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The Effect of Weight Loss on a Stable Biomarker of Inflammation, C- Reactive Protein

Posted on: Thursday, 27 January 2005, 03:00 CST

Inflammation is pivotal in all phases of atherosclerosis. Increasing body weight is positively associated with inflammation. Weight loss studies have shown that decreasing body weight significantly decreases C-reactive protein, the prototypic biomarker for inflammation. Reducing inflammation through weight loss could therefore be associated with reduced risk for cardiovascular disease and other obesity-associated chronic diseases.

Key words: inflammation, weight loss, C-reactive protein, CRP

2005 International Life Sciences Institute

doi: 10.1301/nr.2004.janr.22-28

Introduction

Inflammation has been shown to contribute to the pathogenesis of atherosclerosis, from the initiation of the fatty streak to acute coronary syndromes.1-7 C-reactive protein (CRP), a stable downstream biomarker of inflammation, predicts the risk of cardiovascular disease (CVD) and future cardiac events.3,5,6,8 CRP is secreted primarily by the liver after its synthesis is triggered by pro- inflammatory cytokines such as IL-6 derived from monocytes, macrophages, or adipose tissue. Approximately onefourth of circulating IL-6 is estimated to be released by adipose tissue.9-12 The secretion of these pro-inflammatory cytokines is stimulated by oxidative stress or infectious agents.13,14 Numerous prospective studies have shown that CRP levels in apparently healthy subjects predict cardiovascular events. CRP levels are increased in patients with the metabolic syndrome, and levels increase linearly with the numbers of abnormalities that comprise this syndrome.15,16 The metabolic syndrome is one of the major risk factors for CVD, so patients with this syndrome having higher CRP levels are at greatest risk for CVD. Therefore, significant reductions in CRP levels through weight loss could be associated with reduced risk for CVD and other obesity-associated chronic diseases such as certain types of cancer. In this review we examine the effect of weight loss on the modulation of inflammation, focusing on CRP levels as the chosen biomarker.

CRP and Cytokines

CRP has been used in several studies as the prototypic biomarker of inflammation. It is a member of the pentraxin family17 and consists of five protomers. It has a plasma half-life of 19 hours, and several prospective epidemiologic studies have shown that CRP predicts future cardiovascular events.18 Its synthesis in the liver is triggered by various pro-inflammatory cytokines derived from numerous sources, including monocytes, macrophages,7 and adipose tissue.11,19 The pro-inflammatory response includes an increased secretion of the cytokines IL-1β and TNFα, which then results in the release of the messenger cytokine IL-6 from macrophages. After engagement of its receptor on the liver, IL-6 results in the secretion and release of CRP.

Results from the Women's Health Study showed that in healthy postmenopausal women, CRP levels of greater than 3.0 mg/L added to the risk of CVD conferred by increasing LDL cholesterol and the total cholesterol/ HDL ratio.20 It now has been shown that CRP is present in atherosclerotic lesions and has in vitro effects on endothelial cells, macrophages, and smooth muscle cells that could support a role of CRP in atherosclerosis.7,10 However, studies in animal models need to be conducted to confirm these novel observations.

Obesity and CRP

Obesity is an independent risk factor for CVD, and elevated levels of CRP have been associated with obesity. Obesity is defined as a body mass index (BMI) of *ge;30 kg/m^sup 2^. According to data from the Third National Health and Nutrition Examination Survey of the US population (NHANES III), obesity is associated with elevated odds ratios for increased CRP levels (2.13 and 6.21 for men and women, respectively).21 Furthermore, a doubling of CRP levels was found to be associated with a doubling in the risk for myocardial infarction in healthy men.9 CRP is secreted mainly by the liver after its synthesis is triggered by IL-6. However, approximately one- fourth of circulating 11-6 is estimated to be released by adipose tissue in vivo.11,12 This might explain the observed associations between obesity and elevated CRP levels. Reductions in CRP levels through weight loss may therefore be associated with reduced risk for CVD and other obesity-associated chronic diseases such as diabetes. In addition to lowering CRP, weight loss has also been shown to positively influence other risk factors for CVD, for example, by improving insulin sensitivity and lowering serum triacylglycerides, LDL, and total cholesterol concentrations.

