thirty - eight subjects participated in the experiments ( 18 men and 20 women ; age 1980 years ; bmi 16.2438.10 kg / m ) . fourteen participants had normal body weight , 14 subjects were overweight ( bmi 25 to < 30 kg / m ) and 10 subjects were obese ( bmi 30 kg / m ) . exclusion criteria were a history of diabetes , congestive heart failure , liver or kidney disease , malignancy , signs of inflammation , pregnancy , and any drugs influencing body weight like corticoids or contraceptives . during the study , three subjects ( two men and one woman ) were newly diagnosed with type 2 diabetes as indicated by elevated fasting plasma glucose levels > 7 mmol / l according to the criteria of the american diabetes association . after an overnight fast , subjects reported to the laboratory for simultaneous sampling of blood and cerebrospinal fluid ( 1 ml ) via lumbar puncture after local anesthesia ( 2 ml mepivacain - hcl 1% ) . in addition , body weight , body height , and waist and hip circumferences were assessed . body composition was measured by standard bioelectrical impedance analysis ( bia 2000-mol / l ; data input , frankfurt , germany ) . frequencies of 1 , 5 , 50 , and 100 hz were employed , and eurobody software ( data input ) was used to examine body fat mass . the study was approved by the local ethics committee , and all subjects gave written informed consent . blood samples were immediately centrifuged , and plasma and csf samples were frozen at 80c until assay . visfatin was determined using a commercially available enzyme immunoassay ( phoenix pharmaceuticals , burlingame , ca ) . analyses were performed according to the manufacturer 's protocol , with an intra - assay coefficient of variation ( cv ) < 5% for determination in csf and plasma . in addition , plasma and csf glucose ( cv < 1.1% ; beckman glucose analyser ii ; beckman instruments , fullerton , ca ) , insulin , and adiponectin concentrations were measured . insulin was determined with a commercial competitive double - antibody radioimmunoassay ( pharmacia insulin ria 100 ; pharmacia diagnostics , upsalla , sweden ) that was slightly modified as described previously ( 10 ) ; the assay limit of sensitivity was 1.8 pmol / l , and intra - assay variation was < 4.5% for determination in csf and plasma . adiponectin was determined using a commercially available radioimmunoassay ( hadp-61hk ; linco research , st . charles , mo ) with a sensitivity limit of 0.78 ng / ml ; intra - assay variation was < 6.2% , and interassay variation was < 9.3% . insulin resistance was estimated employing the homeostatic model assessment formula , with high scores denoting a high degree of insulin resistance . where necessary , values were log - transformed to achieve normal distribution . bivariate pearson correlation coefficients were determined , and stepwise multiple regression analyses were performed to detect associations between csf visfatin levels and relevant variables ( sex , age , body weight , bmi , fat mass , plasma visfatin , homeostatic model assessment score , waist and hip circumferences , waist - to - hip ratio , and csf levels of glucose , insulin , and adiponectin ) as well as between the csf - to - plasma visfatin ratio and corresponding variables . in addition , plasma and csf visfatin concentrations were subjected to two - way anova , including the factors sex and , respectively , body weight status ( normal weight / overweight / obese ) and body fat quartile , followed by single comparisons via unpaired bonferroni corrected t tests . for analyses , table 1 summarizes anthropometric and endocrine parameters of our subjects and respective correlations with visfatin levels in plasma and csf and with the csf - to - plasma visfatin ratio . 1a ) , bmi , and waist and hip circumferences . in csf , visfatin was detectable at concentrations approximately 10% of plasma levels . plasma and csf visfatin levels were negatively correlated as csf visfatin levels decreased with increasing body fat mass ( fig . 1b ) , bmi , and waist and hip circumferences , as well as with increasing insulin resistance and age . accordingly , the csf - to - plasma visfatin ratio was also negatively associated with fat mass ( fig . 