Plasma Resistin Levels Research Articles

Genetic variants of resistin and its plasma levels: Association with obesity and dyslipidemia related to type 2 diabetes susceptibility

Resistin, an adipokine, is involved in obesity and Type 2 Diabetes (T2D). The current study evaluates the association between RETN polymorphisms (−638 G/A, −420C/G & −358 G/A) and the risk towards T2D. Controls and T2D patients were enrolled from Gujarat, India. Polymorphisms of RETN were genotyped by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism. For the genotype-phenotype correlation analysis Fasting Blood Glucose (FBG), Body Mass Index (BMI) and plasma lipid profile were used. Plasma levels of resistin were assayed by ELISA. Our study suggests an association of RETN −420C/G polymorphism with T2D risk. The CC genotype of RETN −420C/G polymorphism was found to be associated with FBG, BMI, and total cholesterol. Plasma resistin levels were found to be significantly increased in diabetic patients as compared to controls. Our findings suggest −420C/G polymorphism of RETN as an important factor which could pose a powerful risk towards T2D susceptibility.

Resistin is elevated in cystic fibrosis sputum and correlates negatively with lung function

BackgroundResistin is an immunometabolic mediator that is elevated in several inflammatory disorders. A ligand for Toll-like receptor 4, resistin modulates the recruitment and activation of myeloid cells, notably neutrophils. Neutrophils are major drivers of cystic fibrosis (CF) lung disease, in part due to the release of human neutrophil elastase- and myeloperoxidase-rich primary granules, leading to tissue damage. Here we assessed the relationship of resistin to CF lung disease. MethodsResistin levels were measured in plasma and sputum from three retrospective CF cohorts spanning a wide range of disease. We also assessed the ability of neutrophils to secrete resistin upon activation in vitro. Finally, we constructed a multivariate model assessing the relationship between resistin levels and lung function. ResultsPlasma resistin levels were only marginally higher in CF than in healthy control subjects. By contrast, sputum resistin levels were very high in CF, reaching 50–100 fold higher levels than in plasma. Among CF patients, higher plasma resistin levels were associated with allergic bronchopulmonary aspergillosis, and higher sputum resistin levels were associated with CF-related diabetes. Mechanistically, in vitro release of neutrophil primary granules was concomitant with resistin secretion. Overall, sputum resistin levels were negatively correlated with CF lung function, independently of other variables (age, sex, and genotype). ConclusionsOur data establish relationships between resistin levels in the plasma and sputum of CF patients that correlate with disease status, and identify resistin as a novel mechanistic link between neutrophilic inflammation and lung disease in CF.

The overweight increases circulating inflammatory mediators commonly associated with obesity in young individuals

Obesity is a serious and growing world healthy problem affecting developed and developing countries. The new conception of obesity as a basal inflammatory condition has opened a new window of possibilities to identify inflammatory biomarkers to be used in the diagnosis or prognosis of obesity-associated comorbidities. This present work aims the identification of the adipokines (leptin and resistin), chemokines (CCL2, CCL5, CXCL16) and the BMP-2 and their association with the clinical, biochemical (fasting glucose, hemogram, cholesterol, T3, T4 and TSH) and anthropometric (weight, height, body circumferences, skinfold thickness and percentage of body fat) parameters in young adults (18–30 years old) presenting obesity and overweight. Our data showed increasing in anthropometric parameters and in the plasma inflammatory levels in those individuals presenting overweight and obesity. We observed a higher plasma levels of CCL2, CCL5, CXCL16, leptin and resistin in those overweigh and obese individuals. In addition, the CCL2, CCL5 presented a positive correlation with the body mass index and the body fat percentage. Assuming the obesity as a systemic inflammatory process, in this current study, the overweight individuals possess a close similar pattern of circulating inflammatory mediators which might be a potential risk of the development of obesity comorbidities. Further studies are still needed to precise the role of the biomarkers CCL2, CCL5, CXCL16 and BMP-2 in the clinical prognosis related to the overweight or obese individuals.

