Adipose tissue tumor necrosis factor and interleukin-6expression in human obesity and insulin resistance PHILIP A. KERN, SUBRAMANIAN RANGANATHAN, CHUNLING LI,LINDA WOOD, AND GOURI RANGANATHANDivision of Endocrinology, Department of Medicine, University of Arkansas for Medical Sciencesand the Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205 Received 1 August 2000; accepted in final form 23 January 2001 Kern, Philip A., Subramanian Ranganathan, Chun-
tween obesity, insulin resistance, and type 2 diabetes ling Li, Linda Wood, and Gouri Ranganathan. Adipose
tissue tumor necrosis factor and interleukin-6 expression in Obesity represents an expansion of adipose tissue human obesity and insulin resistance. Am J Physiol Endo- mass, and one explanation for obesity-related insulin crinol Metab 280: E745–E751, 2001.—Adipose tissue ex- resistance is the production of factors by adipose tissue presses tumor necrosis factor (TNF) and interleukin (IL)-6, that render some subjects more insulin resistant than which may cause obesity-related insulin resistance. We mea-sured TNF and IL-6 expression in the adipose tissue of 50 others. Numerous adipocyte secretory products have lean and obese subjects without diabetes. Insulin sensitivity recently been described that play a role in carbohy- drate and lipid metabolism (14, 21, 23). One such I) was determined by an intravenous glucose tolerance test with minimal-model analysis. When lean [body mass index adipocyte secretory product is tumor necrosis factor (BMI) Ͻ25 kg/m2] and obese (BMI 30–40 kg/m2) subjects (TNF)-␣. A new role for TNF was proposed in 1993 with were compared, there was a 7.5-fold increase in TNF secre- the description of TNF expression by adipose tissue tion (P Ͻ 0.05) from adipose tissue, and the TNF secretion and the elevated expression of TNF in obese, insulin- was inversely related to SI (r ϭ Ϫ0.42, P Ͻ 0.02). IL-6 was resistant rodents and humans (17, 20, 24). Although it abundantly expressed by adipose tissue. In contrast to TNF, is unclear how adipose TNF expression may cause plasma (rather than adipose) IL-6 demonstrated the stron- insulin resistance (36), TNF is known to impair insulin gest relationship with obesity and insulin resistance. Plasma receptor signaling (18). TNF also inhibits lipoprotein IL-6 was significantly higher in obese subjects and demon- lipase (LPL) and stimulates lipolysis in adipocytes (34), strated a highly significant inverse relationship with SI (r ϭ Ϫ0.71, P Ͻ 0.001). To separate the effects of BMI from S and the resulting increase in circulating nonesterified fatty acids (NEFA) would be expected to contribute to age, and gender. By use of this approach, subjects with low S demonstrated a 3.0-fold increased level of TNF secretion Another adipocyte secretory product that may be from adipose tissue and a 2.3-fold higher plasma IL-6 level involved in insulin resistance is interleukin (IL)-6, (P Ͻ 0.05) compared with matched subjects with a high SI.
which is a cytokine secreted by many cells, including Plasma IL-6 was significantly associated with plasma nones- adipocytes and adipose stromal cells (11, 15). Like terified fatty acid levels (r ϭ 0.49, P Ͻ 0.002). Thus the local TNF, IL-6 inhibits the expression of LPL, but, unlike expression of TNF and plasma IL-6 are higher in subjects TNF, IL-6 does not stimulate lipolysis (13, 16). IL-6 with obesity-related insulin resistance.
secretion is increased in the adipocytes of obese subjects (29) and may be important either as a cir-culating hormone or as a local regulator of insulinaction.
