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Journal of Parenteral and Enteral Nutrition
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Original Communications

Serum Levels of Interleukin-6 and C-Reactive Protein Correlate With Body Mass Index Across the Broad Range of Obesity

Lalita Khaodhiar, MD*,{dagger}, Pei-Ra Ling, MD{dagger}, George L. Blackburn, MD, PhD* and Bruce R. Bistrian, MD, PhD{dagger}

From the Departments of * Surgery and{dagger} Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

Correspondence: Pei-Ra Ling, MD, Department of Medicine, Beth Israel Deaconess Medical Center, Room 569, 21–27 Burlington Building, RN/99 Brookline Ave., Boston, MA 02215. Electronic mail may be sent to pling{at}bidmc.harvard.edu.

Background: It has been noted that elevated inflammatory markers, such as tumor necrosis factor-{alpha} (TNF), soluble TNF receptor II (sTNF-RII), interleukin 6 (IL-6) and C-reactive protein (CRP), are characteristically found in the serum in obese patients. In this study, we examined the correlation of these markers with BMI in nonobese, obese, and morbidly obese individuals to explore this relationship across the broad range of obesity. Methods: A total of 9 nonobese, including normal and overweight (body mass index [BMI] <30 kg/m2) and 41 obese (BMI ≥30 kg/m2) adults were included in this study. Among obese subjects, 11 subjects were grade I or II obese (BMI ≥30 and <40 kg/m2), and 30 subjects were morbidly obese (grade III obese, BMI ≥40 kg/m2). Serum levels of glucose, insulin, TNF, sTNF-RII, IL-6, and CRP were measured. Results: Obese subjects (BMI ≥30 kg/m2) had significantly higher serum levels of TNF, sTNF-RII, IL-6, and CRP compared with nonobese subjects. Serum levels of sTNF-RII, IL-6, and CRP, but not TNF, were positively correlated with BMI in obese subjects. However, in morbidly obese subjects, only the serum concentrations of IL-6 and CRP remained correlated with BMI, primarily because of this relationship in men. Conclusions: The present results support evidence that obesity represents an inflammatory state. In morbid obesity, the correlation of only IL-6 and CRP with BMI, particularly in males, suggests that IL-6 may be secreted in an endocrine manner in proportion to the expansion of fat mass particularly in the abdominal region, with a corresponding increase in hepatic production of CRP.

Obesity is increasing worldwide at an alarming and accelerating rate that extends to all age groups.1 In adults, obesity is associated with hyperinsulinemia, insulin resistance, dyslipidemia, and vascular dysfunction. Recent evidence indicates that obesity may represent a low-grade chronic inflammatory state as reflected by the elevation in a number of inflammatory markers in the serum, such as interleukin 6 (IL-6), tumor necrosis factor-{alpha} (TNF), soluble tumor necrosis factor receptor II (sTNF-RII), and C-reactive protein (CRP)2–5. Many studies have shown the concentrations of these inflammatory markers are correlated with the BMI and as well with several cardiovascular risk factors in healthy and obese subjects.6–8 Although CRP has historically been used for the detection and monitoring of clinically evident infection, CRP has recently been recognized as a useful marker of low-grade, chronic inflammation in the arterial wall at levels below the usual lower limit of normal. Within the usual normal range, its level in the serum correlates with the risk of stroke, myocardial infarction and peripheral arterial disease.6,9 Adipose tissue-derived cytokines, particularly IL-6, seem to be involved in the elevation of CRP in obesity.10 Therefore, chronic inflammation, as reflected in mild elevation of serum inflammatory cytokines and CRP, may in part explain the increased cardio- and cerebrovascular complications and mortality observed, particularly in severely obese patients.11

Morbid obesity, the most severe form of obesity, is defined as body mass index (BMI; weight in kilograms/height in meters squared) ≥40 kg/m2.1 It is estimated that the prevalence of severe obesity is 3.1% in men and 6.7% in women according to the US 1999 to 2000 population.12 Moreover, the mortality in the morbidly obese is substantially higher than in simple obesity (BMI ≥30 to <40 kg/m2), being 12 times higher in morbidly obese men aged 25 to 34 years and 6 times higher in those aged 35 to 44 years compared with men with healthy weights of the same age.11 This can be contrasted with the approximate doubling of mortality rates in white men with simple obesity.13 It seems that these extremely obese individuals are at greatest risk, although information is limited in this subgroup of obesity, and little information is available for morbidly obese women. Furthermore, it is not known whether the positive association of inflammatory markers is continuous over the entire range of obesity or whether there might be a plateau in the severely obese population with the highest level of BMI. If so, this would suggest that the inflammatory state was not as clearly linked to the increase in mortality risk.