The Interplay between Hyperresistinemia, Elevated ROS, and Hyperglycemia in Diabetic Rats and Their Roles in Diabetes‐Associated Neutrophil Dysfunction

Resistin originally was found as an adipocyte‐derived polypeptide leading to insulin resistanis. Emerging evidence suggests that it plays important roles in various inflammatory diseases. The levels of hyperresistinemia has been associated with immunosuppression and serves as biomarker for the severity of the diseases. Neutrophils play a key role in host defenses against invading microorganisms by releasing large quantities of Reactive Oxygen Species (ROS) via respiratory burst, which are essential for killing bacteria. Diabetic patients have an increased risk of infections mainly as a result of impaired neutrophil functions. Our recent study found that reduced Nrf2 (NF‐E2‐related factor 2), a master transcription factor regulating antioxidant defenses, contributes to elevated ROS levels and increased microvessel permeability in diabetic rats. Diabetes‐associated microvessel dysfunction is highly associated with inflammation. However, the inter‐relationship between the plasma resistin levels, elevated ROS, and their effect on neutrophil function under Diabetic conditions remains unclear and even contradictory. This study aims to examine the interplay between the plasma resistin levels, increased oxidant stress caused by downregulation of Nrf2‐dependent antioxidant defenses, and the neutrophils function in Diabetic rats. Plasma resistin concentrations were determined with a sandwich enzyme immunoassay kit from Wide‐type (WT) Rat, Nrf2 Knock out (Nrf2−/−) out rats and streptozotocin (STZ)‐induced Nrf2−/− diabetic rat. Diabetic rat had experienced elevated blood glucose and A1C level at 404 ± 10 mg/dl and 10.20% ± 0.14% for 14–21 days before the experiments. Neutrophils were isolated from normal and diabetic rats and neutrophil released ROS upon formyl‐Met‐Leu‐OH (fMLP) stimulation was quantified by measuring chemiluminescence (CL). The resistin concentration in WT rats was 6.16 ± 0.97 ng/ml. Nrf2−/− rats significantly increases the resistin level to 15.88 ± 0.45 ng/ml. The resistin levels in diabetic Nrf2−/− rats was markedly increased to 31.67 ± 2.62 ng/ml. Meanwhile, we found neutrophil killing power was significantly reduced in diabetic rats. The peak CL of diabetic neutrophils upon fMLP stimulation was reduced from 826 ± 202 RLU (normal neutrophils) to 259 ± 51 RLU. The CL area under curve, a measure of total ROS production, in normal and diabetic neutrophils was 77614 ± 5509 and 43327 ± 3561 RLU, respectively. When the normal neutrophils were incubated with high glucose solution, a reduced fMLP‐stimulated CL response was also observed, but that couldn't match the reduction of the ROS production in Diabetic rats. These results indicate that increased plasma ROS levels may play a role in increased resistin levels. Further, both increased ROS, hyperresistinemia and hyperglycemia may synergistically contribute to neutrophil dysfunction in diabetes.Support or Funding InformationSupported by HL130363 and DK097391This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Type 2 diabetes mellitus risk and exercise: is resistin involved?

Obesity and associated disorders such as type 2 diabetes mellitus (T2DM) pose an increasing risk to the health of both individuals and society. Adipose tissue is an active endocrine organ, secreting many hormones, known as adipokines. Evidence suggests that one suggest adipokine, resistin, may be elevated in the plasma of individuals with T2DM, and early reports indicated that this may contribute to the impaired glucose tolerance and insulin resistance observed in T2DM, hence its name, resistin, however subsequent evidence suggests it may have a proinflammatory role. Performing regular exercise and dietary interventions improve insulin sensitivity and glucose tolerance in the majority of individuals with T2DM, and we hypothesized that plasma resistin levels may drop in individuals following a long term aerobic and/or resistance exercise intervention program. Articles analyzing the effects of exercise on serum resistin levels were therefore analyzed. Articles were selected and analyzed based on a minimum aerobic and/or resistance training program of 2 sessions per week for 12 weeks. Plasma resistin levels decreased following either endurance aerobic exercise and/or resistance training plans in individuals with obesity and/or insulin resistance, although this was not related to BMI change. Exercise intervention programs generally showed potentially beneficial changes in plasma resistin concentrations. It is possible these effects are mediated through exercise-induced decreases in inflammation via anti-inflammatory cytokine release rather than alterations in glucose metabolism and reductions in BMI per se. A possible link between resistin, exercise and T2DM is discussed.

