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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-1417
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 12 4747-4752
Copyright © 2007 by The Endocrine Society

Impaired ex Vivo Leukotriene B4 Production Characterizes the Metabolic Syndrome and Is Improved after Weight Reduction

I. J. Tsai, L. J. Beilin, I. B. Puddey, K. D. Croft and A. Barden

University of Western Australia, School of Medicine and Pharmacology, Royal Perth Hospital, Perth, Western Australia 6001, Australia

Address all correspondence and requests for reprints to: Dr. Anne Barden, School of Medicine and Pharmacology, Royal Perth Hospital Unit, P.O. Box X2213, Perth 6847, Australia. E-mail: anne.barden{at}uwa.edu.au.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Neutrophil (polymorphonuclear neutrophil) production of leukotriene B4 (LTB4) may be associated with alterations in immune and inflammatory function that characterize the metabolic syndrome (MetS).

Objective: We investigated whether polymorphonuclear neutrophil production of LTB4 and its metabolites 20-hydroxy-LTB4 (20-OH-LTB4) and 20-carboxyl-LTB4 were altered in subjects with features of the MetS before and after weight reduction.

Design, Setting, Patients, and Intervention: In a case-controlled comparison, men and postmenopausal women with features of the MetS were matched with controls. Subjects with MetS were then matched and randomly assigned to either a 12-wk weight reduction study followed by 4-wk weight stabilization or 16-wk weight maintenance.

Main Outcome Measures: Measurements were performed at baseline and at the end of the 16-wk period. Stimulated neutrophil LTB4 and its metabolites were measured by HPLC.

Results: In the case-controlled study, body mass index, waist circumference, blood pressure, fasting triglycerides, and glucose were all significantly increased in subjects with features of the MetS (P < 0.05). Production of LTB4 and 20-OH-LTB4 was significantly lower compared with controls (P < 0.005). The weight loss intervention resulted in a 4.6-kg reduction in body weight and 6.6-cm decrease in waist circumference relative to controls and a significant increase in LTB4 and 20-OH-LTB4.

Conclusions: Subjects with features of the MetS have lower stimulated LTB4, which is not due to increased metabolism of LTB4. Weight reduction restored the production of neutrophil LTB4, suggesting that in addition to modifying cardiovascular risk, weight loss may also help with the management of perturbed inflammatory responses in overweight subjects.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE METABOLIC SYNDROME (MetS) describes a cluster of cardiovascular risk factors and metabolic abnormalities that result from the increasing prevalence of obesity. The cluster of metabolic alterations includes central obesity, hypertension, insulin resistance, glucose intolerance, and dyslipidemia. The MetS is associated with a chronic low-grade inflammatory state, as evidenced by increased production of proinflammatory cytokines, including IL-6 and TNF-{alpha} (1, 2). The MetS is predictive of cardiovascular disease, and a link with markers of inflammation such as C-reactive protein (CRP) enhances this association (3). Obesity is also related to dysregulated cytokine production by immune cells (4). Adipose tissue exerts effects on immune function by releasing adipokines such as leptin, adiponectin, and resistin. Although leptin is not a classical cytokine, leukocytes, monocytes, and lymphocytes have receptors for leptin, and leptin can modulate their activity (5).

Polymorphonuclear neutrophils (PMNs) are the first line of host defense after a microorganism has gained entry into the body. These phagocytic cells function in sequence to cause chemotaxis, adhesion to endothelium and foreign agents, phagocytosis, and microbicidy. Leukotriene B4 (LTB4) is a potent proinflammatory mediator derived from arachidonic acid via the 5-lipoxygenase pathway (6, 7). It is produced upon activation of PMNs after exposure to chemoattractants (8) and in vitro stimulants such as calcium ionophore A23187. LTB4 is known for its potent chemotactic and chemokinetic activities for PMN, and causes PMN aggregation, adhesion, and degranulation (9, 10). Intracellular LTB4 is metabolized by CYP450 {omega}-oxidation to 20-hydroxy-LTB4 (20-OH-LTB4) via a NADPH-dependent mechanism (11), subsequent oxidation leads to the formation of 20-carboxyl-LTB4 (20-COOH-LTB4) (12). The metabolite 20-OH-LTB4 has a similar chemotactic activity to LTB4, but 20-COOH-LTB4 is significantly less active (13, 14, 15). LTB4 has been implicated as having a role in inflammatory and allergic disorders, including rheumatoid arthritis, inflammatory bowel disease, and bronchial asthma (16). Moreover, recent studies have suggested a linkage between the production of LTB4 and atherosclerosis (17). To date there have not been studies examining the influence of the MetS on LTB4 and its metabolites.