On the other hand, because production of TNF in adipose tissue is primarily autocrine (local) and paracrine (regional) rather than endocrine (systemic) in nature, it is possible that the some inflammatory markers will not as accurately or sensitively reflect the risk of systemic inflammation in morbid obesity. In this study, we examined the associations of several inflammatory markers, including serum levels of TNF, sTNF-RII, IL-6, and CRP, with BMI in total of 50 subjects, with particular emphasis on the 30 subjects with morbid obesity.


   MATERIALS AND METHODS
Top
MATERIALS AND METHODS
RESULTS
 DISCUSSION
 
Subjects
A total of 41 obese and 9 nonobese but including overweight subjects were recruited into this study. According to the WHO standard definition, 6 nonobese subjects were normal weight (BMI < 25 kg/m2, with a range from 18.5 to 24.9 kg/m2), 3 nonobese subjects were overweight (BMI: 25–30 kg/m2, with a range from 25.3 to 29.5 kg/m2). Obese subjects (BMI ≥30 kg/m2) ranged from 30 to 77.1 kg/m2. Among the obese, 11 were grade I (BMI ≥ 30–35 kg/m2) or II obese (BMI >35 to <40 kg/m2) and 30 were grade III obese (BMI ≥40 kg/m2). These obese subjects were either the candidates for clinical studies on weight loss medications at the Center for Study of Nutrition Medicine, Beth Israel Deaconess Medical Center, or patients referred to Beth Israel Deaconess Medical Center for an evaluation for bariatric surgery. Nonobese subjects were members of our laboratory research group.

Written informed consent was obtained from each subject, and the study protocol was approved by the institutional review board of the Beth Israel Deaconess Medical Center.

For each obese participant, an extensive medical history was obtained, including comorbid conditions, concomitant medications, and smoking history. A detailed physical examination was performed at the office visit. For nonobese subjects, medical history was conducted to confirm absence of acute and chronic illness.

When the overnight fasting blood samples were taken, a normal body temperature and the absence of signs or symptoms of infections were used to ensure all subjects were free of obvious inflammatory disease or infection.

Samples and Analytical Methods
Blood was collected and immediately put on ice, and serum was separated within 2 hours of the collection, and aliquots were stored at –80°C until later analysis.

Serum concentrations of IL-6 were measured using human ELISA kits (BioSource International, Inc, Camarillo, CA) with a minimum detectable concentration of 0.16 pg/mL, as provided by the manufacturer. Serum concentrations of TNF were measured using human Ultra-sensitive ELISA kits (BioSource International, Inc) with a minimum detectable dose of 0.1 pg/mL. Concentrations of sTNF-RII in serum were determined by human sTNFR-II ELISA kit (BioSource International, Inc) with a minimum detectable concentration of 0.1 ng/mL.

Serum concentration of CRP was determined using human CRP ELISA kit (Alpha Diagnostic International, San Antonio, TX) with a minimum detectable concentration of 0.35 ng/mL if the samples are normally diluted at 1:100.

Fasting concentration of insulin was only determined in obese subjects using a commercial radioimmunoassay kit (ICN, Costa Mesa, CA). The concentrations of fasting glucose in these obese subjects were determined by hospital chemistry laboratory. The homeostasis assessment–insulin resistance (HOMAIR) was calculated by the equation14:

[fasting insulin concentration (µU/mL) x fasting glucose concentration (mM/L)]/22.5], where HOMA-IR ≥2.5 is considered as being insulin resistant.15

Statistical Analysis
Data are presented as mean ± SD. SYSTAT statistical software program (SPSS, Plover, WI) was used for all statistical analyses. The group means, either nonobese and obese groups or groups defined as BMI <30, 30 to 39.9, 40 to 49.9 and >50 kg/m2, were compared by 1-way ANOVA with significance defined as p < .05. The intergroup comparisons were determined by Fisher least square differences when there was overall significance with the 1-way ANOVA.

In order to further determine the relationship between BMI and inflammatory markers, regression with stepwise analysis was used to determine the association between BMI and all the measured variables in the total of 50 subjects, in the total of 41 subjects with BMI ≥30 kg/m2, and in the total of 30 subjects with BMI ≥40 kg/m2, respectively. In addition, the correlation between BMI and inflammatory markers was examined by gender.


