Abstract
Context: Obesity is associated with low-grade inflammation, but the long-term effects of weight change on inflammation are unknown.
Objective: The aim was to examine the association of change in weight, body mass index (BMI), and waist circumference with change in C-reactive protein (CRP) and IL-6 and to assess whether this association is modified by baseline obesity status.
Design and Setting: The design was a prospective cohort study among civil servants (the Whitehall II Study, UK). We used data from two clinical screenings carried out in 1991–1993 and 2002–2004 (mean follow-up, 11.3 yr).
Participants: We studied 2496 men and 1026 women [mean age, 49.4 (sd = 6.0) yr at baseline] with measurements on inflammatory markers and anthropometry at both baseline and follow-up.
Main Outcome Measures: We measured change in serum CRP and IL-6 during follow-up.
Results: The mean increases in CRP and IL-6 were 0.08 [95% confidence interval (CI), 0.07–0.09] mg/liter and 0.04 (95% CI, 0.03–0.05) pg/ml per 1-kg increase in body weight during follow-up. Study members with a BMI less than 25 kg/m2 at baseline had an average increase in CRP of 0.06 (95% CI, 0.05–0.08) mg/liter per 1-kg increase in body weight, whereas the increase in those who were overweight (25 ≤ BMI < 30 kg/m2) and obese (BMI ≥30 kg/m2) was greater: 0.08 (95% CI, 0.06–0.09) mg/liter and 0.11 (95% CI, 0.07–0.14) mg/liter, respectively (P value for interaction = 0.002). Similar patterns were observed for changes in BMI and waist circumference.
Conclusions: Those who were overweight or obese at baseline had a greater absolute increase in CRP per unit increase in weight, BMI, and waist circumference than people who were normal weight.
An increase in weight, body mass index and waist circumference was associated with an increase in inflammatory markers over 11 years, especially among overweight and obese people.
Low-grade systemic inflammation is associated with atherosclerosis and other chronic conditions such as diabetes (1,2). C-reactive protein (CRP; a plasma protein synthesized by the liver) and IL-6 (a cytokine that governs inflammatory cascades and modulates CRP) are key biochemical markers of inflammation (3,4). It is well established that overweight and obese persons have, on average, higher concentrations of CRP and other inflammatory markers than their leaner counterparts (5,6). It has also been shown that intentional weight loss leads to reduced inflammatory marker levels in the short term (7,8). However, the long-term associations of change in weight or central obesity with changes in inflammatory markers in larger populations are poorly understood (9,10). Accordingly, we assessed how changes in weight, body mass index (BMI), and waist circumference over a period of 11 yr were associated with changes in CRP and IL-6 in a large cohort of middle-aged British adults (11). We also examined whether weight-related changes in inflammatory markers differed between normal-weight, overweight, and obese individuals.
Subjects and Methods
Study population
Whitehall II, a prospective cohort study, was established in 1985. Participants were all office staff, aged 35–55 yr at enrollment, and working in 20 London-based Civil Service departments. In total, 10,308 people (6,895 men and 3,413 women), 73% of those invited, were included at baseline (1985–1988) (11). Initial cohort members were subsequently invited to participate in seven data collection phases.
In the present analysis, we used data from phases three (1991–1993) and seven (2002–2004)—the only occasions when CRP and IL-6 were measured. After excluding participants who reported having had a cold or flu in the 14 d preceding blood collection and those who had a CRP over 10 mg/liter at either phase three or seven, a total of 3522 participants (2496 men and 1026 women) had values on inflammatory markers and anthropometric measures from both phases three and seven; this was our analytical sample (Supplemental Table 1, published on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org). The mean follow-up time between phases three and seven was 11.3 yr (range, 9.5–12.9 yr).
The Whitehall II study has approval from the University College London Medical School Committee on the Ethics of Human Research. Informed consent was gained from all participants.