Weight control is widely used to modify cardiovascular risk in subjects with the MetS (18). Weight reduction in overweight subjects reduces insulin resistance and improves insulin sensitivity (19, 20). The effects of a weight loss program also extend to improvements in other established cardiovascular risk markers, including fasting glucose levels and blood lipids (21), and improvements in vagal tone (22, 23). However, no study has been conducted to examine the effect of weight loss on the production of LTB4 and its metabolites in the MetS.

The first objective of this study was to compare the production of neutrophil LTB4 and its metabolites 20-OH-LTB4 and 20-COOH-LTB4 in men and women with MetS who were matched for and age and gender with healthy subjects. The second was to conduct a controlled trial of the effect of a 12-wk weight loss program on the production of neutrophil LTB4 level in subjects with the MetS.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The two studies were run sequentially. In the first study, men and women with features of the MetS were studied in comparison with age and gender-matched controls. Subjects with the MetS then entered a controlled weight loss intervention.

Recruitment of men and women with the MetS and controls

Men and postmenopausal women not taking hormone replacement therapy, aged 20–70 yr, were recruited from the Perth general population by newspaper advertisements. Subjects were recruited on the basis of being untreated but having features of the MetS using the criteria of the National Cholesterol Education Program Adult Treatment Panel III. They were invited to participate if they had a waist circumference more than 102 cm for males and more than 88 cm for females, and systolic blood pressure (SBP) 130 mm Hg or higher.

Age and gender-matched healthy control subjects were recruited from the general population by newspaper advertisement. Subjects were included if in the age range 20–70 yr, with a waist circumference less than 102 cm for males and less than 88 cm for females, and not more than one other defining criterion for the MetS.

Screening

At a screening visit, all volunteers had height, weight, and waist circumference measured. They completed a lifestyle questionnaire, which included details of medical history medication usage and alcohol consumption. BP was measured in the seated position using a manual sphygmomanometer on 2 separate days. The average of four readings taken at 1-min intervals after 5-min seated rest was obtained for each day. Subjects completed 3-d diet records to estimate their caloric intake. A fasted blood sample was taken for measurement of triglycerides, total and high-density lipoprotein (HDL) cholesterol, glucose, liver function tests, and creatinine.

Exclusion criteria

Subjects with symptoms of the MetS and controls were excluded if they were smokers, consuming more than 30 g alcohol/d or more than 40 g alcohol in a single session, had a history of cardiovascular or peripheral vascular disease, diabetes, renal disease, liver disease, or were taking antihypertensive agents, lipid lowering drugs, aspirin, or nonsteroidal antiinflammatory drugs.

All procedures followed were in accordance with institutional guidelines. The studies were approved by the University of Western Australia Human Ethics Committee, and all subjects provided written informed consent before inclusion in the studies. The weight loss intervention was registered with the Australian Clinical Trials Registry no. ACTRN12605000107628.

Study designs

Comparison of LTB4 in subjects with the MetS and controls. A total of 30 subjects with the MetS was matched for age and gender with 30 controls and examined in a case-controlled comparison. Within 3 wk of the initial screening visit, weight and waist circumference were measured, and a fasting blood sample was collected. BP was monitored over 24 h using a Spacelabs 90207 monitor set (Spacelabs Healthcare, Issaquah, WA) to record at 20-min intervals while awake and 30-min intervals while asleep. Subjects with the MetS then participated in a controlled weight loss intervention.

The effect of a weight loss intervention on LTB4 in subjects with the MetS. After baseline measurements, 40 men and women with the MetS were matched for age and gender, and randomly assigned into one of two groups: weight reduction or weight maintenance. Subjects in the weight reduction group received diet counseling every 2 wk and participated in a 12-wk calorie restriction program (~2000–6500 kJ/d, depending on baseline caloric intake and designed to reduce weight by ~5 kg), followed by 4-wk weight stabilization. The weight maintenance group was asked to maintain their weight unchanged throughout the 16-wk period. They visited the research unit at 8 and 16 wk to have their weight measured by the research nurse. As an incentive to remain in the study, the weight maintenance group was offered individual weight loss programs run by the dietitian at the completion of the study. All subjects were instructed not to change their level of physical activity or alcohol consumption during the study. All subjects completed a questionnaire at baseline, and 12 and 16 wk, relating to their level of physical activity and alcohol consumption. At baseline and 16 wk, all subjects had BP monitored for 24 h, and a fasting blood sample was collected.