OBESITY HAS BECOME a national epidemic with enormous Although many studies have examined the role of public health implications (25), and recent studies TNF in insulin resistance, relatively few of these have have demonstrated a further 6% increase in the inci- been in humans, and none has examined cytokine dence of obesity [body mass index (BMI) Ͼ30 kg/m2] expression in detail along with the measurement of over a 7-yr period (30). There is a strong correlation insulin resistance. In this study, we examined the between obesity and insulin resistance in both diabetic expression of TNF and IL-6 in human adipose tissue and nondiabetic subjects (27), and the risk of diabetes from nondiabetic subjects with varying degrees of obe- increases 11-fold as the BMI increases from 20 to 30 sity and insulin resistance. We found that TNF secre- (8). Although insulin resistance accompanies all pa- tion from human adipose tissue and circulating plasma tients who become obese, the degree of insulin resis- IL-6 were both highly associated with obesity-associ- tance varies considerably, and the relationships be- Address for reprint requests and other correspondence: P. A. Kern, The costs of publication of this article were defrayed in part by the Central Arkansas Veterans Healthcare System, 598/151 LR 4300 payment of page charges. The article must therefore be hereby West 7th St., Little Rock, AR 72205 (E-mail: KernPhilipA marked ‘‘advertisement’’ in accordance with 18 U.S.C. Section 1734 Table 1. Characteristics of the study subjects Data are expressed as means Ϯ SEM. BMI, body mass index; TG, triglyceride; LDL and HDL, low- and high-density lipoprotein, respectively; FBG, fasting blood glucose.
medium. Immediately after the biopsy, adipose tissue piecesof ϳ500 mg were minced and placed into serum-free DMEM Subjects. Fifty subjects were recruited for these studies.
(pH 7.4, 10 mM HEPES) at 37°C for varying times. Figure 1 This research was approved by the Institutional Review illustrates the secretion of TNF and IL-6 into the medium of Board, and all subjects gave informed consent. All subjects three subjects. There was little secretion of either cytokine were weight stable at the time of the study. Subjects initially into the medium for the first 60 min, followed by an increase underwent an oral glucose tolerance test using 75 g of glu-cose, and blood glucose was measured fasting and at 2 h.
in secretion over the next 60 min. Medium cytokine levels Subjects with diabetes (fasting blood sugar Ͼ126 mg/dl, 2-h continued to increase for up to 24 h. To compare TNF and glucose Ͼ200 mg/dl) were excluded. Of the 50 subjects, 15 IL-6 secretion among different subjects, we measured cyto- had impaired glucose tolerance based on a 2-h glucose of kine levels in the medium after 2 h at 37°C. All data were 140–200 mg/dl, and three of these subjects had impaired normalized to adipose DNA content to control for differences fasting glucose based on a fasting glucose of 110–126 mg/dl.
in fat cell size. In general, IL-6 secretion from adipose tissue Subjects then underwent a frequently sampled intravenous was much higher than TNF. In all subjects studied, the TNF glucose tolerance test (FSIVGTT) and an adipose tissue bi- level in the medium at 2 h was 0.78 Ϯ 0.14 pg/␮g DNA, and opsy. The FSIVGTT and the biopsy were performed at least 3 the IL-6 level in the medium was 9.8 Ϯ 1.8 pg/␮g DNA.
Measurement of TNF and IL-6. Adipose tissue TNF protein Characteristics of the subjects that comprised this study was measured using an ELISA (R&D Systems, Minneapolis, are shown in Table 1. Blood lipids were measured using MN). This assay demonstrates an 8% intra-assay and a 15% standard clinical assays, and plasma NEFA were measured interassay variation. This ELISA method was used to mea- using a colorimetric assay (Waco Chemical, Richmond, VA).
sure TNF in fasting plasma as well as TNF secretion by Of the 50 subjects studied, 39 were women and 8 were adipose tissue (see Relationship between TNF and obesity).
African-American. The subjects ranged from lean to very TNF mRNA levels were measured by competitive RT-PCR, obese, and insulin sensitivity (SI; using the SI index from the as described by us previously (24). IL-6 was measured in FSIVGTT] varied considerably. Some subjects demonstrated fasting plasma and secreted from adipose tissue using an moderate dyslipidemia, but no subject demonstrated fasting ELISA assay (R&D Systems). This assay demonstrates intra- triglycerides Ͼ400 mg/dl. Body composition was determined Statistics. All data are expressed as means Ϯ SE. To SI measurements. The measurement of in vivo SI was analyze data between groups, a one-way ANOVA was per- performed in the fasting state with the minimal-model anal- formed, and secondary analysis was performed with the ysis of the FSIVGTT (4, 5). We used the classic tolbutamide- Student’s t-test with Bonferroni correction. Analysis of modified test, which has been validated against the euglyce- trends was performed using linear regression after log trans- mic clamp in humans (6, 41). In brief, catheters were placedfor glucose injection and blood sampling. Four basal blood formation. The Wilcoxon matched-pair sign-rank test was samples were obtained, and the patient was given an intra- used for the paired data in Table 2.