1c ) , bmi , and waist and hip circumferences , as well as with the degree of insulin resistance , plasma insulin levels , and age . supporting analyses relying on spearman 's rank correlations and partial correlations including the control variables age and sex yielded essentially the same results . in the stepwise multiple linear regression analyses , body fat mass was the only factor independently associated with csf visfatin , explaining 58% of the variation of csf visfatin levels ( r = 0.58 , b 0.066 , se 0.009 [ 95% ci 0.085 to 0.047 ] ,  0.768 , p < 0.0001 ) , whereas none of the other variables , including sex , age , and csf levels of glucose , insulin , and adiponectin , were independently related to csf visfatin ( all p > 0.11 ) . with our sample size , we had 99% power to detect an increment to the model r of 0.58 ( at  = 0.05 ) . body fat was also the only factor independently associated with the csf - to - plasma visfatin ratio , explaining 64% of the ratio 's variation ( r = 0.64 , b 0.004 , se 0.001 [ 95% ci 0.006 to 0.003 ] ,  0.806 , p < 0.0001 ) . none of the other parameters , including sex and age , was independently related to the csf - to - plasma visfatin ratio ( all p > 0.12 ) . exclusion of the three subjects newly diagnosed with type 2 diabetes did not essentially alter the results . again , body fat mass was the only factor independently correlated with csf visfatin levels ( n = 35 ; r = 0.59 , b 0.067 , se 0.010 [ 95% ci 0.087 to 0.047 ] ,  0.773 , p < 0.0001 ) and with the csf - to - plasma visfatin ratio ( r = 0.61 , b 0.004 , se 0.001 [ 95% ci 0.006 to 0.003 ] ,  0.789 , p < 0.0001 ) . strong associations between adiposity and plasma and csf visfatin concentrations were confirmed by comparisons across body fat quartiles ( table 2 ) . plasma visfatin levels of subjects in the highest quartile significantly exceeded those of subjects in the other quartiles [ f(3,30 ) = 8.72 , p < 0.0001 , for main effect of body fat quartile ] and a reverse pattern was observed for csf visfatin levels [ f(3,30 ) = 16.38 , p < 0.0001 ] . corresponding results were obtained when obese subjects were compared with normal - weight and overweight subjects [ plasma visfatin f(2,32 ) = 8.64 , p < 0.001 ; csf visfatin f(2,32 ) = 6.42 , p < 0.005 , for main effects of body weight status ] . visfatin concentrations were comparable between men and women in plasma [ f(1,30 ) = 2.46 , p > 0.13 , for main effect of sex ] and csf [ f(1,30 ) = 0.27 , p > 0.61 ] . also , the factor sex did not statistically interact with measures of body fat ( all p > 0.10 ) , excluding pronounced effects of sex on visfatin concentrations in plasma and csf . our results indicate that visfatin is present in human csf and , furthermore , that csf visfatin concentrations decrease in conjunction with increasing adiposity . we also found a strong positive association between plasma visfatin levels and body fat mass , body weight , and waist and hip circumferences . this observation confirms previous results indicating that obesity ( 7,8 ) and type 2 diabetes ( 9,11 ) are linked to elevated circulating visfatin concentrations . accordingly , massive weight loss is accompanied by a drop in plasma visfatin ( 12 ) . other studies have indicated no association between body fat and plasma visfatin ( 13 ) or have even reported on reduced visfatin levels in obesity ( 14 ) . the initial assumption that visceral fat is the determining factor in visfatin production ( 3 ) has likewise been challenged ( 4,7 ) . however , increases in visfatin mrna in visceral adipose tissue of obese subjects and a positive correlation between bmi and visceral visfatin mrna have been observed even in the absence of an association between circulating visfatin concentrations and body fat ( 14 ) . more recently , visfatin has been shown to be secreted by adipocytes through a nonclassical secretory pathway that probably represents a highly regulated process ( 5,15 ) . therefore , plasma in comparison with cellular levels of the adipokine may display greater variance , which , in conjunction with the fact that visfatin is abundantly produced by the stromal vascular fraction of adipose tissue ( 16 ) and that relatively low levels of circulating visfatin are found under physiological conditions , might explain the conflicting results on plasma visfatin in obesity . our observations agree with the majority of previous studies ( 79,11,12 ) indicating that plasma visfatin concentrations increase with rising adiposity . to our knowledge , this is the first study investigating the presence of visfatin in csf . our results indicate that in humans visfatin is found in csf at