Anthropometry
Data on weight, height, and waist circumference were collected by trained study nurses at clinical screening sessions both at phase three and phase seven. Weight was measured to the nearest 0.1 kg. Height was measured with participants standing erect with their head in the Frankfort plane and was recorded to the nearest 0.1 cm. BMI was calculated as weight (kilograms)/height (meters)2. Waist circumference was measured halfway between the costal margin and the iliac crest; measurements were recorded to the nearest 0.1 cm.
Inflammatory markers
Fasting serum was collected between 0800 and 1300 h and was stored at −70 C. Samples from phases three and seven were analyzed at the same time. CRP was measured using a high-sensitivity immunonephelometric assay in a BN ProSpec nephelometer (Dade Behring, Milton Keynes, UK). IL-6 was measured using a high-sensitivity ELISA (R&D Systems, Oxford, UK). Values lower than the detection limit (0.154 mg/liter for CRP and 0.08 pg/ml for IL-6) were assigned a value equal to half the detection limit.
Covariates
Covariates included in the present study, measured at baseline, were: age, ethnicity (White, South Asian, Black, other), socioeconomic position based on civil service employment grade (low, intermediate, high), smoking (never smoker, ex-smoker, current smoker), and leisure-time physical activity (none or mild physical activity vs. moderate activity at least three times per week or vigorous activity at least one or two times per week). Coronary heart disease (CHD) was defined by using the Multinational Monitoring of trends and determinants in cardiovascular disease (MONICA) criteria (12). Diabetes was defined by a fasting glucose of 7.0 mmol/liter or more, a 2-h postload glucose of 11.1 mmol/liter or more, self-report of doctor diagnosis, or use of diabetes-related medications (13).
Statistical analysis
The distributions of CRP and IL-6 at baseline and follow-up were skewed, so the geometric means and sd values of logged values are presented for these variables. The distributions for the changes in CRP and IL-6 between phases three and seven were not skewed, so the arithmetic means and sd values are presented for these variables.
Multivariable linear regression models were used to evaluate the relationships of change in weight, BMI, and waist circumference (exposure variables) with changes in CRP and IL-6 (outcome variables). Throughout these analyses, we simultaneously took into account the effect of a range of potential confounding factors. To examine whether the association was dependent on baseline obesity status, we stratified analyses by the following baseline categories of BMI: underweight/normal weight (BMI <25.0 kg/m2), overweight (25.0 ≤ BMI < 30.0 kg/m2), and obese (BMI ≥30.0 kg/m2) (14). Statistical interaction was evaluated by including product terms between baseline BMI category and the exposure variable of interest in the respective models (i.e. weight change, BMI change, or change in waist circumference during the follow-up). These analyses were performed separately for the two outcome measures.
All analyses were performed using SAS version 9.1 (SAS Institute Inc., Cary, NC; 2002–2003).
Results
In the analytical sample, mean age at baseline (phase three) was 49.4 (sd = 6.0) yr; men constituted 71% of the sample; and most study participants were white (Table 1). Mean weight increased in this sample by 3.0 (sd = 5.8) kg over 11 yr of follow-up. The increase in BMI and waist circumference was 1.4 (sd = 2.0) kg/m2 and 7.7 (sd = 7.4) cm for all participants. On average, CRP increased by 0.53 (sd = 1.81) mg/liter and IL-6 by 0.45 (sd = 1.79) pg/ml.
Table 1.