   RESULTS
Top
MATERIALS AND METHODS
 RESULTS
DISCUSSION
 
General Information
The mean age of nonobese and obese subjects was 41.9 ± 7.6 and 43.1 ± 12.3 years, respectively. Most nonobese subjects were between 30 to mid-40s, whereas the obese subjects ranged from 19 to 67 years old. A total of 35 females (70.0%) and 15 males (30.0%) were included in this study. In the nonobese group, 5 subjects were females, and there were 30 females in the obese group. The mean weight of obese subjects was 113.3 ± 34.0 kg (81.2–259.0 kg) with a mean BMI of 47.0 ± 10.4 kg/m2 (30–77.1), and the mean weight of nonobese controls was 62.7 ± 20.2 kg, with a mean BMI of 24.5 ± 1.2 kg/m2 (19.1–29.5). There were no significant differences in BMI between male and female in overall subjects or in the different obese groups.

Among the 41 obese subjects, 2 (BMI: 33.5 and 51 kg/m2, respectively) were active smokers at the time of study, and 2 (BMI: 48 and 67 kg/m2, respectively) had a history of coronary heart disease but were in a stable condition at the time of study. However, most of the morbidly obese subjects (BMI ≥40 kg/m2) had comorbid conditions, including 4 subjects (13.8%) with diabetes mellitus (2 on insulin and 2 on oral medication), 16 (55.2%) with hypertension (14 on medication), 14 (48%) with sleep apnea, and 12 (41%) had a history of clinical depression. Moreover, 3 obese subjects were on hormone replacement therapy, 3 were receiving regular aspirin, and 5 lipid-lowering medication with statins. Liver function tests including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin were examined in 80% of obese subjects. Only 5.4% of results were elevated for any of these tests.

None of the obese subjects were on a diet when they were enrolled into this study. None of the nonobese controls was on a special diet or taking any medication.

Serum Concentrations of Cytokines
Obese subjects had significantly higher concentration of TNF, sTNF-RII, and IL-6 compared with nonobese subjects (p < .001; 0.3 ± 0.3 vs 1.0 ± 0.8 pg/mL, 1.1 ± 0.9 vs 12.9 ± 6.9 ng/mL, and 0.1 ± 0.1 vs 3.2 ± 2.5 pg/mL, respectively). However, the changes in these inflammatory markers varied greatly. For instance, TNF was 4-fold increased from nonobese (BMI <30 kg/m2) to grade I and II obese (BMI ≥30 to <40 kg/m2) but then was maintained at this high level even when BMI increased further (Fig. 1). As a result, there was no significant correlation between BMI and TNF in total subjects and in obese subjects. In contrast, serum concentrations of sTNF-RII (Fig. 2) and IL-6 (Fig. 3) continued to rise with increases in BMI. There were significant correlations between BMI and the levels of sTNF-RII (r = .81, p < .001) and IL-6 (r = .84, p < .05) in the total of 50 subjects and in the total of 41 obese subjects (r = .74, p < .005 for sTNF-RII, r = .62, p < .001 for IL-6, respectively). When the relationships of BMI and the measured cytokines were examined in the morbidly obese subgroup, the correlation was only observed between BMI and the serum levels of IL-6 (r = .61, p < .005), but not between BMI and the levels of TNF or sTNF-RII.


Figure 1
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  		FIG. 1. Serum levels of TNF in studied subjects grouped by BMI. Each box plot indicates the distribution of measured TNF (mean ± SD) in each group. Inside of the box, the solid line indicates the median of TNF in this group and the dotted line indicates the mean value of TNF in this group. Under each box, the number indicates the numbers of subjects in each group. *p < .01 vs group with BMI ≥30 kg/m2.

 

Figure 2
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  		FIG. 2. Serum levels of sTNF-RII in studied subjects grouped by BMI. Each box plot indicates the distribution of measured sTNF-RII (mean ± SD) in each group. Inside of the box, the solid line indicates the median of sTNF-RII in this group and the dotted line indicates the mean value of sTNF-RIIin this group. Under each box, the number indicates the numbers of subjects in each group. *p < .001 and **p < .005 vs group with BMI ≥40 kg/m2.

 

Figure 3
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  		FIG. 3. Serum levels of IL-6 in studied subjects grouped by BMI. Each box plot indicates the distribution of measured IL-6 (mean ± SD) in each group. Inside of the box, the solid line indicates the median level of IL-6 in this group and the dotted line indicates the mean value of IL-6 in this group. Under each box, the number indicates the numbers of subjects in each group. *p < .05 vs group with BMI >40 to 49.9 kg/m2, **p < .001 vs group with BMI ≥50 kg/m2.