Weight Loss Studies

Several studies have been conducted to investigate the association between weight loss and CRP levels, as well as with other inflammatory proteins such as the cytokines IL-6 and TNFα. These studies were conducted in healthy obese subjects and in obese patients with hyperinsulinemia, diabetes, or rheumatoid arthritis. Eleven studies22-32 conducted from the year 2000 to the present were reviewed (Table 1). In these studies, weight loss was accomplished either through dietary approaches (eight studies) or through surgical methods (three studies). Ten of these 11 studies measured CRP solely or in combination with IL-6 and/or TNFa22-27,29- 32; one measured IL-6 and TNFα only.28 Some studies used low- fat diets; others used high-protein or hypocaloric diets. The duration of the diet programs ranged from 1 week to 2 years. Of the eight studies on dietary approaches,22,24-28,30,32 seven measured CRP2222,24-27,30,32 and six of these observed significant decreases in CRP levels after weight loss.22,24-26,30,32 The one study that did not measure CRP but did measure cytokines28 found significant decreases in IL-6 and TNFα levels achieved through a multidisciplinary weight loss program. All of the three studies investigating the effect of gastric surgery on CRP observed significantly decreased CRP levels after weight loss.23,29,31 Two of these studies also measured IL-6 and TNFα,23,29 and one found significant decreases in IL-6.23

In summary, of the 10 studies that measured CRP, nine observed significant reductions in CRP levels through weight loss (achieved either through dieting or through gastric surgery). Seven of the 11 studies measured IL-6, and in six of these, IL-6 decreased significantly and one observed a moderate but non-significant increase. Five studies measured TNFα, of which only one study observed a significant decrease.

The majority of studies using a dietary approach have associated weight loss with significant decreases in inflammation. For example, the study by Heilbronn et al.26 performed in 83 healthy obese women demonstrated a reduction of CRP concentrations by 26% following an average weight loss of 7.9 0.3 kg after 12 weeks of energy restriction using a low-fat diet (15% fat). The study subjects started out with a BMI of 33.8 0.4 kg/m^sup 2^ and relatively high CRP baseline levels of 5.6 0.4 mg/L. Unfortunately, the body weight in kilograms or the BMI after weight loss were not provided, so the percent weight loss or the percent BMI change cannot be compared with other studies; only the absolute weight change in kilograms can be compared. Tchernof et al.24 also observed a significant decrease in CRP levels (by 32%) in 25 obese postmenopausal women. The average weight loss in these subjects was 14.5 6.2 kg (15.6%). The subjects' baseline BMI of 35.2 4.0 kg/m^sup 2^ was similar to that of the subjects in the study by Heilbronn et al.,26 but the baseline CRP levels were lower (median = 3.1 mg/L). Although the baseline CRP levels were lower, the weight loss was almost twice as high, which could explain the similar percent decreases in CRP. The CRP levels decreased to 4.1 0.4 mg/L and 1.6 0.7 mg/L in the Heilbronn26 and Tchernof24 studies, respectively. In both studies, there was a positive correlation between reductions in CRP and weight loss.

A relatively large study by Esposito et al.22 in 60 obese premenopausal women observed a similar magnitude of change in CRP levels with 34.4% (baseline median CRP = 3.2 mg/L; after 2 years = 2.1 mg/L ) with similar baselineVBMI (35 2.3 kg/m^sup 2^) and body weight changes (-14 kg) compared with the two studies above. Women in that study also received guidance on increasing physical activity, which likely contributed to the observed weight loss, but also could be partly associated with the decrease in CRP. In NHANES III,33 lower inflammatory cytokines were observed in joggers, and a recently published study of more than 200 healthy Japanese women reported that exercise training significantly decreased CRP levels.34 Similar results have been observed in the other studies we reviewed. The only study we reviewed that did not find a significant reduction in CRP plasma levels was one by Bastard et al.,27 which was conducted in 14 non-diabetic obese women. The mean weight loss in these subjects was rather small: only 3 kg of body fat mass. Such a small change in body weight might not have significant effects on CRP levels. In addition, the sample size was relatively small and the 3-week duration of the diet was relatively short.

Table 1. Studies Conducted Investigating the Associati\on between Weight Loss and CRP Levels and Changes in the Cytokins IL-6 and TNFα. Results are Reported in Means SEM Unless Otherwise Noted.

Table 1. Studies Conducted Investigating the Association between Weight Loss and CRP Levels and Changes in the Cytokins IL-6 and TNFα. Results are Reported in Means SEM Unless Otherwise Noted.

Figure 1. Pathway of C-reactive protein (CRP) synthesis.

The three studies we reviewed on the effects of gastric surgery on CRP,23,29,31 done mostly in women, observed large mean body weight changes of approximately 31, 44, and 44 kg, respectively. The subjects in the study by Laimer et al.29 had a baseline BMI of 42 kg/ m^sup 2^; those in the study by Kopp et al.23 49 7 kg/m^sup 2^; and those in the study by Hanusch-Enserer et al.31 50 10 kg/m^sup 2^. These baseline BMIs are much higher than those of the subjects in the dieting studies and, accordingly, CRP levels decreased more dramatically. CRP levels in Kopp et al.23 decreased by 71% (from 8.6 to 2.5 mg/L); 70% in Laimer et al.29 (from 13.3 to 4.0 mg/L); and 29% in Hanusch-Enserer et al.31 (from 12 8 to 8.5 6.9 mg/L).