venous glucose bolus (11.4 g/m2) at time 0. At 20 min after theglucose injection, patients were given an injection of tolbut-amide (125 mg/m2), again followed by frequent blood sam-pling, according to the standard protocol. Together, 4 basaland 27 postglucose blood samples were taken, the last one at240 min. Glucose was measured in a glucose analyzer by useof the glucose oxidase method, and insulin was measuredusing radioimmunoassay. These measurements were per-formed in the Endocrinology Laboratory of the Indiana Uni-versity School of Medicine (Indianapolis, IN). The SI wascalculated using the MINMOD program (4) and was ex-pressed in microunits per milliliter per minute.
Adipose tissue biopsy. Abdominal subcutaneous adipose tissue (ϳ10 g) was removed from each patient by incision,which avoids trauma to fat cells and minimizes the amount ofblood in contact with the fat cells. Some of the tissue wasimmediately frozen in liquid N2 for later RNA extraction,whereas the rest of the tissue was placed into cold DMEM forother assays.
Fig. 1. Tumor necrosis factor (TNF)-␣ and interleukin (IL)-6 secre- Adipose tissue cytokine secretion. TNF and IL-6 may func- tion from adipose tissue. TNF and IL-6 are secreted into the medium tion in an autocrine or paracrine manner; hence, we wished over time from adipose tissue. Data represent means and SE of 3 to measure the local secretion of these cytokines into the representative subjects. Both cytokines are expressed as pg/␮g DNA.
in subjects with a BMI between 30 and 40 kg/m2 (P Ͻ0.05). Subjects with a BMI Ͼ45 kg/m2 demonstratedslightly lower TNF secretion (0.90 Ϯ 0.21 pg/␮g DNA),but this was not significantly decreased compared withsubjects with a BMI of 30–40 kg/m2. This effect of BMIon TNF secretion was still present when women andCaucasians were each considered separately and whensubjects with impaired glucose tolerance were elimi-nated. TNF secretion from adipose tissue was also lowin subjects with low body fat. TNF secretion in subjectswith Ͻ30%, 30–45%, and Ͼ45% body fat was 0.16 Ϯ0.07 (n ϭ 10), 0.76 Ϯ 0.16 (n ϭ 14), and 1.1 Ϯ 0.28pg/␮g DNA (n ϭ 18, P Ͻ 0.05 vs. Ͻ30% group).
TNF expression and insulin sensitivity. As expected, there was a significant relationship between obesityand insulin sensitivity. As described previously by oth-ers (22), the relationship between BMI and SI is curvi-linear and best represented by a log/log transforma-tion, and in our subjects, BMI and SI were significantlyrelated (r ϭ Ϫ0.65, P Ͻ 0.001). Because SI variesconsiderably among nonobese subjects with normalglucose tolerance, we did not divide SI into subgroupsbut instead examined TNF expression over the spec-trum of SI. There was no significant relationship be-tween either plasma TNF or TNF mRNA levels and SI(data not shown). However, there was a significantdecrease in TNF secretion with increasing SI (Fig. 3),such that most of the insulin-sensitive subjects (SI Ͼ5)had lower levels of TNF secretion, and most of theinsulin-resistant subjects (SI Ͻ2) had the highest lev-els of TNF secretion.