 

Serum Concentrations of CRP
The concentration of CRP continued to rise with increases of BMI (Fig. 4). In the nonobese group, the average serum levels of CRP were <1 mg/L (0.8 ± 1.0 mg/L). When the BMI was increased to 30 kg/m2 (the group with BMI ≥30 but <39.9 kg/m2), the levels of CRP were significantly increased to 4.3 ± 2.3 kg/m2 (5-fold increases compared with those in the nonobese group). In this group, no subject had a CRP level <1 mg, and only 2 subjects (6.7%) had CRP at 1 to 3 mg/L. In contrast, 63.6% of subjects had CRP levels >3 mg/L, 45.5% >4 mg/L, and 9.1% >8 mg/L, the latter that would be in the usual clinically elevated range. In the severely obese group (BMI >40 kg/m2), there were 93.3% of subjects with CRP >3 mg/L, 90% >4 mg/L, and 56.7% >8 mg/L. When BMI exceeded 50 kg/m2, 50% of these morbidly obese subjects had CRP >10 mg/L, and the highest value was at 20.0 mg/L, levels that would clearly indicate clinical inflammation.


Figure 4
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  		FIG. 4. Serum levels of CRP in studied subjects grouped by BMI. Each box plot indicates the distribution of measured CRP (mean ± SD) in each group. Inside of the box, the solid line indicates the median level of CRP in this group and the dotted line indicates the mean value of CRP in this group. Under each box, the number indicates the numbers of subjects in each group. *p < .05 vs group with BMI 30 to 39.9 kg/m2; **p < .001 vs group with BMI 40 to 49.9 kg/m2; #p < .005 vs all.

 

There were significant correlations between BMI and CRP in the total 50 subjects (r = .72, p < .001), in the 41 obese subjects (r = .76, p < .05) and in the 30 morbidly obese subjects (r = .38, p < .05), respectively.

Correlations Between BMI and Inflammatory Markers by Gender
In this study, there were more female subjects than male subjects. In order to further explore whether gender could influence the relationship between BMI and inflammatory markers, the correlation was further examined in women and men, respectively.

In the total of 36 females, BMI was significantly correlated with sTNF-RII (r = .50, p < .001), IL-6 (r = .36, p < .001), and CRP (r = .40, p < .001) but not with TNF, which was the same relationship found in the overall 50 subjects. Similarly, BMI also was correlated with sTNF-RII (r = .56, p < .002), IL-6 (r = .71, p < .001) and CRP (r = .91, p < .001) but not TNF in the 14 males.

There were 23 females and 7 males with a BMI >40 kg/m2. BMI was significantly correlated only with IL-6 (r = .69, p < .02) and CRP (r = .96, p < .001) and only in males. No correlation between BMI and any measured inflammatory marker was found in morbidly obese females.

Glucose and Insulin in Obese Subjects
Serum fasting glucose and insulin concentrations were measured only in obese subjects. Morbidly obese individuals had significantly higher serum concentrations of glucose and insulin compared with grade I and II obese subjects (Table I). The index of insulin resistance, HOMA-IR, was also significantly higher in morbidly obese subjects compared with those with BMI <40 kg/m2, indicating insulin action was more impaired in morbidly obese subjects. However, no correlation was observed between BMI and HOMA-IR in obese subjects.


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  		TABLE I Changes of plasma glucose, insulin, ratio of insulin/glucose in obese subjects grouped by BMI

 


   DISCUSSION
Top
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 
The present results confirm previous findings that obesity is associated with elevated serum levels of TNF, sTNF-RII, IL-6, and CRP. Although there was impairment in insulin action in the obese, the relationship was not monotonic as with measures of inflammation. The morbidly obese were, however, substantially more insulin resistant than those with simple obesity.

Adipose tissue is an important source for the production of proinflammatory cytokines. Bullo et al16 reported that BMI was positively correlated with adipose tissue TNF and sTNFr-II mRNA. The levels of TNF mRNA, in turn, are associated with the concentrations of plasma TNF in obese subjects.17 In addition, studies in women have also shown an increase in sTNF-RII expression in adipose tissue and a 6-fold increase in circulating soluble TNF-RII levels with obesity.18 Indeed, in this study, there were substantial increases in TNF and sTNF-RII in circulation when BMI increased from <30 to ≥30 kg/m2. Interestingly, however, no further increases in TNF were observed in subjects when their BMI exceeded 40 kg/m2, up to a level of 71 kg/m2 (Fig. 1). In contrast, serum levels of sTNF-RII continuously increased with the increases in BMI (Fig. 2). Interpreting these seemingly contradictory findings may relate to the 3 principal types of secretion (ie, systemic, regional, or local) of cytokines by adipose tissue.