concentrations that are 10% of those in plasma . it is not yet known whether the peptide penetrates the central nervous system from the circulation . leptin , an adipokine that is considerably smaller than visfatin ( 16 vs. 52 kda ; 167 vs. 473 amino acids ) , crosses the blood - brain barrier ( bbb ) via an active , saturable transport system ( 17 ) and displays a 5- to 10-fold less pronounced csf - to - plasma ratio than that observed for visfatin in the present experiments ( 18 ) . this pattern suggests that circulating visfatin can likewise enter the brain compartment , probably also via an active transport mechanism , although it can not be ruled out that there are central nervous secretion sites for the peptide ( 19 ) . in our study , csf visfatin levels decreased with increasing plasma visfatin levels and adiposity , supporting the assumption that visfatin transport across the bbb is impaired when circulating visfatin increases as a result of excess body fat . however , this preliminary conclusion is in need of corroboration by studies investigating the actual transport of visfatin across the bbb in normal weight and obesity . moreover , although we could exclude a significant influence of sex and age on csf visfatin levels in our study , the potential contribution of , e.g. , sex - specific endocrine factors ( 20 ) to the observed pattern still has to be examined . adiposity turned out to be the only variable independently associated with the variance of csf levels and the csf - to - plasma ratio of visfatin , suggesting obesity to be closely connected with reduced csf visfatin levels . with the physiological role of visfatin in energy homeostasis far from being elucidated , low csf visfatin levels may be a mere by - product of increased body fat stores . however , remarkably similar patterns have been revealed for leptin ( 18,21 ) and insulin ( 10,22 ) , two endocrine adiposity signals that provide the brain with negative feedback on the amount of body fat . dysfunctional central nervous insulin and leptin signaling has been well established as a key feature of obesity ( 1 ) , and preliminary findings in animals hint at the involvement of central nervous visfatin in the regulation of food intake ( 23 ) . plasma visfatin levels are reduced by diet - induced weight loss in obese nondiabetic patients ( 24 ) and by exercise in patients with type 1 diabetes ( 25 ) , and it remains to be seen whether these clinical interventions in turn increase central nervous levels of the peptide . in sum , our results support the intriguing , albeit tentative , assumption that central nervous visfatin insufficiency or resistance might be linked to pathogenetic mechanisms of obesity .
objective  observations of elevated circulating concentrations of visfatin ( pbef / nampt ) in obesity and diabetes suggest that this recently described adipokine is involved in the regulation of body weight and metabolism . 
 we examined in humans whether visfatin is found in cerebrospinal fluid ( csf ) and , if so , how csf visfatin concentrations relate to adiposity and metabolic parameters.research design and methods  we measured visfatin concentrations in the plasma and csf of 38 subjects ( 18 men and 20 women ; age 1980 years ) with a wide range of body weight ( bmi 16.2438.10 kg / m2 ) . 
 in addition , anthropometric parameters and endocrine markers were assessed . 
 bivariate correlation coefficients were determined and stepwise multiple regression analyses were performed to detect associations of csf and plasma visfatin levels with relevant parameters.resultsplasma visfatin levels increased with rising bmi ( p < 0.0001 ) and body fat mass ( p < 0.0001 ) . 
 in contrast , csf visfatin levels decreased with increasing plasma visfatin concentrations ( p < 0.03 ) , bmi ( p < 0.001 ) , body fat mass ( p 
 < 0.0001 ) , and insulin resistance ( p < 0.05 ) . body fat was the only factor independently associated with csf visfatin , explaining 58% of the variation of csf visfatin levels ( p < 0.0001 ) . 
 neither plasma ( p > 0.13 ) nor csf ( p > 0.61 ) visfatin concentrations differed between men and women.conclusionsour data indicate that visfatin concentrations in human csf decrease with rising body fat , supporting the assumption that visfatin transport across the blood - brain barrier is impaired in obesity and that central nervous visfatin insufficiency or resistance are linked to pathogenetic mechanisms of obesity .