Fig. 2. Effect of body mass index (BMI) on plasma TNF, adipose IL-6 expression with obesity and insulin resistance. secretion of TNF into the medium, and TNF mRNA levels. Subjectswere divided into BMI groups as described in the text, representing The adipose tissue fragments secreted relatively high lean subjects (BMI Ͻ25) and subjects with increasing degrees of levels of IL-6. When IL-6 expression was examined in obesity. A: plasma TNF was measured and expressed as pg/ml, along the same BMI groups, as described in the preceding with TNF secreted into the medium of the adipose tissue expressed section for TNF, there was a tendency for an increase as pg/␮g DNA, as described in METHODS. B: TNF mRNA levels weremeasured using RT-PCR, as described in METHODS. *P Ͻ 0.05 vs. BMI in IL-6 secretion from adipose tissue with increasing BMI and increasing body fat (Fig. 4B); however, thesechanges were not statistically significant. Plasma IL-6,however, was strongly associated with increasing obe- sity (Fig. 4A). In lean subjects (BMI Ͻ25), plasma IL-6 Relationship between TNF and obesity. To better was 0.73 Ϯ 0.23 pg/ml and increased about fourfold to define the effects of obesity on TNF expression, we 2.86 Ϯ 0.61 pg/ml in the most obese subjects (BMI Ͼ40, measured TNF mRNA in the adipose tissue from eachsubject, along with plasma TNF and TNF secretionfrom the adipose tissue. Subjects were divided into fourBMI groups representing lean (BMI Ͻ25, n ϭ 9), over-weight (BMI 25–30, n ϭ 9), moderately obese (BMI30–40, n ϭ 17), and very obese subjects (BMI Ͼ40, n ϭ15). Figure 2B shows TNF mRNA levels from subjectswith increasing BMI. There was considerable variabil-ity among the obese subject groups with respect to TNFmRNA levels, such that the differences between nor-mal lean subjects (BMI Ͻ25 kg/m2) and obese subjectswere not statistically significant (NS; Fig. 2B). TNFprotein was also measured in these subjects; however,as shown in Fig. 2A, there was no relationship betweenplasma TNF and BMI. However, TNF secretion fromthe adipose tissue was higher in obese subjects. Mean Fig. 3. Relationship between TNF expression and insulin sensitivity(SI). TNF secretion into the medium was measured in subjects along TNF secretion was 0.16 Ϯ 0.06 pg/␮g DNA in lean with measurements of SI. TNF secretion is expressed as pg/␮g DNA subjects (BMI Ͻ25 kg/m2), and 1.21 Ϯ 0.36 pg/␮g DNA of adipose tissue, and the data are log transformed.
Fig. 5. Relationship between plasma IL-6 and SI. Plasma IL-6 wasmeasured as described in METHODS and expressed as pg/ml. Data arelog transformed.
TNF secretion. As shown in Fig. 6, there were signifi-cant increases in plasma NEFA levels in subjects withhigher levels of plasma IL-6 (r ϭ 0.54, P Ͻ 0.001).
There was also a significant association betweenplasma NEFA and TNF secretion (r ϭ 0.35, n ϭ 37, P Ͻ0.05), although this association was less robust thanthe association with IL-6.
Cytokines and insulin resistance independent of obe- sity. Insulin resistance is exacerbated by obesity, lead-ing to a significant relationship between SI and BMI.
Therefore, we examined the relationship between adi-pose cytokine expression and SI without the confound-ing effects of BMI. To factor out obesity, we identifiedsubjects who were of the same BMI but who werediscordant for SI. We compared the cytokine expression Fig. 4. Effect of BMI on IL-6 expression. A: plasma IL-6 (pg/ml) was of subjects with insulin resistance (SI Ͻ2.0) with that measured in subjects from the same BMI groups as described in Fig.
of subjects with less insulin resistance (SI Ͼ3.0) who 2. *P Ͻ 0.05 vs. BMI 30–40 and BMI Ͼ40 groups. **P Ͻ 0.05 vs. BMI were matched for BMI (Ϯ5 kg/m2), age (Ϯ10 yr), and Ͼ40 group. B: adipose tissue IL-6 secretion (pg/␮g DNA) was mea-sured in subjects as described in METHODS.
gender. Using these criteria, we were able to matchnine subjects with SI Ͻ2.0 with nine subjects with SI Ͼ3.0. As shown in Table 2, these subjects were well P Ͻ 0.05). In a similar manner, plasma IL-6 was lower matched for age and BMI, and there were significant in subjects with low percent body fat. Plasma IL-6 was differences in SI by virtue of subject selection. No 0.84 Ϯ 0.19 pg/ml (n ϭ 10) in subjects with Ͻ30% body differences were noted between plasma TNF or adipose fat and was 2.05 Ϯ 0.38 (n ϭ 14) and 2.58 Ϯ 0.44 (n ϭ18) pg/ml in subjects with 30–45 and Ͼ45% fat, respec-tively (P Ͻ 0.05). The relationship between SI andplasma IL-6 was examined in the same manner asdescribed for TNF. In contrast to TNF, adipose-se-creted IL-6 demonstrated no significant relationshipwith SI (r ϭ Ϫ0.04, P ϭ NS). However, there was ahighly significant relationship (r ϭ Ϫ0.71, n ϭ 38, P Ͻ0.001) between plasma IL-6 and SI, as shown in Fig. 5.
