| BackgroundAdipose tissue is classically considered a tissue that stores excess energy and provides insulation for the body; however, it is now considered to be an endocrine organ. The adipose tissue secretes multiple metabolic proteins known as adipokines. Since the discovery of the most notable adipokines, leptin and adiponectin, the member of adipokine extends continuously. Some of these adipokines play important roles in glucose and lipid metabolism, insulin resistance, obesity and type2diabetes.Chemerin, a newly found adipokine, is secreted as an18-kDa inactive proprotein named prochemerin and is converted into the16-kDa active chemerin by a serine protease cleavage of the C-terminal portion of the protein. It is most highly expressed in the white adipose tissue and liver, which are followed by the lung, kidney, pituitary, placenta and ovary. Chemerin is a novel chemoattractant protein that plays roles in adaptive and innate immunity. Recent research found that chemerin participated in the regulation of adipocyte differentiation and had effects on insulin sensitivity. Until now, the majority of studies have demonstrated that chemerin induces insulin resistance in the adipose tissue and skeletal muscle.Ethanol consumption is a lifestyle factor and is relevant to type2diabetes. Moderate alcohol consumption and a high amount of alcohol intake produced different effects on lipid metabolism and insulin sensitivity. Until now, few studies have focused on the effectts of ethanol on adipokines. Our previous study demonstrated that ethanol consumption elevated the leptin, resistin and visfatin levels and decreased the adiponectin concentrations in both the sera and visceral adipose tissues (VAT) of rats. Unlike the other adipokines, chemerin was highly expressed in the adipose and liver tissues. Until now, there was no study on the correlations between chemerin and ethanol. Therefore, this study aimed to observe the effects of a long-term intake of different doses of ethanol on chemerin in humans and rats and to evaluate the relationship of chemerin with metabolic parameters in humans.Objective1To observe the effect of chronic ethanol consumption on human serum chemerin.2To explore correlations between serum chemerin and metabolic paratems in humans.3To observe the effect of different dose of ethanol on chemerin in serum, liver and VAT in rats.4To explore correlations between serum chemerin, liver chemerin and VAT chemerin in rats.Materials and Methods1Human study1.1SubjectsData were obtained from an epidemiological investigation of type2diabetes in the Shandong Provincial Hospital in China. According to the study criteria,148healthy men who consumed alcohol and55healthy men who abstained from alcohol were included in the study. The body mass indexes (BMI) of all of the subjects were less than25kg/m2. The subjects were classified into four groups:a control group, a low-dose group (group L; ethanol consumption<15g·d-1), a middle-dose group (group M; ethanol consumption15-47.9g·d-1), and a high-dose group (group H; ethanol consumption≥48g·d-1).1.2Anthropometric measurementsA complete physical examination was conducted on each individual under the condition of an empty bladder and stomach. The values of height, weight, waist circumference and hip girth were taken and the BMI and the waist-to-hip ratio (WHR) was calculated. The body fat, percentage of body fat and waist-hip ratio of body fat were assessed using the body composition analyzer.1.3Laboratory measurementsThe fasting blood glucose (FBG) was determined by the glucose oxidase method. The fasting serum insulin (FINS) was measured using a radioimmunoassay kit. The plasma concentrations of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured using routine enzymatic methods. The insulin sensitivity was estimated using the homeostasis model assessment for insulin resistance (HOMA-IR), which was calculated as fasting insulin (mU·L-1) multiplied by fasting glucose (mmol·L-1) divided by22.5. The chemerin levels of humans was determined by enzyme-linked immunosorbent assay (ELISA).2Animal study2.1Animal protocols and housingTwenty-seven male Wistar rats were divided into four groups and given the following different treatments:control group (group C; distilled water at5.0g·kg-1·d-1), low-dose group (group L; ethanol at0.5g·kg-1·d-1), middle-dose group (group M; ethanol at2.5g·kg-1·d-1), and high-dose group (group H; ethanol at5.0g·kg-1·d-1). Distilled water or edible ethanol was given by a gastric tube every morning for22weeks.2.2Blood and tissue collectionBlood samples from all of the rats were obtained from the inferior