The Main Determinants of Serum Resistin Level in Type 2 Diabetic Patients are Renal Function and Inflammation not Presence of Microvascular Complication, Obesity and Insulin Resistance.

The association of increased resistin levels in chronic kidney disease with diabetic nephropathy has not yet been clarified. Our aim was to analyze the relationship between serum resistin levels and various diabetic microvascular complications in patients. A total of 83 patients were enrolled in this cross-sectional study. The subjects were divided into 3 groups: 27 patients with type 2 diabetes mellitus (T2DM) having no diabetic retinopathy (DRP) or microalbuminuria and having normal renal function were included in Group-1, 28 patients with T2DM having DRP and normal renal function in Group-2, and 28 patients with T2DM with DRP and microalbuminuria and an estimated glomerular filtration rate (eGFR) of<60 ml/min/1.73 m2 in Group-3. Serum resistin levels were analyzed by enzyme-linked immunosorbent assay. The mean age of the patients [46 female (55.4%)] was 54.8±9.1 years. The resistin level in Group-3 was significantly higher than in Group-1 and Group-2 (p<0.001).However the resistin level was not different between Group-1 (without microvascular complications) and Group-2 (with microvascular complications). The resistin level was found to be correlated negatively with eGFR (r=-0.459; p<0.001) and albumin (r=-0.402; p<0.001), and positively with high-sensitivity C-reactive protein (hs-CRP) (r=0.366; p=0.001). In multivariate analysis, it was observed that eGFR and hs-CRP were independent determinants of plasma resistin level. The main determinants of resistin level in patients with T2DM are the level of renal function and inflammation rather than presence of microvascular complications, obesity and insulin resistance.

Inflammatory biomarkers responses after acute whole body vibration in fibromyalgia.

The aims of this study were 1) to characterize the intensity of the vibration stimulation in women diagnosed with fibromyalgia (FM) compared to a control group of healthy women (HW) matched by age and anthropometric parameters, and 2) to investigate the effect of a single session of whole body vibration (WBV) on inflammatory responses. Levels of adipokines, soluble tumor necrosis factor receptors (sTNFr1, sTNFr2), and brain-derived neurotrophic factor (BDNF) were determined by enzyme-linked immunosorbent assay. Oxygen consumption (VO2) was estimated by a portable gas analysis system, heart rate (HR) was measured using a HR monitor, and perceived exertion (RPE) was evaluated using the Borg scale of perceived exertion. Acutely mild WBV increased VO2 and HR similarly in both groups. There was an interaction (disease vs vibration) in RPE (P=0.0078), showing a higher RPE in FM compared to HW at rest, which further increased in FM after acute WBV, whereas it remained unchanged in HW. In addition, there was an interaction (disease vs vibration) in plasma levels of adiponectin (P=0.0001), sTNFR1 (P=0.000001), sTNFR2 (P=0.0052), leptin (P=0.0007), resistin (P=0.0166), and BDNF (P=0.0179). In conclusion, a single acute session of mild and short WBV can improve the inflammatory status in patients with FM, reaching values close to those of matched HW at their basal status. The neuroendocrine mechanism seems to be an exercise-induced modulation towards greater adaptation to stress response in these patients.

POSSIBLE CONTRIBUTION OF SOME ADIPOKINES ON TYPE II DIABETES IN OBESE AND NON-OBESE ADULT MALE RATS

Background: Type 2 diabetes results from a complex interplay between genetic and environmental factors. Overweight/obesity is a major risk factor for type 2 diabetes. Objective: Examining the changes in leptin, adiponectin and resistin levels in obese and non-obese rats with type 2 diabetes mellitus, and the effects on body weight, BMI, insulin resistance, HbA1c and fasting blood sugar. Materials and methods: Forty adult male albino rats of local strain were chosen as an animal model for this study. They were divided into normal control, control obese, diabetes mellitus and diabetes mellitus obese rats. Rats were rendered diabetic by a single intraperitoneal injection of STZ (40mg/kg B.W) that successfully induced type 2 diabetes. The high fat diet was used to induce obesity.It was prepared by increasing the fat content of diet to 11-12%. At the end of the experimental period, rats were weighed and BMI was calculated. The rats were anesthetized, blood samples were collected, and the separated plasma was stored at -20˚C for biochemical assays. Results: Regarding plasma leptin and resistin levels, all groups showed a significant increase as compared with control. There was a significant decrease in plasma adiponectin levels in all groups as compared with control group. There was a significant increase in plasma L/A ratio in all groups as compared with control group. Conclusion: The decrease in adiponectin and the increase in resistin and leptin levels inplasma could be attributed to hyperglycemia and the increased insulin resistance observed in obese, diabetic and diabetic obese rats.