Plasma IL-6 was 3.0 Ϯ 0.53 pg/ml in the most insulin-resistant subjects (SI Ͻ2) and was 0.82 Ϯ 0.19 pg/ml inthe most insulin-sensitive subjects (SI Ͼ5, P Ͻ 0.05).
One mechanism by which TNF may cause insulin resistance is through an increase in adipocyte lipolysis,leading to a rise in plasma NEFA. Hence, the relation-ship between cytokine expression and plasma NEFA Fig. 6. Relationship between plasma IL-6 and plasma nonesterified was examined. The only significant relationship with fatty acids (NEFA). Plasma IL-6 levels were plotted against the plasma NEFA levels was with plasma IL-6 and adipose Table 2. Insulin-sensitive and insulin-resistant subjects matched for BMI and age Values are means Ϯ SE. SI, insulin sensitivity; TNF, tumor necrosis factor; IL-6, interleukin-6. * P Ͻ 0.05 vs. insulin sensitive.
IL-6 expression. However, the insulin-resistant sub- resistance (9, 19, 40), although one such study (37) jects had significantly higher levels of plasma IL-6 as found no role for TNF or the TNF receptor in insulin well as significantly higher levels of adipose TNF se- cretion (P Ͻ 0.05). In these matched subjects, TNF Relatively few studies have examined the relation- secretion and plasma IL-6 were two- to threefold ship between TNF and insulin resistance in humans.
higher in the insulin-resistant subjects.
Studies by us (24) and others (1, 17) demonstrated Previous studies have demonstrated that IL-6 and elevated levels of adipose TNF mRNA and protein in TNF interact with each other in both 3T3-L1 adipo- obese subjects and a decrease in TNF with weight loss.
cytes and mice (3, 16). We examined TNF and IL-6 No study has examined the relationship between SI expression from each subject’s adipose tissue to deter- and TNF, although one study noted a significant cor- mine whether there was any relationship between IL-6 relation between TNF mRNA levels and fasting insulin and TNF expression. As shown in Fig. 7, there was a (17), and several studies observed a decrease in TNF strong linear relationship between the secretions of after weight loss (12, 17, 24). High TNF secretion from IL-6 and TNF from the adipose tissue (r ϭ 0.81, P Ͻ human adipose tissue was associated with decreased 0.0001). On the other hand, there was no significant [3H]glucose incorporation into lipids (26).
relationship between plasma IL-6 and plasma TNF It is not clear whether TNF functions locally or circulates in a sufficiently high concentration to influ-ence distant targets. Plasma TNF has been measured, DISCUSSION
and several studies have observed increased plasma Since the initial description of TNF expression by TNF levels in obese subjects and in subjects with adipose tissue, several lines of evidence have suggested hyperinsulinemia or insulin resistance (10, 42, 43).
that TNF overproduction by adipose tissue may be Plasma TNF was elevated in male diabetic subjects involved in the pathogenesis of the insulin resistance of compared with male controls, but no such relationship obesity. TNF mRNA levels were high in obese, insulin- was observed in women (35). In an attempt to bind resistant rodents, and the infusion of a soluble TNF plasma TNF and reverse insulin resistance in humans, binding protein into insulin-resistant fa/fa rats im- diabetic or insulin-resistant subjects have been given proved insulin sensitivity and improved the defect in an injection of anti-TNF binding protein. In both stud- insulin receptor and insulin receptor substrate-1 auto- ies, there was no improvement in insulin resistance phosphorylation in fat and muscle (18, 20). Recent studies using genetic manipulations resulting in The role of IL-6 in insulin resistance has been much knockout or depletion of TNF or TNF receptor have less studied. IL-6 is secreted by many cells, including confirmed the importance of TNF in rodent insulin adipocytes and adipose stromal cells (11, 15) and isincreased after a meal (32). Like TNF, IL-6 inhibits theexpression of LPL, but unlike TNF, IL-6 does notstimulate lipolysis (13, 16). Linking IL-6 to insulinresistance are studies demonstrating increased IL-6secretion in the adipocytes of subjects with obesity (29)and diabetes (2).