Baseline characteristics and changes between baseline at follow-up (Δ) in obesity measures and inflammatory markers of the study sample with full measurements on inflammatory markers and anthropometry at both baseline (phase three, 1991–1993) and follow-up (phase seven, 2002–2004)—the Whitehall II study
| All | Men | Women | |
|---|---|---|---|
| n | 3522 | 2496 | 1026 |
| Age (yr) | 49.4 (6.0) | 49.3 (6.0) | 49.7 (6.0) |
| Ethnicity, n (%) | |||
| White | 3224 (92) | 2330 (93) | 894 (87) |
| South Asian | 168 (5) | 110 (4) | 58 (6) |
| Black | 96 (3) | 36 (1) | 60 (6) |
| Other | 31 (1) | 18 (1) | 13 (1) |
| Civil service grade, n (%) | |||
| High | 1441 (41) | 1242 (50) | 199 (20) |
| Intermediate | 1606 (46) | 1124 (46) | 482 (47) |
| Low | 438 (13) | 103 (4) | 335 (33) |
| Smoking, n (%) | |||
| Never-smoker | 1825 (53) | 1235 (51) | 590 (59) |
| Ex-smoker | 1226 (36) | 951 (39) | 275 (275) |
| Current smoker | 383 (11) | 253 (10) | 130 (130) |
| Exercise level, n (%) | |||
| High | 1107 (32) | 909 (37) | 198 (19) |
| Low | 2382 (68) | 1564 (63) | 818 (81) |
| CHD, up to and including phase three, n (%) | |||
| No | 3256 (92) | 2331 (93) | 952 (90) |
| Yes | 266 (8) | 165 (7) | 101 (10) |
| Diabetes type 2 at phase three, n (%) | |||
| No | 3444 (98) | 2440 (98) | 1004 (98) |
| Yes | 78 (2) | 56 (2) | 22 (2) |
| Weight (kg) | 74.4 (12.2) | 77.6 (10.7) | 66.7 (12.4) |
| BMI (kg/m2) | 25.0 (3.6) | 24.9 (3.0) | 25.3 (4.6) |
| Waist circumference (cm) | 85.1 (11.3) | 88.5 (9.1) | 76.8 (11.9) |
| CRP (mg/liter), G-mean (sdlog)a | 0.75 (1.09) | 0.72 (1.08) | 0.84 (1.10) |
| IL-6 (pg/ml), G-mean (sdlog)a | 1.42 (0.56) | 1.36 (0.53) | 1.58 (0.60) |
| ΔWeight (kg) | 3.0 (5.8) | 3.0 (5.5) | 2.9 (6.3) |
| ΔBMI (kg/m2) | 1.4 (2.0) | 1.4 (1.8) | 1.5 (2.4) |
| ΔWaist (cm) | 7.7 (7.4) | 6.5 (6.1) | 10.5 (9.4) |
| ΔCRP (mg/liter) | 0.53 (1.81) | 0.45 (1.75) | 0.73 (1.95) |
| ΔIL-6 (pg/ml) | 0.45 (1.79) | 0.57 (1.71) | 0.15 (1.9) |
Data are expressed as mean (sd), unless otherwise indicated. Δ, Change between baseline and follow-up.
Geometric mean and sd of logged values.
The crude changes in mean CRP and IL-6 during the follow-up by quartiles of change in weight, BMI, and waist circumference are shown in Supplemental Fig. 1. These data suggest a linear association between increase in inflammatory markers and increase in weight, BMI, and waist circumference. Linear regression showed a 1-kg increase in body weight over the 11 yr of follow-up to be associated with a mean increase in CRP of 0.08 [95% confidence interval (CI), 0.07–0.09] mg/liter, whereas the corresponding increase in IL-6 was 0.04 (95% CI, 0.03–0.05) pg/ml (Table 2). The relationship between change in weight and BMI in relation to change in CRP was stronger among women than men (P“Sex × change in weight” interaction < 0.0001 and P“Sex × change in BMI” interaction = 0.0004), whereas no sex differences were noted in the associations between change in weight, BMI, or waist circumference and IL-6.
Table 2.
