in Leptin and Adiponectin protein levels, but Chemerin protein levels were decreased in the PHiov group (p < 0.05). Regarding de novo synthesis of steroids, the PHanov group showed increased protein levels of Cyp17a1 and Cyp19, while the PHiov group only showed decreased protein levels of Cyp19 (p < 0.05). These results suggest that prenatal androgen exposure affects females’ gonadal adipose tissue in adulthood, disturbing different lipid pathways, Chemerin expression, and de novo synthesis of steroids.

A new perspective: Fat tissue and adipokines in rheumatic heart valves.

To observe fat tissue and the expression of adipokines in rheumatic heart valves and explore the possible role of fat tissue and adipokines in the pathology of rheumatic heart disease (RHD). In this retrospective study, a total of 29 patients who received mitral valve replacement surgery were included. The study group consisted of 25 patients with RHD while the control group consisted of 4 patients with secondary mitral insufficiency caused by coronary heart disease (CAD). The clinical data of the patients including medical history, age, body mass index (BMI), fasting blood glucose (FBG), total triglycerides (TG), total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), apolipoprotein(a) [apo(a)], apolipoprotein(b) [apo(b)] were collected and compared. Cardiac ultrasonography was used to assess valve conditions before surgery. The removed valves were collected. The hematoxylin-eosin (HE) staining, oil-red O staining, and Masson's trichrome staining were adopted to evaluate the histological changes in the mitral valve. Immunohistochemical (IMC) staining was performed to evaluate the expression of adiponectin, leptin, and chemerin. There was no significant difference in general information and blood lipid levels between the two groups (all p > .05). Preoperative ultrasonography showed adipose tissue in the mitral valve of RHD patients. In the study group, rheumatic mitral valve samples showed thickening, adherence at the junction of the leaflets, calcification, and yellowish or fat mass by naked observation. The HE staining showed that there was calcification, inflammatory cell infiltration, fibrous tissue arranged disorder, and neovascularization. The oil-red O staining suggested fatty infiltration. Masson's trichrome staining suggested disorderly arrangement of collagen fiber and elastic fiber in rheumatic lesions, and the lesions were dominated by collagen fiber hyperplasia and less elastic fiber hyperplasia. The results of IMC indicated that chemerin was not expressed in valves of the control group. Most of the valve samples from the study group also did not show leptin and the leptin was seen in only a few rheumatic mitral valves with vascular hyperplasia. Adiponectin was not found in the valves of the study group and the control group. Adipose tissue in the rheumatic mitral valve could be observed by ultrasound. The fat mass and adipokines existed in rheumatic mitral valves, the adipocytokine chemerin is involved in the progression of the pathology in RHD.

Loss of Chemerin in Rhabdomyosarcoma Cells Polarizes Adjacent Monocytes to an Immunosuppressive Phenotype.

Chemerin is a multifunctional adipokine that regulates adipogenesis, insulin signaling and blood pressure and has thus a central function in metabolism. Mounting evidence confirmed a function of chemerin in various cancers. In this study, we investigated the role of chemerin in rhabdomyosarcoma (RMS), an aggressive soft tissue cancer that affects mainly children and young adults. We found chemerin expression in 93.8% (90 of 96) of RMS cases, with a range of 86.7–96.7% for the four RMS subgroups. While chemerin is uniformly expressed in normal skeletal muscle, its expression in RMS is patchy with interspersed areas that are devoid of chemerin. This variable chemerin expression is reflected by RMS cell lines as two of them (Rh41 and Rd18) were found to secrete chemerin while the two other ones (JR1 and RD) were negative. Deletion of chemerin in Rh41 and Rd18 cells did not alter their growth rate or morphology. We investigated the potential influence of chemerin on immune surveillance by coculturing parental and chemerin-deficient RMS cells with resting- or lipopolysaccharide (LPS)-activated human peripheral monocytes. The absence of chemerin in the RMS cells led to increased expression levels of the coinhibitory molecules PD-L1 and PD-L2 while levels of the costimulatory molecule CD86 were not changed. Further, the absence of chemerin enhanced the secretion of cytokines (IL-1β, IL-6, IL-10 and TNF) that have been shown to support RMS pathogenesis. These data indicate that the loss of chemerin expression by RMS cells repolarizes monocytes in the tumor microenvironment to supporting tumor progression.