In the studies described herein, we measured TNF and IL-6 gene expression at several levels from theadipose tissue of lean and obese subjects and relatedthis expression to SI, a reliable measure of insulinsensitivity. Both IL-6 and TNF were expressed andsecreted by human adipose tissue, although IL-6 levelswere much higher in both adipose tissue and plasma.
The most consistent relationship between cytokine ex-pression and obesity-related insulin resistance in-volved increased TNF secretion from adipose tissueand increased plasma IL-6 levels. Elevated TNF and Fig. 7. Relationship between IL-6 and TNF secretion from adipose IL-6 expression was found in subjects who were only tissue. IL-6 and TNF (pg/␮g DNA) were measured in the medium from adipose tissue pieces cultured for 2 h, and the level of medium IL-6 was plotted against the level of TNF.
sively with decreasing SI. The relationship between plasma IL-6 and SI was very strong, with a highly the major circulating component of obesity-related in- significant inverse correlation and a fivefold difference between the most insulin-resistant and most insulin- The development of insulin resistance with increas- sensitive subjects. Thus both TNF and IL-6 were asso- ing adiposity suggests that an adipocyte product may ciated with both obesity and insulin resistance; how- be important in insulin resistance. Both TNF and IL-6 ever, it was the adipose-secreted form of TNF and the are adipocyte products that are overexpressed in obese plasma level of IL-6 that displayed the strongest rela- insulin-resistant subjects, and we have shown that the secretion of these cytokines is interrelated. Some of The subjects in this study were heterogeneous with these cytokines may function systemically, others may regard to degree of obesity, gender, and race, and it is function locally, and still others may function to in- possible that a study using a more focused group of crease the secretion or synthesis of other adipocyte subjects would yield different results. However, we factors or to act as an adjuvant to the actions of other observed no consistent effect of gender or race on cyto- insulin resistance factors. One such insulin resistance kine expression in these subjects. This study also relied factor is NEFA, which are closely associated with in- on plasma cytokine levels and cytokine secretion from sulin resistance (28, 39). TNF stimulates lipolysis in adipose tissue, and these measurements may not be adipocytes (34); hence, it is possible that TNF functions reflective of cytokine biological effects at the tissue at the level of the adipocyte to stimulate lipolysis.
Although IL-6 is not known to stimulate lipolysis (13, Because obesity and insulin resistance are related to 16), we found a significant relationship between each other, we wished to determine whether TNF and plasma IL-6 and plasma NEFA levels, whereas the IL-6 expression were related to insulin resistance in- relationship between TNF expression and plasma dependently of obesity. As described in Table 2, we paired insulin-resistant subjects with more-insulin- These studies provide the first comprehensive anal- sensitive subjects and matched them for BMI and age.
ysis of IL-6 expression in obese, insulin-resistant hu- By use of this analysis, high levels of TNF secretion mans and add to the data on TNF expression. To- and plasma IL-6 were both significantly associated gether, these studies suggest that obesity-related with insulin resistance. Thus the expression of these insulin resistance represents a complex syndrome, me- cytokines was associated with insulin resistance inde- diated by a number of adipocyte secretory products, which ultimately lead to defects in insulin action in There are differences in the expression of TNF and IL-6 that may be important in understanding their We thank Dr. Richard Evans for statistical assistance, Denise functions. IL-6 was secreted at high levels from adipose Hargrove for assistance with subject recruitment, and the nurses of tissue, and there was a significant arteriovenous dif- the General Clinical Research Center at the University of Arkansas ference in IL-6 across the adipose tissue bed, whereas for Medical Sciences and Central Arkansas Veterans Healthcare there was no arteriovenous difference with TNF (29).
System. We also thank Dr. Richard Bergman for supplying theMINMOD program, and Sarah Dunn for excellent secretarial assis- We found no relationship between plasma TNF and obesity or insulin resistance, although other studies This study was supported by a Veterans Affairs Department Merit have noted increased plasma TNF with obesity (2, 10, Review Grant M01-RR-14288 of the General Clinical Research Cen- 42, 43). IL-6 and TNF may interact with each other, as ter, a Career Development Award from the American Diabetes As-sociation, and DK-39176 from the National Institutes of Health.
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