Cerebrospinal Fluid Adiponectin Research Articles

Adiponectin in Cerebrospinal Fluid from Patients Affected by Multiple Sclerosis Is Correlated with the Progression and Severity of Disease

Adiponectin exerts relevant actions in immunity and is modulated in several disorders, such as multiple sclerosis (MS). In this study, we characterized adiponectin expression and profiles in cerebrospinal fluid (CSF) from MS patients to investigate its potential relationship with the severity and progression of the disease. Total adiponectin in CSF was measured by ELISA in 66 unrelated CSF MS patients and compared with 24 age- and sex-matched controls. Adiponectin oligomer profiles were analysed by Western blotting and FPLC chromatography. Total CSF adiponectin was significantly increased in MS patients compared with controls (9.91 ng/mL vs 6.02 ng/mL) (p < 0.001). Interestingly, CSF adiponectin positively correlated with CSF IgG, and CSF/serum albumin directly correlated with CSF/serum adiponectin. Our data demonstrated that CSF adiponectin predicts a worse prognosis: patients with the progressive form of MS had higher levels compared with the relapsing remitting form; patients with higher EDSS at baseline and a higher MS severity score at 4.5-year follow-up had significantly elevated adiponectin levels with respect to patients with a less severe phenotype. Finally, the adiponectin oligomerization profile was altered in CSF from MS patients, with a significant increase in HMW and MMW. The correlation of CSF adiponectin with the severity and prognosis of MS disease confirmed the role of this adipokine in the inflammatory/immune processes of MS and suggested its use as a complementary tool to assess the severity, progression and prognosis of the disease. Further studies on larger MS cohorts are needed to clarify the contribution of adiponectin to the etiopathogenesis of MS.

Association of Cerebrospinal Fluid Adiponectin Levels With Cerebral Glucose Metabolism In Mild Cognitive Impairment: A Pilot Study.

Adiponectin has been implicated in the pathophysiology of dementia, especially Alzheimer's disease. However, the association between cerebrospinal fluid (CSF) adiponectin levels and positron emission tomography (PET) imaging remains unclear. To explore whether CSF adiponectin levels are associated with 11C-Pittsburgh compound B (PiB) or 18F-fluorodeoxyglucose (FDG) uptake in amnestic mild cognitive impairment (MCI) subjects. Thirty-four amnestic MCI subjects underwent PiB-PET, FDG-PET, and CSF analysis. The CSF adiponectin levels were measured using the Bio-Plex 200 suspension array system. PET uptake was assessed for the frontal and temporoparietal lobes and posterior cingulate gyrus, referenced against the cerebellar cortex. The increased brain amyloid burden was defined as a mean uptake value ratio greater than 1.4. Spearman's rank correlation analysis and a multiple regression model were used to examine the association between CSF adiponectin levels and PiB or FDG uptake. The mean age was 76.3 years; 38.2% were men, and 61.8% were women. A high amyloid burden was identified in 18 (52.9%) subjects. CSF adiponectin levels positively correlated with global FDG uptake (β = 0.45; 95% confidence interval (CI), 0.13 to 0.76, p < 0.01), especially in the parietotemporal lobe and posterior cingulate gyrus (β = 0.70; 95% CI, 0.41 to 0.99, p<0.01, β = 0.33; 95% CI, 0.03 to 0.63, p = 0.03, respectively) after adjusting for covariates, including age, sex, education years, body mass index, vascular risk factors, ApoEε4 status, and PiB status in all amnestic MCI subjects. CSF adiponectin levels were associated with cortical glucose metabolism, particularly in the specific regions that connect with the medial temporal, but not brain amyloid burden in amnestic MCI subjects.

Effects of running on adiponectin, insulin and cytokines in cerebrospinal fluid in healthy young individuals

Exercise can prevent the sedentary lifestyle-related risk of metabolic and cognitive decline, but mechanisms and mediators of exercise effects on human brain are relatively unexplored. We measured acute exercise-induced changes in adiponectin, insulin and other bioactive molecules in cerebrospinal fluid (CSF) and serum from young lean individuals. Samples of serum and CSF were obtained before and 1-h after the 90-min run (75–80% HRmax; maximal heart rate), additional serum was taken at finish-line. Body composition, physical fitness, metabolic rate, cognitive functions, food preference, glucose, insulin and albumin were measured. The spectrum of 174 cytokines was assessed by protein arrays, adiponectin was also determined by ELISA and immunoblotting. CSF adiponectin decreased post-exercise by 21.3% (arrays) and 25.8% (ELISA) (p < 0.009). Immunoblotting revealed reduction in a low-molecular-weight-adiponectin (p < 0.005). CSF adiponectin positively correlated with CSF/serum albumin ratio (p < 0.022), an indicator of blood-brain-barrier permeability. CSF and serum adiponectin were positively associated with memory and running-induced changes in insulinemia and CSF insulin. Additionally, running modulated CSF levels of 16 other cytokines. Acute running reduced CSF adiponectin and modulated insulin and albumin in CSF and serum. Associations of adiponectin with memory and metabolism indicate the potential role of this bioactive molecule in mediating exercise-induced adaptive response in human brain.