Change in CRP and IL-6 values between baseline and follow-up per unit change in weight, BMI, and waist circumference
| ΔCRP (mg/liter)
|
ΔIL-6 (pg/ml)
|
|||||
|---|---|---|---|---|---|---|
| n | β (95% CI)a | P value for interaction | n | β (95% CI)a | P value for interaction | |
| ΔWeight (kg) | 3401 | 0.08 (0.07–0.09) | 3132 | 0.04 (0.03–0.05) | ||
| ΔBMI (kg/m2) | 3392 | 0.23 (0.20–0.26) | 3126 | 0.12 (0.09–0.15) | ||
| ΔWaist (cm) | 3363 | 0.05 (0.04–0.06) | 3095 | 0.03 (0.02–0.04) | ||
| By sex | ||||||
| ΔWeight (kg) | ||||||
| Men | 2417 | 0.06 (0.05–0.07) | <0.0001 | 2236 | 0.04 (0.03–0.06) | 0.64 |
| Women | 984 | 0.11 (0.09–0.13) | 896 | 0.04 (0.02–0.06) | ||
| ΔBMI (kg/m2) | ||||||
| Men | 2411 | 0.19 (0.15–0.22) | 0.0004 | 2232 | 0.14 (0.09–0.18) | 0.25 |
| Women | 981 | 0.29 (0.24–0.34) | 894 | 0.11 (0.05–0.16) | ||
| ΔWaist (cm) | ||||||
| Men | 2385 | 0.05 (0.04–0.06) | 0.39 | 2205 | 0.03 (0.02–0.05) | 0.17 |
| Women | 978 | 0.06 (0.04–0.07) | 890 | 0.02 (0.01–0.03) | ||
| By BMI at baseline | ||||||
| ΔWeight (kg) | ||||||
| BMI <25 | 1888 | 0.06 (0.05–0.08) | 0.002 | 1753 | 0.03 (0.01–0.05) | 0.22 |
| 25 ≤ BMI < 30 | 1243 | 0.08 (0.06–0.09) | 1143 | 0.05 (0.03–0.06) | ||
| BMI ≥30 | 263 | 0.11 (0.07–0.14) | 231 | 0.05 (0.02–0.09) | ||
| ΔBMI (kg/m2) | ||||||
| BMI <25 | 1887 | 0.18 (0.14–0.22) | 0.003 | 1753 | 0.09 (0.05–0.14) | 0.43 |
| 25 ≤ BMI < 30 | 1243 | 0.22 (0.17–0.27) | 1143 | 0.13 (0.07–0.18) | ||
| BMI ≥30 | 262 | 0.31 (0.22–0.40) | 230 | 0.15 (0.05–0.25) | ||
| ΔWaist (cm) | ||||||
| BMI <25 | 1863 | 0.04 (0.03–0.05) | <0.0001 | 1729 | 0.02 (0.01–0.03) | 0.002 |
| 25 ≤ BMI < 30 | 1231 | 0.05 (0.03–0.06) | 1132 | 0.02 (0.01–0.04) | ||
| BMI ≥30 | 262 | 0.11 (0.07–0.14) | 230 | 0.08 (0.05–0.12) | ||
Participants with CRP values greater than 10 mg/liter at baseline or follow-up, or having cold/flu during the last 14 d before blood sampling at baseline or follow-up were excluded. Δ, Change between baseline and follow-up. β, The regression coefficient reflects the average change in the outcome variable with one unit increase in the exposure variable.
Adjusted for sex, ethnicity, baseline age, socioeconomic position (civil service grade), smoking, physical activity, and baseline weight/BMI/waist circumference.
In analyses stratified by baseline BMI categories, the relationship between change in the anthropometric measures and change in CRP was stronger in those overweight and obese at baseline, as compared with those who were lean or normal weight at baseline (Table 2). This observation was unchanged irrespective of whether we used change in weight (P“Baseline BMI category × change in weight” interaction = 0.002), BMI (P“Baseline BMI category × change in BMI” interaction = 0.003) or waist circumference (P“Baseline BMI category × change in waist” interaction < 0.0001) as the exposure variable in the models. For example, the average change in CRP was 0.31 (95% CI, 0.22–0.40) mg/liter per unit change in BMI in the obese group, whereas the corresponding figures in the overweight and lean/normal-weight groups were 0.22 (95% CI, 0.17–0.27) mg/liter and 0.18 (95% CI, 0.14–0.22) mg/liter, respectively. A similar pattern, albeit weaker, was observed in relation to change in IL-6, but only the interaction between change in waist circumference and baseline BMI category was statistically significant (P = 0.002).