Preparation of human neutrophils. Neutrophils were prepared to more than 90% purity, using modified methods of Boyum (24). Briefly, neutrophils were isolated from venous blood collected into citrated tubes using Ficoll-Paque (Amersham Biosciences, Piscataway, NJ) density centrifugation, followed by dextran sedimentation and removal of contaminant erythrocytes by hypotonic lysis. Neutrophils were identified, counted, and suspended in Hank’s Balanced Salt Solution (Life Technologies, Inc.-Invitrogen Corp., Carlsbad, CA) containing 1 mM Ca2+, 0.8 mM Mg2+, and 0.1% BSA (4–10 ml; 4.5 x 106cells/ml).

Stimulation of neutrophils and measurement of leukotrienes. Suspensions of neutrophils were preincubated for 5 min at 37 C, then stimulated with calcium ionophore A23187 (final concentration 2.5 µg/ml; Sigma-Aldrich Co., St. Louis, MO), and incubated for an additional 10 min. The samples were centrifuged immediately, and the supernatants were stored at –80 C until extraction and assay of leukotrienes by reverse-phase HPLC as previously described (25). The method allows the simultaneous measurement of LTB4 and its metabolites (20-OH-LTB4 and 20-COOH-LTB4) using prostaglandin B2 as an internal standard.

Peaks corresponding to LTB4, 20-OH-LTB4, and 20-COOH-LTB4 were identified using authentic standards purchased from Cayman Chemical Co. (Ann Arbor, MI). UV spectral analysis at 270 nm was used to quantitate the peak area ratio of LTB4 and its metabolites to the internal standard prostaglandin B2. Leukotrienes released by the neutrophils were quantified using standard curves, prepared on the day of analysis, and subjected to the same extraction conditions as the samples.

Enzyme immunoassay (EIA) of plasma LTB4. Plasma LTB4 was measured with the experimental protocols provided by the manufacturer of the EIA kit (Cayman). Plasma samples were collected in the EDTA tubes and stored at –80 C immediately after collection. All samples underwent purification before EIA. A total of 10,000 dpm 3H-LTB4 (PerkinElmer, Inc., Wellesley, MA) was added as an internal standard to obtain the recovery factor. For radiolabeled product profiles, 10% of the eluate was counted in 4.0 ml Hisafe scintillation fluid (PerkinElmer), and the mixture was sent to Department of Medical Physics at Royal Perth Hospital for scintillation counting.

Other biochemical measurements. Fasting glucose, triglycerides, cholesterol, HDL-cholesterol, and high-sensitivity CRP (Hs-CRP) were analyzed in the Department of Biochemistry at Royal Perth Hospital, Western Australia.

Statistical analysis

Statistical analysis was performed with the Statistical Package for the Social Sciences (version 11.5; SPSS, Inc., Chicago, IL). Results are presented as mean ± SEM. Univariate ANOVA was used to determine differences between the groups; a P value less than 0.05 was considered statistically significant. Between-group differences after the weight loss intervention were determined using univariate ANOVA with adjustment for baseline values. Between-group differences in 24-h ambulatory BP were determined using a mixed model in SAS (SAS Institute Inc., Cary, NC).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Comparison of LTB4 in subjects with the MetS and controls

The two groups of subjects were well matched with respect to age and gender (Table 1Go). The men and women with the MetS had larger waist circumferences and were more overweight than controls. They had significantly higher BP, triglycerides, total cholesterol, glucose, and Hs-CRP levels, whereas HDL-cholesterol was significantly lower (Table 1Go). Subjects with the MetS had significantly higher neutrophil counts. Using the National Cholesterol Education Program Adult Treatment Panel III criteria, 86.7% of subjects in the control group had no features of the MetS, and 13.3% had one feature of the MetS. In the MetS group, 60% of subjects had two features of the MetS, whereas 40% had three or more (Table 1Go).