Association between Adipokines and Biomarkers of Alzheimer's Disease: A Cross-Sectional Study.

Adipose tissue dysfunction has been implicated in the pathophysiology of Alzheimer's disease. However, the involvement of adipokines, particularly adiponectin, remains unclear. To compare serum and cerebrospinal fluid (CSF) levels of adiponectin, leptin and leptin-to-adiponectin ratio in patients within the spectrum of Alzheimer's disease and evaluate their relationship with classical biomarkers and their value as markers of progression. Amnestic mild cognitive impairment (MCI, n = 71) and Alzheimer's dementia (AD, n = 53) subjects were consecutively recruited for serum and CSF adiponectin and leptin determination using an analytically validated commercial enzyme-linked immunosorbent assay (ELISA). Correlations were explored using adjusted Spearman's correlation coefficients. A logistic regression model and ROC analysis were performed to evaluate the staging predictive value of adipokines. Serum adiponectin was 33% higher in AD when compared to MCI patients. Adiponectin CSF levels, similar in both groups, were positively correlated with Aβ42 and cognitive function, though only in women. The area under the ROC curve was 0.673 (95% CI:0.57-0.78) for serum adiponectin as predictor of dementia stage and the cut-off 10.85μg/ml maximized the sum of specificity (87%) and sensitivity (44%). Although longitudinal studies are required, we hypothesize that higher serum adiponectin in AD patients constitutes a strategy to compensate possible central signaling defects. In addition, adiponectin might be specifically assigned to neuroprotective functions in women and eventually involved in the female-biased incidence of Alzheimer's disease.

Serum and CSF adiponectin, leptin, and interleukin 6 levels as adipocytokines in Egyptian children with febrile seizures: a cross-sectional study.

BackgroundA febrile seizure (FS) is the most common convulsive disorder in children. Activation of cytokine network is involved in FS pathogenesis. Adiponectin, leptin and IL-6 are the major adipocytokines secreted by fat cells. To date, only a few studies concerned the association of adipocytokines with febrile seizures. In this study, we tried to investigate serum and CSF levels of adiponectin, leptin, and interleukin-6 (IL-6); as adipocytokines, for the first time in Egyptian children with febrile seizures.MethodsThis was a prospective cross-sectional study included one hundred patients with febrile seizure, and matched with age, gender, 100 children with febrile illness without seizures (febrile control, FC) and 100 healthy control group (HC). Serum and cerebrospinal fluid (CSF) levels of adiponectin, leptin, and (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA) method.ResultsSerum adiponectin was significantly higher in children with FS (16.8 ± 3.7 ug/ml) and the FC group (18.3 ± 4.3 ug/ml) compared to the HC group (9.5 ± 2.2 ug/ml); P < 0.05, respectively. Serum leptin was significantly lower in children with FS (0.9 ± 0.3 ng/ml) compared to both the FC group (4.7 ± 1.2 ng/ml) and the HC group (1.8 ± 0.4 ng/ml); P < 0.01, respectively. Children with FS had significantly higher serum IL-6 levels (43.7 ± 11.7 ng/ml) than the FC group (21.9 ± 4.5 ng/ml) and the HC group (6.5 ± 1.8 ng/ml); P < 0.01, respectively. Patients with simple febrile seizures (SFS) had serum and CSF adiponectin levels similar to those with complex febrile seizures (CFS); (P > 0.05). Serum and CSF leptin levels were significantly lower in patients with CFS compared to the SFS group (P < 0.05). Serum and CSF IL-6 levels were significantly higher in patients with CFS compared to the SFS group (P < 0.01). On multivariate logistic regression analysis, the high serum IL-6 levels was the most significant risk factor associated with febrile seizures among studied children (OR: 6.2; 95 % CI: 3.58 –10.57; P = 0.0001).ConclusionOur data brought a novel observation that some adipocytokines like leptin and IL-6 could be, at least in part, an aetiopathogenetic factor in the manifestation of febrile seizures in susceptible Egyptian children. Moreover, we observed a significant association between high CSF IL-6 levels and susceptibility to complex febrile seizures as did the low CSF leptin levels.