Kern et al19 have reported that the highest levels of TNF mRNA tend to be in subjects with mild to moderate obesity (BMI from 27 to 45 kg/m2); lower levels of TNF mRNA are found in subjects with a BMI >45 kg/m2. In this study, a total of 27 subjects had BMI >45 kg/m2. Thus, according to their findings, a large portion of severely obese individuals (66%) in this study could also be partially responsible for the lack of association between circulating TNF and BMI in morbid obesity. In addition, other cytokines, such as IL-6, can bind to the TNF receptors even in the absence of changes in TNF concentrations.20 Furthermore, IL-6 has anti-inflammatory effects and stimulates the expression of the SOCS3 gene,21 which could reduce TNF secretion in severe obesity and increase insulin resistance. Finally, it is possible and likely that the increased sTNF-RII with BMI reflects the continuous secretion of the shed receptors as a consequence of the regional and local actions of TNF derived from adipose tissues with only the sTNF-RII released quantitatively into the systemic circulation. Recent study also has shown that changes in TNF associated with BMI seem to be more consistent when there is a predominant genetic component to the obesity.22 Unfortunately, genetic information was not available in this study.

In severely obese subjects, the levels of IL-6 and CRP significantly increased and were correlated with the increases in BMI (Figs. 3 and 4). IL-6 is another proinflammatory cytokine secreted by adipose tissue23 but, unlike TNF, principally secreted in an endocrine (systemic) fashion. Furthermore, CRP is mainly synthesized in the liver in response to IL-6 stimulation, which would explain its proportional increase. Adipose tissue IL-6 content expressed as picogram per total fat mass has been significantly correlated with plasma concentration of CRP.23 It has been also suggested that the omental adipose tissue expresses mRNA for IL-6 to a greater extent than subcutaneous adipose tissue.24 The reverse is true for TNF and sTNF-RII.25 Although we did not directly examine the body fat mass and fat distribution, particularly the proportion of abdominal or upper-body fat in this study, the present results seem consistent with such regional effects. In severe obesity, moreover, the evidence that the correlations between BMI and IL-6 or CRP were found only in males further supports the regional effects of fat deposition. In general, obese men primarily have abdominal fat deposition, whereas women tend to accumulate excess adipose tissue in the gluteo-femoral regions.26 Men also are at higher risk for the development of complications related to obesity than are women.27

It is now well accepted that CRP levels of <1, 1 to 3, and >3 mg/L, but all below 8 mg/L indicating clinical levels of inflammation, using the highly sensitive testing method for CRP, correspond to low-, moderate-, and high-risk groups for future cardiovascular events.28 In this study, we used a less sensitive test for CRP to explore the intermediate range of CRP levels extending up into the clinical range to be anticipated in the greater inflammatory state seen in obesity. Moreover, a level of CRP >4 mg/L is considered as abnormal and at 8 mg/L is the traditional threshold for clinically significant inflammation. In this study, most of obese subjects (85.4% of obese subjects) had CRP levels >3 mg/L, and many had CRP levels >4 mg/L (78.0% of obese subjects) or >8 mg/L (43.9% of obese subjects). Although the comorbidities such as diabetes could have made some contributions to the inflammatory state, elevations of CRP into the clinical range probably reflect the major contribution of the severity of the obesity. This degree of inflammation could well account also for the much greater mortality experience because of heart disease seen in morbid obesity12,13 of up to 12 times greater compared with the approximate doubling or tripling of mortality in mild obesity.13,29 On the other hand, success of weight loss in treating obesity with complications is most likely related to the reduction of inflammatory mediators.30 In morbidly obese patients, particularly, it has been reported that weight loss induces a significant decrease of CRP and IL-6 concentration.31 Furthermore, the closer association of morbid obesity with inflammatory indicators in males would suggest at least preliminarily greater risks for them and greater benefits with weight loss.

In conclusion, it is widely appreciated that obesity is characterized by elevation in inflammatory markers and impairment of insulin action. The results of this study suggest that with the progression of obesity only IL-6 and its hepatic byproduct, CRP, continue to correlate with the increase in adipose tissue as reflected in BMI, particularly in males. Although more studies are needed to explore the implications of these preliminary findings, the greater degree of insulin insensitivity and clinical evidence for increased mortality with greater degrees of obesity suggest that IL-6 and CRP levels best indicate the intensity of the systemic inflammation that develops with increasing levels of obesity.


  
Top
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 
Supported in part by DK46200, CA78521, AT00863, DK57154 and the Center for Study of Nutrition and Medicine.

Received for publication March 25, 2004. Accepted for publication July 29, 2004.

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Journal of Parenteral and Enteral Nutrition, Vol. 28, No. 6, 410-415 (2004)
DOI: 10.1177/0148607104028006410
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