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  		TABLE 1. Characteristics of subjects with MetS and controls

 
In the MetS group, stimulated LTB4 levels (8.22 ± 1.3 ng/106cells) and the levels of the metabolite 20-OH-LTB4 (5.58 ± 0.56 ng/106cells) were significantly lower compared with controls (13.1 ± 1.17 and 9.42 ± 0.89 ng/106cells), respectively. There was no statistical difference between the levels of 20-COOH-LTB4 in the two groups. When the production of LTB4 and 20-OH-LTB4 was adjusted for differences in neutrophil count, the group with MetS was still significantly reduced compared with controls (Fig. 1Go). In contrast, plasma LTB4 levels tended to be higher in the MetS group, 100.2 ± 9.3 pg/ml compared with 84.6 ± 9.9 pg/ml in controls, but did not achieve statistical significance. Hs-CRP, a marker of inflammation, was significantly elevated in the MetS group (Table 1Go).


Figure 1
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  		FIG. 1. Between-group comparison of total production of LTB4 and its metabolites in the subjects with features of the MetS (closed bars) and controls (open bars). Values are mean ± SEM. *, P < 0.05.

 
The effect of a weight loss intervention on LTB4 in subjects with features of the MetS

A total of 42 subjects was randomized to the intervention, and 37 completed the study. Two subjects in the weight maintenance group withdrew after randomization because they wanted to commence a weight loss program immediately; another subject from this group withdrew during the study for the same reason. Two subjects withdrew from the weight reduction program because of time commitments. The two groups of subjects were well matched for age and gender at baseline. At baseline, waist circumference, body mass index (BMI), BP, triglycerides, total and HDL-cholesterol, and neutrophil count were similar in the two groups (Table 2Go). Energy intake in the two groups was similar at baseline. The number of components of the MetS present in each group was not different.


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  		TABLE 2. Baseline group characteristics of men and women with features of the MetS who participated in the weight loss intervention

 
After adjustment for baseline values, the weight loss intervention resulted in a significant decrease in weight relative to controls of 4.6 kg and 6.6 cm in waist circumference (Fig. 2Go). The decrease in weight reflected a significant decrease in total energy intake estimated from 3-d diet records in the weight reduction group after 12-wk caloric restriction (Fig. 3Go). Self-reported levels of physical activity did not change in either group throughout the study. There were no significant differences between the groups in plasma glucose, insulin, triglycerides, cholesterol, or HDL-cholesterol after the intervention (Table 3Go). Twenty-four hour ambulatory BP decreased by 2.2 ± 0.74 mm Hg systolic (P = 0.0025) and 1.3 ± 0.61 mm Hg diastolic (P = 0.038). LTB4 and 20-OH-LTB4 were significantly elevated compared with controls after the weight loss intervention, but 20-COOH-LTB4 was not different (Fig. 4Go). These findings were independent of neutrophil count in the two groups. There were no significant between-group differences in plasma LTB4 or Hs-CRP at the end of the intervention (Table 3Go).


Figure 2
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  		FIG. 2. Changes in waist circumference and weight from baseline to the end of intervention in the weight maintenance (open bars) and weight reduction group (closed bars). Values are presented as mean ± SEM. Group differences were assessed using a general linear model ({dagger}, P < 0.01), after adjusting for baseline values.

 

Figure 3
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  		FIG. 3. Total energy intake during the 12-wk intervention and weight stabilization period in the weight maintenance group (open squares) and weight reduction group (closed squares). *, Significant difference between the two groups (P < 0.05).

 

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  		TABLE 3. Baseline and postintervention levels of triglycerides, total, HDL, and low-density lipoprotein (LDL) cholesterol, glucose, insulin, and Hs-CRP for the 37 subjects who completed the trial

 

Figure 4
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  		FIG. 4. Changes in the total production of LTB4 and its metabolites 20-OH-LTB4 and 20-COOH-LTB4 from baseline to the end of intervention in the weight maintenance group (open bars) and weight reduction group (closed bars). Values are mean ± SEM. Between-group differences were assessed using a general linear model ({dagger}, P < 0.01), after adjusting for baseline values.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We have shown that compared with controls, overweight subjects with features of the MetS have impaired ex vivo LTB4 production and that in a controlled weight loss intervention, ex vivo LTB4 production in subjects with the MetS is restored after weight loss.