vena cava after an overnight fast. The serum samples were separated after centrifugation and immediately stored at-80℃for subsequent analyses. The epididymal and perirenal fat pads and livers were removed and weighted and rapidly frozen in liquid nitrogen for adipokine measurements.2.3Laboratory measurementsThe FBG was determined by the glucose oxidase method. The FINS was measured using a radioimmunoassay kit. The insulin sensitivity was estimated using HOMA-IR, which was calculated as fasting insulin (mU·L-1) multiplied by fasting glucose (mmol·L-1) divided by22.5. Samples of the liver and adipose tissues (200mg) were excised from the frozen specimens. The excised tissues were added to200μL of phosphate-buffered saline (PBS) and homogenized. The tissue homogenates were frozen overnight at-80℃and thawed on ice the following day. After two freeze-thaw cycles, the homogenates were centrifuged. The middle layer of the adipose tissue homogenate and the supernatant of the liver homogenate were isolated and stored at-80℃to determine the total protein level and chemerin concentration.2.4ELISAThe chemerin levels in serum, adipose tissue and liver were determined by commercially available ELISA kits according to the manufacturer's instructions.Results1Human study1.1Anthropometric and metabolic characteristics of the human participantsThe body fat, percentage of body fat, waist-hip ratio of body fat, TG, FPG, FINS, and HOMA-IR in group H were significantly elevated compared with group C.1.2Chronic ethanol consumption increased serum chemerin in humansChronic ethanol consumption caused a dose-dependent increase of chemerin in human sera. The chemerin levels in group L, group M, and group H increased by9.75%(P=0.265),13.84%(P=0.094), and40.83(P<0.001), respectively, compared to group C. Furthermore, even after the adjustment for age, chemerin remained significantly different among the groups.1.3Serum chemerin levels are associated with TG and HOMA-IR in humansA pearson's correlation analysis was performed between the serum chemerin concentrations and clinical characteristics. The results showed that the chemerin levels positively correlated with the BMI, body fat, TG, FPG, FINS and HOMA-IR and negatively correlated with the HDL-C. A multivariate linear regression analysis using chemerin as the dependent variable revealed that the TG, FPG, FINS and HOMA-IR were independently associated with the chemerin concentrations.2Animal study 2.1High-doses ethanol intake decreased body weight (BW) and increased epididymal adipose tissue to BW ratio in ratsRats of the four groups had similar body weight at baseline. But after the22-week treatment, the BW of group M and group H decreased by5.28%and6.23%, respectively (both P<0.01). The epididymal adipose tissue to BW ratio increased by18.28%in group H in relation to the control group (P<0.01).2.2High-dose ethanol consumption increased FINS and HOMA-IRThe FINS levels and HOMA-IR of rats increased in ethanol-treated groups compared with controls. High doses of ethanol increased FINS levels by48.34%(P<0.05) and HOMA-IR values by44.04%(P<0.05) compared to the control group respectively.2.3Chronic ethanol treatment increased the chemerin levels in the sera and VAT of the ratsEthanol increased chemerin level in a dose-dependent manner in rats. Serum chemerin levels in group L, group M and group H increased by7.96%(p=0.524),25.33%(p=0.005) and50.60%(p<0.001) in relation to those in group C. Chemerin levels in VAT in group L, group M and group H increased by13.59%(p=0.357),34.84%(p=0.025) and50.17%(p=0.002) compared with those in group C. Chemerin levels in liver in group L, group M and group H increased by5.71(p=0.493),9.85%(p=0.242) and16.06%(p=0.063) compared with those in group C.2.4Positive correlation of chemerin levels between the serum and VATA correlation analysis between the serum and VAT or liver chemerin showed that the serum chemerin concentrations were positively associated with the chemerin in the VAT after adjusting for the liver chemerin. The relationship between the serum and liver chemerin was not statistically significant after adjusting for the chemerin in the VAT.Conclusions1Chronic ethanol consumption increases serum chemerin levels in human in a dose-dependent manner. 2Chronic ethanol consumption increases chemerin levels of serum and VAT in rats in a dose-dependent manner. The increase of serum chemerin is mainly attributed to the elevation of chemerin in VAT after ethanol treatment.3The chronic high-dose ethanol consumption increases body fat in humans and VAT in rats. |
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