Exercise and obesity in fibromyalgia: beneficial roles of IGF-1 and resistin?

IntroductionSevere fatigue is a major health problem in fibromyalgia (FM). Obesity is common in FM, but the influence of adipokines and growth factors is not clear. The aim was to examine effects of exercise on fatigue, in lean, overweight and obese FM patients.MethodsIn a longitudinal study, 48 FM patients (median 52 years) exercised for 15 weeks. Nine patients were lean (body mass index, BMI 18.5 to 24.9), 26 overweight (BMI 25 to 29.9) and 13 obese. Fatigue was rated on a 0 to 100 mm scale (fibromyalgia impact questionnaire [FIQ] fatigue) and multidimensional fatigue inventory (MFI-20) general fatigue (MFIGF). Higher levels in FIQ fatigue and MFIGF indicate greater degree of fatigue. Free and total IGF-1, neuropeptides, adipokines were determined in serum and cerebrospinal fluid (CSF).ResultsBaseline FIQ fatigue correlated negatively with serum leptin (r = -0.345; P = 0.016) and nerve growth factor (NGF; r = -0.412; P = 0.037). In lean patients, baseline MFIGF associated negatively with serum resistin (r = -0.694; P = 0.038). FIQ Fatigue associated negatively with CSF resistin (r = -0.365; P = 0.073). Similarly, FIQ fatigue (r = -0.444; P = 0.026) and MFIGF correlated negatively with CSF adiponectin (r = -0.508; P = 0.01). In lean patients, FIQ fatigue (P = 0.046) decreased after 15 weeks. After 30 weeks, MFIGF decreased significantly in lean (MFIGF: P = 0.017), overweight (MFIGF: P = 0.001), and obese patients (MFIGF: P = 0.016). After 15 weeks, total IGF-1 increased in lean (P = 0.043) patients. ∆Total IGF-1 differed significantly between lean and obese patients (P = 0.010). ∆Total IGF-1 related negatively with ∆MFIGF after 15 weeks (r = -0.329; P = 0.050). After 30 weeks, ∆FIQ fatigue negatively correlated with ∆NGF (r = -0.463; P = 0.034) and positively with ∆neuropeptide Y (NPY) (r = 0.469; P = 0.032). Resistin increased after 30 weeks (P = 0.034). ∆MFIGF correlated negatively with ∆resistin (r = -0.346; P = 0.031), being strongest in obese patients (r = -0.815; P = 0.007). In obese patients, ∆FIQ fatigue after 30 weeks correlated negatively with ∆free IGF-1 (r = -0.711; P = 0.032).ConclusionsExercise reduced fatigue in all FM patients, this effect was achieved earlier in lean patients. Baseline levels of resistin in both serum and CSF associated negatively with fatigue. Resistin was increased after the exercise period which correlated with decreased fatigue. Changes in IGF-1 indicate similar long-term effects in obese patients. This study shows reduced fatigue after moderate exercise in FM and indicates the involvement of IGF-1 and resistin in these beneficial effects.Trial registrationClinicalTrials.gov: NCT00643006

Adiponectin activates endothelial nitric oxide synthase through AMPK signaling after subarachnoid hemorrhage

Adiponectin is produced from fatty tissue and has been reported to be involved with metabolic syndrome. Recently, adiponectin has been demonstrated to play a neuroprotective role against cerebral ischemia. In this study, we explored the time-course serial expression changes of adiponectin in cerebrospinal fluid (CSF) after subarachnoid hemorrhage (SAH) and the effects of adiponectin on cerebral arteries. The concentrations of adiponectin were measured serially until day 14 in CSF of 8 patients with SAH. The CSF samples obtained from 6 patients suffering from an unruptured aneurysm were used as controls. Serum samples were collected from 6 healthy adult volunteers. Rat cerebral arteries were incubated with adiponectin (2μg/ml). Western blot analysis using AMP-activated protein kinase α (AMPKα), phosphorylated (p)-AMPKα at Thr172, endothelial nitric oxide synthase (eNOS), p-eNOS at Ser1177 and actin antibodies was then performed. The adiponectin concentrations in serum and control CSF were 17,670±3748ng/ml and 9.2±3.0ng/ml, respectively. After SAH, the concentration of adiponectin in the CSF significantly increased on the first post-SAH day and gradually decreased thereafter. Adiponectin significantly phosphorylated both the AMPKα and eNOS of the cerebral arteries. Our findings suggest that adiponectin is significantly increased in the CSF after SAH, resulting in the activation of AMPKα and eNOS. Adiponectin plays an important role against cerebral vasospasm via the AMPK/eNOS signaling pathway.