To test the robustness of our findings, we repeated the main multivariable linear regression analyses of weight change and change in inflammatory markers after excluding participants who had any CHD up to and including phase three (n = 266), type 2 diabetes at phase three (n = 78), as well as those who reported taking lipid-lowering drugs any time during follow-up (n = 420) (lipid-lowering medication may affect levels of inflammation). In these analyses, our conclusions were essentially unchanged (results are not shown but are available upon request).
Discussion
We found that CRP and IL-6 levels increased over an 11-yr follow-up period in a middle-aged population. The size of this increase in inflammatory markers was associated with the change in weight, BMI or waist circumference. These associations were more pronounced among those who were overweight or obese at baseline relative to normal-weight persons.
The strengths of this study are the use of multiple indicators of both adiposity and inflammation and a large sample size. With little difference between the characteristics of participants at baseline and those included in this analytical sample, there was no strong evidence of selection bias (Supplemental Table 1). However, our study uses observational data, which can never provide complete inferences about causality.
In a United Kingdom community-based cohort study of 1222 participants followed over 9 yr, an average increase in CRP of 0.09 mg/liter per kg increase in weight was observed, which is consistent with our findings (9). Our findings also accord with a French study of 1099 middle-aged participants that found significant correlations between change in BMI, waist-hip ratio, and waist girth and change in CRP, haptoglobin, and orosomucoid; and between change in waist-hip ratio and waist girth and change in white blood cells over a period of 5 yr (10).
To our knowledge, this is the first study to report that those who are obese may have a greater absolute increase in CRP per unit increase in subsequent weight, BMI, and waist circumference than those who are normal weight. This observed effect is plausible. Obese persons are known to have enlarged adipocytes (8,15), and adipose tissue in obese persons shows higher expression of several proinflammatory proteins as compared with adipose tissue in leaner persons (15,16). It has been shown that both high BMI and increased adipocyte size predict a proportionally higher macrophage infiltration and accumulation in adipose tissue, increasing cytokine production in obese adipose tissue (16,17). Mouse models have demonstrated that diet-induced obesity leads to a shift in the adipose tissue macrophage type, from the antiinflammatory alternatively activated type to the proinflammatory classically activated type (18). Furthermore, a higher incidence of proinflammatory comorbidities, such as osteoarthritis, has been observed among obese persons (19). Additional research is needed to examine whether these and other mechanisms may be responsible for the interaction effect observed in our study.
Supplementary Material
Acknowledgments
We thank all participating men and women in the Whitehall II Study; all participating Civil Service departments and their welfare, personnel, and establishment officers; the Occupational Health and Safety Agency; and the Council of Civil Service Unions. The Whitehall II Study team comprises research scientists, statisticians, study coordinators, nurses, data managers, administrative assistants, and data entry staff, who make the study possible.
Footnotes
The Whitehall II study is supported by the Medical Research Council; British Heart Foundation; Wellcome Trust; Health and Safety Executive; Department of Health; Agency for Health Care Policy Research, United Kingdom; John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socioeconomic Status and Health; National Heart, Lung, and Blood Institute (R01HL036310) and National Institute on Aging (R01AG013196 and R01AG034454), National Institutes of Health, Bethesda, Maryland; Academy of Finland, Finland; BUPA Foundation, United Kingdom; and European Science Foundation. E.I.F. is supported by a University College London Balzan fellowship and a fellowship from the Swedish Council for Working Life and Social Research (Grant 2009-1450). G.D.B. is a Wellcome Trust Fellow. The Medical Research Council Social and Public Health Sciences Unit receives funding from the UK Medical Research Council and the Chief Scientist Office at the Scottish Government Health Directorates. M.J.S. is supported by the British Heart Foundation. A.S.-M. is supported by a “European Young Investigator Award” from the European Science Foundation. Mi.K. is supported by the Academy of Finland.
Disclosure Summary: None of the authors declared conflicts of interest.
First Published Online August 18, 2010
Abbreviations: BMI, Body mass index; CHD, coronary heart disease; CI, confidence interval; CRP, C-reactive protein.
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