Shift work is associated with metabolic syndrome in male steel workers-the role of resistin and WBC count-related metabolic derangements

AimsThere is increasing evidence linking a shift work schedule with various adverse health effects. The present study aimed to examine the relationship between shift work and the metabolic syndrome (MetS) in male steel workers, and also the possible mechanism of shift work-related metabolic derangements.MethodsA total of 1732 men aged 42 ± 8 years were enrolled in this cross-sectional study, including 862 day workers and 870 shift workers. Circulating levels of resistin were measured by ELISA using monoclonal specific antibodies.ResultsThe shift workers had higher rates of MetS and its components (central obesity, hypertension, and hypertriglyceridemia) than the day workers. In multiple logistic regression analysis, shift work was independently associated with MetS. In further analysis, the shift workers had elevated circulating levels of resistin (13 ± 10 vs. 10 ± 7 ng/mL) and total white blood cell (WBC) count (6.865 ± 1.819 vs. 6.304 ± 1.547 109/L) than the day workers. In addition, both resistin level and total WBC count were significantly associated with shift work, MetS, and its components (body mass index, fasting glucose, triglyceride, and high-density lipoprotein-cholesterol levels), and plasma resistin levels were significantly associated with total WBC count (β = 0.34, p < 0.0001).ConclusionShift work was independently associated with MetS in male steel workers. Resistin and WBC count were associated with shift work-related metabolic derangements.

The levels of adipokines in relation to hormonal changes during the menstrual cycle in young, normal-weight women.

ContextThe aim of this study was to assess the plasma leptin, adiponectin, resistin, visfatin/NAMPT, omentin-1, vaspin, apelin, TNF-α, IL-6 and RBP4 levels in relation to hormonal changes during the menstrual cycle in young, healthy, normal-weight women.MethodsThe study involved 52 young, healthy, normal-weight women. Anthropometric parameters, body composition and levels of plasma leptin, adiponectin, resistin, visfatin/NAMPT, omentin-1, vaspin, apelin, TNF-α, IL-6 and RBP4 in addition to serum FSH, LH, estradiol, progesterone, 17-OH progesterone, androgens, SHBG and insulin concentrations were measured during a morning in fasting state three times: between days 2–4, days 12–14 and days 24–26 of the menstrual cycle.ResultsPlasma adiponectin, omentin-1, resistin and visfatin/NAMPT, apelin, TNF-α, IL-6 and RBP4 concentrations were stable during the menstrual cycle, while leptin and vaspin levels were significantly higher in both the midcycle and the luteal phases than those in the follicular phase. Multivariate regression analyses revealed that changes in leptin and vaspin levels between the follicular and the luteal phase are strongly related to changes in total testosterone levels.ConclusionsOur results revealed stable levels of adipokines during the phases of the physiological menstrual cycle, except for leptin and vaspin, which showed increased levels in both the midcycle and the luteal phases. This effect was significantly associated with changes in the secretion of testosterone, 17-OH progesterone and insulin in the luteal phase.