Adiponectin in plasma and cerebrospinal fluid in MCI and Alzheimer’s disease

Life style-related disorders such as hypertension, diabetes, dyslipidemia, and obesity are reported to be a great risk of dementia. Adipocytokines released from adipose tissue are thought to modulate some brain functions including memory and cognition. We here analysed adiponectin, one of the most important adipocytokines, in plasma and cerebrospinal fluid (CSF) from cognitive normal controls (NC), mild cognitive impairment (MCI) subjects, and patients with Alzheimer's disease (AD) and discussed if/how adiponectin could relate to the pathogenesis of AD. Normal controls (n = 28), MCI (n = 18), and AD (n = 27) subjects were recruited at Tohoku University Hospital. The diagnosis of AD was based on NINCDS-ADRDA criteria. All the blood and CSF samples were obtained from each fasted subject. Adiponectin was assayed using a sandwich ELISA system. The levels of adiponectin between in plasma and in CSF showed a positive correlation. Plasma adiponectin was significantly higher in MCI and AD compared to NC, whereas CSF adiponectin was significantly higher in MCI compared to NC. It is possible that the level of adiponectin in plasma reflects its level in CSF. The tendency to have higher adiponectin in plasma and CSF from MCI and AD suggests that this molecule plays a critical role in the onset of AD.

Leptin and adiponectin in plasma and CSF from Alzheimer's patients and normal controls

Life style related diseases such as hypertension, diabetes, and dyslipidemia are reported to be a great risk for dementia (1). Adipocytokines released from fat tissue are supposed to be related to the etiology of Alzheimer's disease (AD). We here analyzed leptin and adiponectin in cerebrospinal fluid (CSF), serum and plasma from AD patients and normal controls (NC) and discussed how these adipocytokines could contribute to the pathomechanism of AD. AD patients and NCs were recruited in Tohoku University Hospital. The diagnosis of AD was based on NINCDS-ADRDA criteria. Cognitive functions were examined using MMSE and ADAS-Cog. All the samples were obtained from each fasted patient or NC. Leptin in serum, plasma and CSF was assayed using a sandwich ELISA system (R&D) and adiponectin was assayed in three multimer forms, high molecular weight (HMW), middle molecular weight (MMW), and low molecular weigh (LMW) using a sandwich ELISA system (Daiichi Pure Chemicals Co) (2). We succeeded in quantification of leptin and HMW, MMW and LMW of adiponectin in both human plasma and serum. The levels of leptin and each form of adiponectin were comparable between in plasma and in serum. However, it was difficult to analyze three forms of adiponecin in CSF because of their concentrations looked too low. The levels of Leptin and three forms of adiponectin in CSF are highly correlated to those in plasma in both ADs and NCs. It was suggested that the levels of leptin and total adiponectin in serum or plasma reflect the levels of these adipocytokines in CSF from AD and NCs. Therefore the levels in serum or plasma could estimate the intracerebral concentrations of these molecules. Comparison of the levels of leptin and adiponectin between ADs and NCs are now underway.

Improved ELISA for Selective Measurement of Adiponectin Multimers and Identification of Adiponectin in Human Cerebrospinal Fluid

Human serum adiponectin exists in 3 multimer forms: high molecular weight (HMW), middle molecular weight, and low molecular weight (LMW), with some of the latter bound to albumin (Alb)-LMW. Some studies have suggested that adiponectin crosses the blood-brain barrier and plays a central role in energy homeostasis. To determine cerebrospinal fluid (CSF) adiponectin at extremely low concentrations, we modified the protocol of the ELISA system used to assay serum adiponectin. The 3 multimers of adiponectin were measured separately by pretreating CSF with 2 proteases. We measured the CSF adiponectin concentrations in anonymous human samples (n = 19). The molecular sizes of adiponectin in CSF pretreated with proteases or untreated were determined by use of native PAGE and immunoblotting. The ELISA system measured adiponectin in the range of 1.0-167 microg/L. The between-assay imprecision estimates (CVs) were 6%-17% for the 3 forms. The mean total CSF adiponectin concentration (7.2 microg/L) was approximately 1/1000 of the mean concentration in serum. Unlike serum adiponectin, the LMW and Alb-LMW forms predominated in all of the CSF samples. Immunoblotting analysis revealed that most LMW forms were bound to Alb, although the HMW form was detected in some samples. The modified ELISA system measures the 3 multimers separately and is sufficiently sensitive to measure adiponectin in CSF.