The impaired production of LTB4 in the MetS was not due to increased metabolism of LTB4 because the major metabolite of LTB4, 20-OH-LTB4, was also reduced compared with controls. The reduced production of LTB4 occurred against a background of relative neutrophilia associated with the MetS. However, LTB4 production was still reduced compared with controls after accounting for differences in neutrophil numbers. LTB4 levels are regulated by enzymatic breakdown by cytochrome P4F3A and a negative feedback mechanism that relies on the interaction of released LTB4 with its receptor BLT1 (26). Plasma LTB4 levels were not found to be different in subjects with the MetS, suggesting that prior in vivo release of LTB4 was unlikely. Although the receptor regulation of LTB4 is very important in vivo, the use of calcium ionophore in our ex vivo studies largely bypasses the receptor events, suggesting that the defect in LTB4 production is possibly due to an inability to mobilize effectively calcium in neutrophils from subjects with the MetS.

The elevation in neutrophil counts in subjects with the MetS is important in view of the fact that elevated white cell counts and neutrophilia are risk factors for long-term ischemic cardiovascular disease (27). Our findings confirm previous reports of elevated leukocyte counts in subjects who are overweight (28), hypertensive (29, 30), or with type 2 diabetes (31) or the MetS (32). Although abnormal LTB4 production has not to our knowledge been previously described in the MetS, there are a small number of studies examining LTB4 synthesis in type 1 and 2 diabetes (33, 34, 35). They have generally reported decreased LTB4 production, but the effects of specific agonists on release of LTB4 vary (33, 34). A defect in neutrophil calcium signaling has been reported in subjects with type 2 diabetes (36) and is consistent with impaired neutrophil function in these subjects. Previous reports of alterations in neutrophil function in diabetic patients include abnormalities in adhesion and migration to inflammatory sites, bactericidal activity, chemotactic responses, phagocytosis, and production of reactive oxygen species (37, 38). Such abnormalities may contribute to the high incidence of infections in some diabetic patients. The impaired neutrophil LTB4 production we observed occurred against a background of relative neutrophilia. It is possible that neutrophilia in subjects with the MetS is a homeostatic response to impaired neutrophil function. The factors that initiate this increased neutrophil production are not known. Interestingly, however, there is some evidence that the adipokine leptin can influence myeloid differentiation into granulocytes in animals and humans (39, 40). This may be relevant to the relative neutrophilia in overweight subjects with the MetS. Although our findings of lower stimulated neutrophil LTB4 in subjects with the MetS are consistent with previous studies in diabetic subjects, they contrast with those studies that suggest that increased neutrophil LTB4 may confer a risk for the development of atherosclerosis. More studies will be required to clarify how our findings relate to the risk for atherosclerosis in subjects with the MetS.

The implementation of calorie restriction alone led to a modest decrease in weight and 24-h ambulatory BP. There was a significant increase in neutrophil LTB4 and the metabolite 20-OH-LTB4 after weight loss. The increase in neutrophil LTB4 was again independent of neutrophil counts. This supports the hypothesis that neutrophil function can be affected by body fat and suggests that even a modest weight loss can help restore neutrophil function.

The improvement in neutrophil function occurred without significant changes in lipids, glucose, or insulin, suggesting that these factors had little influence on neutrophil function. Similarly, we did not observe any significant alterations in plasma LTB4 or Hs-CRP, which has been reported to improve after weight loss (41, 42, 43). Although previous studies have shown that weight reduction can reduce leukocyte count (44), this was not observed in our study. The lack of differences in Hs-CRP and leukocyte count after weight loss in our study may possibly due to differences in the study design, the relatively modest amount of weight lost, and the shorter duration of our study.

In conclusion, we have shown that neutrophil LTB4 levels are reduced in subjects with the MetS and, importantly, that LTB4 levels can be restored after modest weight reduction in subjects with the MetS. These changes occurred after modest weight loss and without significant alteration to other markers of inflammation such as Hs-CRP, suggesting that neutrophil LTB4 may be particularly sensitive to changes in body fat. These findings have important implications in terms of mounting an appropriate immune response to infection in subjects with the MetS.


   Footnotes
 
This study was funded by a grant from the National Heart Foundation of Australia.

Disclosure Statement: The authors have nothing to disclose.

First Published Online October 9, 2007

Abbreviations: BMI, Body mass index; BP, blood pressure; 20-COOH-LTB4, 20-carboxyl-leukotriene B4; CRP, C-reactive protein; EIA, enzyme immunoassay; HDL, high-density lipoprotein; 20-OH-LTB4, 20-hydroxy-leukotriene B4; Hs-CRP, high-sensitivity CRP; LTB4, leukotriene B4; MetS, metabolic syndrome; PMN, polymorphonuclear neutrophil; SBP, systolic BP.

Received June 26, 2007.

Accepted September 27, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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