PP.15.42] ADIPOKINES IN RESISTANT HYPERTENSION WITH OR WITHOUT TYPE 2 DIABETES MELLITUS

Objective: As adipokines relates with increases sympathetic activity and hyperinsulinemia, we aimed to assess the relationship between blood pressure (BP) and plasma adiponectin, leptin and resistin levels in resistant hypertension (RHTN), comparing the groups with and without type 2 diabetes mellitus (T2D). Design and method: Forty four RHTN pts (mean age 56.2 ± 8.6 years; mean 24 h BP: 162/91 mmHg; 20 male (46%)) underwent ambulatory BP monitoring, evaluating body mass index (BMI), plasma adiponectin, leptin and resistin concentrations. Results: Similar values of adiponectin, leptin and resistin were found in the T2D group (n = 17) and the non-T2D (n = 27) (p > 0.05). There were positively correlations of leptin level with BMI in both groups (r = 0.75, p = 0.00 for non-T2D and r = 0.71, r = 0.02 for T2D). The non-T2D pts with obesity (n = 19) have higher plasma leptin levels than those without (n = 8) (50.8 ± 25.2 vs. 18.4 ± 16.5ng/ml, p = 0.003), whereas in the T2D group plasma leptin level had no significant difference in the pts with (n = 4) and without obesity (n = 13) (27.6 ± 17.9 vs. 46.9 ± 25.6 ng/dL, p = 0.19). Furthermore, pts with obesity have similar leptin level in the non-T2D and T2D groups (p > 0.5). Values of adiponectin and resistin were similar in pts with and without obesity in both groups. Plasma leptin positively correlated with variability of 24 h systolic BP (SBP) and diastolic BP (DBP) in the non-T2D group (r = 0.41, P = 0.04 and r = 0.40, p = 0.04) and negatively correlated with the nighttime drop in SBP and DBP in the T2D group (r = −0.62, P = 0.01 for SBP and r = −0.59, P = 0.02 for DBP). Plasma adiponectin negatively correlated with SBP-24 h (r = −54, p = 0.04), SBP-day (r = −0.57, h = 0.03), loads of SBP-24 h (r = −0.64, p = = 0.009) and loads of SBP-day (r = −0.57, p = 0.03) only in the T2D group, whereas plasma resistin positively correlated with BP only in the non-T2D group (r = 0.56, p = 0.02 for SBP-24 h, r = 0.67, p = 0.000 for DBP-24 h.). Conclusions: These findings suggests that RHTN pts with or without type 2 diabetes have similar values of adipokines, but those adipokines differently contribute to blood pressure abnormalities in these groups. Plasma leptin has close relationship with BMI, and obesity RHTN pts have similar plasma leptin level regardless of the presence of T2D.

The Beneficial Effect of Anthocyanidin-Rich Vitis vinifera L. Grape Skin Extract on Metabolic Changes Induced by High-Fat Diet in Mice Involves Antiinflammatory and Antioxidant Actions.

We hypothesized that a polyphenol-rich extract from Vitis vinifera L. grape skin (GSE) may exert beneficial effects on obesity and related metabolic disorders induced by a high-fat diet (HFD). C57/BL6 mice were fed a standard diet (10% fat, control, and GSE groups) or an HFD (60% fat, high fat (HF), and HF + GSE) with or without GSE (200 mg/kg/day) for 12 weeks. GSE prevented weight gain; dyslipidemia; insulin resistance; the alterations in plasma levels of leptin, adiponectin, and resistin; and the deregulation of leptin and adiponectin expression in adipose tissue. These beneficial effects of GSE may be related to a positive modulation of insulin signaling proteins (IR, pIRS, PI3K, pAKT), pAMPK/AMPK ratio, and GLUT4 expression in muscle and adipose tissue. In addition, GSE prevented the oxidative damage, evidenced by the restoration of antioxidant activity and decrease of malondialdehyde and carbonyl levels in muscle and adipose tissue. Finally, GSE showed an anti-inflammatory action, evidenced by the reduced plasma and adipose tissue inflammatory markers (TNF-α, IL-6). Our results suggest that GSE prevented the obesity and related metabolic disorders in HF-fed mice by regulating insulin sensitivity and GLUT4 expression as well as by preventing the oxidative stress and inflammation in skeletal muscle and adipose tissue. Copyright © 2017 John Wiley & Sons, Ltd.

Effect of barley supplementation on the fecal microbiota, caecal biochemistry, and key biomarkers of obesity and inflammation in obese db/db mice.