Detection of adiponectin in cerebrospinal fluid in humans

Adiponectin circulates in the body in high concentrations, and 100-fold lower amounts were described in the cerebrospinal fluid (CSF) of mice, whereas in humans, contradictory results have been published. To clarify whether adiponectin is present in human CSF and is derived from the circulation, it was determined in human CSF and plasma of 52 nonselected patients. Adiponectin was detected by immunoblot in CSF and was quantified in CSF and serum by ELISA. CSF adiponectin was positively correlated to systemic levels, and the CSF/serum adiponectin ratio was correlated to the CSF/serum albumin ratio. Furthermore, disturbed function of the blood-brain barrier (BBB) was associated with an elevated CSF/serum adiponectin ratio. Adiponectin mRNA was not found in the brain, indicating that adiponectin crosses the BBB and/or the blood-cerebrospinal fluid barrier (BCB). Rat adiponectin with a COOH-terminal tag was injected into the tail vein of rats and was detected 3 h later in CSF. However, CSF adiponectin in humans and rats was approximately 0.1% of the serum concentration and therefore was below the 0.5% expected in the CSF because of the residual leakage of an undisturbed BBB/BCB. Taken together, data from the present study show that adiponectin in human CSF is far below the level expected by the baseline BBB/BCB permeability, indicating that adiponectin enters the brain much less efficiently than albumin, thus supporting recent data that exclude adiponectin transport to the CSF. Additional studies are needed to reveal whether these low levels of adiponectin in CSF have a physiological function.

Adiponectin: Starving for Attention

Maintaining energy balance involves the dynamic control of appetite and energy expenditure. A new study from the Kadowaki laboratory (Kubota et al., 2007) shows that the adipocyte-derived hormone adiponectin increases appetite and reduces energy expenditure by stimulating AMPK in the hypothalamus.

Adiponectin and Resistin in Human Cerebrospinal Fluid and Expression of Adiponectin Receptors in the Human Hypothalamus

The adipokine leptin has critical importance in central appetite regulation. In contrast to some suggestion of adiponectin influencing energy homeostasis in rodents, there is no evidence for adiponectin or resistin entering the human blood-brain barrier. The objective was to establish the presence of adiponectin or resistin in human cerebrospinal fluid (CSF) and to compare their distribution with leptin. Furthermore, we wished to examine the expression of the adiponectin receptors 1 and 2 (AdipR1, AdipR2) in the human hypothalamus. For this purpose, serum and CSF samples were collected from 20 men and 19 women matched for age [men, 69.8 +/- 8.6 yr (mean +/- SD); women, 69.4 +/- 4.3 yr] and BMI (men, 29.4 +/- 3.4 kg/m(2); women, 27.3 +/- 4.8 kg/m(2)) undergoing elective surgery under spinal anesthesia. Adiponectin was identified in CSF with levels 1000-fold less than serum, whereas resistin and leptin levels were 100-fold less. Unlike their serum levels, adiponectin CSF levels showed no gender difference or correlation with insulin resistance, which is similar to resistin CSF levels. The adiponectin and leptin CSF/serum ratios in our study exhibit the same pattern of gender-specific BMI association with inverse correlation in women (r = -0.61; P = 0.02) and no correlation in men (r = 0.026; P = not significant). Furthermore, immunostaining established AdipR1 and -2 in the hypothalamus and increased AdipR2 expression in the paraventricular nucleus, which is involved in energy regulation. In summary, our findings show both the presence of adiponectin and resistin in human CSF, with no effect of insulin resistance on CSF levels. The CSF entry of adiponectin and leptin in women appears to be impaired in obesity.

Adiponectin acts in the brain to decrease body weight.

Adiponectin (ADP) is an adipocyte hormone involved in glucose and lipid metabolism. We detected a rise in ADP in cerebrospinal fluid after intravenous (i.v.) injection, consistent with brain transport. In contrast to leptin, intracerebroventricular (i.c.v.) administration of ADP decreased body weight mainly by stimulating energy expenditure. Full-length ADP, mutant ADP with Cys39 replaced with serine, and globular ADP were effective, whereas the collagenous tail fragment was not. Lep(ob/ob) mice were especially sensitive to i.c.v. and systemic ADP, which resulted in increased thermogenesis, weight loss and reduction in serum glucose and lipid levels. ADP also potentiated the effect of leptin on thermogenesis and lipid levels. While both hormones increased expression of hypothalamic corticotropin-releasing hormone (CRH), ADP had no substantial effect on other neuropeptide targets of leptin. In addition, ADP induced distinct Fos immunoreactivity. Agouti (A(y)/a) mice did not respond to ADP or leptin, indicating the melanocortin pathway may be a common target. These results show that ADP has unique central effects on energy homeostasis.