In summary, all but one of the studies reviewed here observed significantly decreasing CRP levels through weight loss. The weight loss and the CRP changes were more dramatically achieved through gastric surgery than through diet programs. The weight loss achieved through diet programs ranged from 3 to 15 kg and was accompanied by a 7% to 48% reduction of CRP levels, whereas the weight loss achieved by gastric surgery ranged between 31 and 44 kg and was accompanied by CRP level decreases of 29% to 71%. Several cross- sectional studies have shown a strong positive association between BMI and CRP.35,36 The magnitude of the change in CRP seems to depend on how obese the subjects were at baseline. Higher baseline BMIs, and thus higher baseline CRP levels, are associated with greater decreases in CRP levels. Overall, the magnitude of these observed decreases are comparable to those achieved with statin therapy.37 In most of the studies reviewed here, the subjects' CRP levels changed from the high-risk category for CVD (>3.0 mg/L) to the average-risk category (1.0-3.0 mg/L).38

The majority of the studies we reviewed here were conducted solely in women, and those that were not contained only a small proportion of male subjects. Although most of these weight loss studies consistently showed a significant decrease in biomarkers of inflammation, future studies should include more men to investigate if weight loss is associated with decrease in CRP in both sexes. It also needs to be made clear whether women in these studies were pre- or postmenopausal, because CRP baseline levels have been found to be associated with hormonal status. Hak et al.35 found that postmenopausal women have somewhat higher CRP levels than premenopausal women. Menopausal status might therefore be a confounder in studies of the association of weight loss and CRP. Studies in postmenopausal women should also take into account hormone replacement therapy, which has been found to be associated with increased CRP levels.39

Weight loss studies should also measure plasma antioxidant levels at baseline and after diet programs. Diets within weight loss programs might include more fruits and vegetables and would thus lead to higher antioxidant plasma levels, which could also explain the decrease in CRP after weight loss. This would indicate that not only a decrease in adipose tissue (thus a decrease in IL-6 excretion) but also a higher antioxidant intake may lead to lower CRP concentrations.

Some studies reviewed here encouraged subjects to exercise and others did not. It is therefore possible that physical exercise was responsible in part for the decrease in CRP in some studies. However, it is difficult to separate how much of the observed effect was due to physical exercise and how much was due to reduced adipose tissue.

In most of the studies, a CRP reduction was accompanied by a IL- 6 reduction, and thus the reduction in IL-6 is likely to be responsible for the reduction in CRP. However, results with regard to TNFα are less consistent. IL-6 was decreased in all of the studies except one. TNFα, on the other hand, was found to be decreased in only one study. Circulating TNFα and IL-6 are produced by adipocytes, and TNFα also induces IL-6 production, which triggers CRP production in the liver. Weight reduction would therefore be expected to be correlated with both IL-6 and TNFα. However, these cytokines have shorter half-lives than CRP and are derived from numerous sources. It might be more instructive to assay monocyte or adipose tissue release of these cytokines following dietary intervention.

Conclusion

Obesity has been clearly associated with elevated CRP (and IL-6) levels, and the majority of studies conducted on weight loss have shown significant decreases in these inflammatory proteins. Weight loss may reduce inflammation, and therefore may be associated with potential health benefits in addition to having favorable effects on the lipoprotein profile and insulin sensitivity.

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Marion Dietrich, PhD, and Ishwarlal Jialal, MD, PhD

Dr. Dietrich is with the School of Public Health, University of California, Berkeley, CA, USA; Dr. Jialal is director of the Laboratory for Atherosclerosis and Metabolic Research and Professor of Internal Medicine and Pathology, University of California at Davis Medical Center, Sacramento CA, USA.

Address for correspondence: I. Jialal MD, PhD, Director, Laboratory for Atherosclerosis and Metabolic Research, UC Davis Medical Center, Department of Pathology, Research I Bldg., Room 3005, 4635 2nd Ave., Sacramento, CA 95817; Phone: 916-734-6590; Fax: 916-734-6593; E-mail: ishwarlal.jialal@ucdmc. ucdavis.edu.

This paper was supported by NIH grants K-24 at 00596 and ROI-HL 074360.

Copyright International Life Sciences Institute and Nutrition Foundation Jan 2005

Source: Nutrition Reviews

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