Barley is a low-glycemic index grain that can help diabetic and obese patients. The effect of barley intake depends on the host and the associated gut microbiota. This study investigated the effect of barley intake on the fecal microbiota, caecal biochemistry, and key biomarkers of obesity and inflammation. Obese db/db mice were fed diets with and without barley during 8weeks; lean mice were used as lean controls. Fecal microbiota was evaluated using 16S marker gene sequencing in a MiSeq instrument; several markers of caecal biochemistry, obesity, and inflammation were also evaluated using standard techniques. Bacterial richness (i.e., Operational Taxonomic Units) and Shannon diversity indexes were similar in all obese mice (with and without barley) and higher compared to lean controls. Barley intake was associated with increased abundances of Prevotella, Lactobacillus, and the fiber-degraders S24-7 (Candidatus Homeothermaceae) compared to both lean and obese controls. The analysis of unweighted UniFrac distances showed a separate clustering of samples for each experimental group, suggesting that consumption of barley contributed to a phylogenetically unique microbiota distinct from both obese and lean controls. Caecal butyrate concentrations were similar in all obese mice, while succinic acid was lower in the barley group compared to obese controls. Barley intake was also associated with lower plasma insulin and resistin levels compared to obese controls. This study shows that barley intake is associated with a different fecal microbiota, caecal biochemistry, and obesity biomarkers in db/db mice that tend to be more similar to lean controls.

Role of atorvastatin in improving the inflammation-induced adipokine imbalance in mice with acute myocardial infarction

To investigate the effect of acute myocardial infarction (AMI)-activated inflammation on adipokine imbalance and the therapeutic effects of statin. Methods: A total of 32 C57BL/6 mice were divided into 4 groups: a sham group, an AMI group, a low-dose atorvastatin [2 mg/(kg.d)] group and a high-dose atorvastatin [20 mg/(kg.d)] group. AMI models were established by surgical coronary artery ligation. Plasma levels of high sensitive C reaction protein (hs-CRP), adiponectin and resistin were measured. Adiponectin and resistin expressions were determined. In addition, mouse 3T3-L1 preadipocytes in vitro were differentiated and they were stimulated by oxidized low density lipoprotein (ox-LDL). The protein expressions of adiponectin and resistin in adipocytes were detected. The effects of atorvastatin on ox-LDL-induced adipokine imbalance in adipocytes were identified. Results: The plasma levels of hs-CRP and resistin in AMI mice were significantly increased, whereas the plasma levels of adiponectin were remarkably decreased. However, atorvastatin treatment blocked the changes in the plasma levels of hs-CRP, resistin and adiponectin in AMI mice in a dose-dependent manner. Consistent findings regarding the adipose expressions of the two adipokines were obtained. The plasma levels of hs-CRP were positively correlated with resistin but negatively with adiponectin. In vitro study, ox-LDL increased resistin protein and adiponectin expressions in adipocytes, which were dose-dependently reversed by atorvastatin. Conclusion: Inflammation activation in AMI mice leads to adipokine imbalance. Atorvastatin ameliorates the AMI-induced adipokine imbalance via anti-inflammation.

Erratum to: Exogenous Adipokine Peptide Resistin Protects Against Focal Cerebral Ischemia/Reperfusion Injury in Mice.

Previous studies have demonstrated that plasma resistin levels were increased in patients with acute ischemic stroke. However, the role of resistin after ischemic brain injury is still unclear. In this study, we investigated the protective effects of resistin on cerebral ischemia/reperfusion injury in a middle cerebral artery occlusion mouse model. We found that resistin (i.c.v.) significantly reduced infarct volume and improved neurological deficits after 45 min of ischemia and 24 h of reperfusion. Furthermore, our data demonstrate that intraperitoneal administration of resistin (10 µg/kg body weight) also had protective effects on infarct volume, indicating the crossing of resistin through the impaired BBB after ischemia injury. Resistin treatment reduced cleaved protein level of Poly(ADP-ribose)polymerase-1 (PARP-1), a marker of cellular apoptosis, showing the anti-apoptotic activity of resistin. Resistin increased the level of phosphorylated Akt after ischemic brain injury. The neuroprotective effect of resistin was partially reversed by a PI3K inhibitor wortmannin, demonstrating that the PI3K/Akt signal pathway is involved in the anti-apoptotic mechanisms of resistin. Finally, we found that resistin treatment improved neurological function recovery at 14 days after treatment, including balance ability and muscle strength. Given these findings, resistin may have therapeutic potential for the treatment of stroke.

Exogenous Adipokine Peptide Resistin Protects Against Focal Cerebral Ischemia/Reperfusion Injury in Mice.

Previous studies have demonstrated that plasma resistin levels were increased in patients with acute ischemic stroke. However, the role of resistin after ischemic brain injury is still unclear. In this study, we investigated the protective effects of resistin on cerebral ischemia/reperfusion injury in a middle cerebral artery occlusion mouse model. We found that resistin (i.c.v.) significantly reduced infarct volume and improved neurological deficits after 45min of ischemia and 24h of reperfusion. Furthermore, our data demonstrate that intraperitoneal administration of resistin (10µg/kg body weight) also had protective effects on infarct volume, indicating the crossing of resistin through the impaired BBB after ischemia injury. Resistin treatment reduced cleaved protein level of Poly(ADP-ribose)polymerase-1 (PARP-1), a marker of cellular apoptosis, showing the anti-apoptotic activity of resistin. Resistin increased the level of phosphorylated Akt after ischemic brain injury. The neuroprotective effect of resistin was partially reversed by a PI3K inhibitor wortmannin, demonstrating that the PI3K/Akt signal pathway is involved in the anti-apoptotic mechanisms of resistin. Finally, we found that resistin treatment improved neurological function recovery at 14 days after treatment, including balance ability and muscle strength. Given these findings, resistin may have therapeutic potential for the treatment of stroke.

Increased anxiety-like behavior is associated with the metabolic syndrome in non-stressed rats.

Metabolic syndrome (MS) is a cluster of signs that increases the risk to develop diabetes mellitus type 2 and cardiovascular disease. In the last years, a growing interest to study the relationship between MS and psychiatric disorders, such as depression and anxiety, has emerged obtaining conflicting results. Diet-induced MS rat models have only examined the effects of high-fat or mixed cafeteria diets to a limited extent. We explored whether an anxiety-like behavior was associated with MS in non-stressed rats chronically submitted to a high-sucrose diet (20% sucrose in drinking water) using three different anxiety paradigms: the shock-probe/burying test (SPBT), the elevated plus-maze (EPM) and the open-field test (OFT). Behaviorally, the high-sucrose diet group showed an increase in burying behavior in the SPBT. Also, these animals displayed both avoidance to explore the central part of the arena and a significant increase in freezing behavior in the OFT and lack of effects in the EPM. Also, high-sucrose diet group showed signs of an MS-like condition: significant increases in body weight and body mass index, abdominal obesity, hypertension, hyperglycemia, hyperinsulinemia, and dyslipidemia. Plasma leptin and resistin levels were also increased. No changes in plasma corticosterone levels were found. These results indicate that rats under a 24-weeks high-sucrose diet develop an MS associated with an anxiety-like behavior. Although the mechanisms underlying this behavioral outcome remain to be investigated, the role of leptin is emphasized.

Abstract 497: Sex Differences in the Relationship Between Pro-Inflammatory Adipokines, Chemerin and Resistin, and Carotid Atherosclerotic Plaque Instability

Introduction: Sex differences in plaque morphology and composition exist; men develop more unstable plaques than women. Yet, stroke kills more women than men. Despite these differences, no sex-specific guidelines for carotid disease management exist. Thus, markers that reflect sex-specific morphological features in the plaque should be explored for better prediction of stroke risk. Pro-inflammatory adipokines, chemerin and resistin, influence vascular function. Herein we are the first to investigate sex differences in the relationship between carotid plaque instability and the expression of these adipokines. Methods: Subjects with ≥50% carotid stenosis scheduled for a carotid endarterectomy were recruited from McGill-affiliated hospitals. Pre-operative plasma chemerin and resistin levels were measured using ELISA. Stability of carotid plaque specimens was assessed by two gold standard histological classifications. Stable and unstable plaques were immunostained for chemerin, chemerin’s receptor (ChemR23), and resistin. Digital and semi-quantifications assessed the % area of expression as well as staining intensity (mild to high) and % of positively stained macrophages/foam cells. Plaque mRNA expression was assessed by quantitative PCR. Sex-hormone analyses are ongoing. Results: Men (n=171) had more unstable plaque features, i.e., greater hemorrhage (P=0.022), lipid core size (P&lt;0.001), inflammation (P=0.007), cap infiltration (P=0.006), and less fibrous tissue (P&lt;0.001) than women (n=79). Circulating chemerin and resistin levels were similar between men and women and no sex differences were observed in relation to plaque instability. The % area of chemerin and resistin staining in the plaque was greater in unstable vs stable plaques in men only (P=0.040; P=0.005, respectively). Similarly, greater intensity in chemerin, ChemR23, and resistin staining was associated with plaque instability in men only (P&lt;0.001; P=0.013; P=0.033, respectively). In contrast, lower resistin plaque mRNA expression was associated with plaque instability in women only (P=0.040). Conclusion: Our results suggest the possibility of a sex-dependent regulatory mechanism underlying the connection between these adipokines and plaque instability.

Differential adipokine DNA methylation and gene expression in subcutaneous adipose tissue from adult offspring of women with diabetes in pregnancy

BackgroundOffspring of women with diabetes in pregnancy are at increased risk of type 2 diabetes mellitus (T2DM), potentially mediated by epigenetic mechanisms. The adipokines leptin, adiponectin, and resistin (genes: LEP, ADIPOQ, RETN) play key roles in the pathophysiology of T2DM. We hypothesized that offspring exposed to maternal diabetes exhibit alterations in epigenetic regulation of subcutaneous adipose tissue (SAT) adipokine transcription.We studied adipokine plasma levels, SAT gene expression, and DNA methylation of LEP, ADIPOQ, and RETN in adult offspring of women with gestational diabetes (O-GDM, N = 82) or type 1 diabetes (O-T1DM, N = 67) in pregnancy, compared to offspring of women from the background population (O-BP, N = 57).ResultsCompared to O-BP, we found elevated plasma leptin and resistin levels in O-T1DM, decreased gene expression of all adipokines in O-GDM, decreased RETN expression in O-T1DM, and increased LEP and ADIPOQ methylation in O-GDM. In multivariate regression analysis, O-GDM remained associated with increased ADIPOQ methylation and decreased ADIPOQ and RETN gene expression and O-T1DM remained associated with decreased RETN expression after adjustment for potential confounders and mediators.ConclusionsIn conclusion, offspring of women with diabetes in pregnancy exhibit increased ADIPOQ DNA methylation and decreased ADIPOQ and RETN gene expression in SAT. However, altered methylation and expression levels were not reflected in plasma protein levels, and the functional implications of these findings remain uncertain.

Chemotherapy and plasma adipokines level in patients with colorectal cancer.

Adipokines are molecules produced and secreted by adipose tissue and are linked to multiple malignancies. Adipokines can suppress or promote particular cell behaviors in different types of cancer. The aim of this study was to investigate the impact of chemotherapy on select adipokines in patients with colorectal cancer (CRC). Blood samples were collected from 42 patients with pathologically documented advanced CRC, who required palliative chemotherapy. Leptin, adiponectin, resistin and visfatin levels were measured by ELISA before and 3 months after the administration of chemotherapy. Among the 42 patients evaluated, 18 achieved a partial response (PR), 16 achieved stable disease (SD) and 8 patients experienced disease progression (PD). We found that 5-fluorouracil-based chemotherapy regimens significantly increased plasma levels of leptin and adiponectin and decreased plasma levels of resistin and visfatin in PR and SD patients, whereas the plasma levels of these molecules were not affected in PD patients. Furthermore, the mean plasma levels of leptin were significantly lower, and the mean plasma levels of resistin and visfatin were significantly greater in patients with PD compared with PR and SD both before and after chemotherapy treatment. We conclude that palliative chemotherapy in CRC patients, in addition to providing clinical benefits, positively affects cytokine production and secretion in PR and SD patients. Specifically, we found that palliative chemotherapy increased plasma levels of the anti-inflammatory adipokine adiponectin and decreased the plasma levels of visfatin and resistin, molecules known to promote angiogenesis and cancer cell proliferation in PR and SD patients. Moreover, the baseline values of leptin, visfatin and resistin might serve as prognostic indicators of a poor response to chemotherapy.