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Keywords:

  • inflammation;
  • postprandial;
  • insulin resistance;
  • visceral obesity

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Objective: Abdominal obesity is associated with a fasting proinflammatory condition. However, not much is known of the potential variations in circulating inflammatory markers after food intake. The purpose of the present study was to examine postprandial changes in plasma tumor necrosis factor (TNF)-α, interleukin (IL)-6, and C-reactive protein (CRP) concentrations in men and their potential associations with fat distribution and metabolic profile variables.

Research Methods and Procedures: Thirty-eight men were given a high-fat meal in the morning after an overnight fast, and TNF-α, IL-6, and CRP levels were measured in plasma at 0, 4, and 8 hours after the meal. Physical and metabolic profiles were also assessed for each participant.

Results: We observed a substantial increase in circulating IL-6 levels (p < 0.0001) after the meal. Although postprandial variations in circulating TNF-α levels across time failed to reach statistical significance (p = 0.02), we noted a significant decrease in plasma TNF-α concentrations 4 hours (−10%, p < 0.001 vs. 0 hours) after food intake. Plasma CRP levels were not affected by the fat load. We also noted that insulin-sensitive individuals displayed a less pronounced inflammatory response after food intake than insulin-resistant subjects.

Discussion: Results of the present study show that consumption of a high-fat meal leads to an increase in plasma IL-6 concentrations and transient decrease in circulating TNF-α levels in overweight men. Our results suggest a possible role of insulin resistance in the modulation of the postprandial inflammatory response, which could, in turn, contribute to worsen the state of insulin resistance.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Visceral adipose tissue (AT)1 accumulation has been associated with a cluster of metabolic alterations known to increase the risk of cardiovascular disease (1). For example, viscerally obese patients are characterized by fasting hypertriglyceridemia, elevated apolipoprotein (apo) B concentrations, and reduced high-density lipoprotein cholesterol levels (1). We (2) and others (3, 4, 5) have previously reported that visceral obesity was associated with postprandial hyperlipidemia. On the other hand, AT is known to produce and secrete inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 (6, 7), and the role of macrophages present within AT in this production has been recently underlined (8). Among the metabolic effects related to TNF-α and IL-6, suppression of lipoprotein lipase activity (9) and stimulation of very-low-density lipoprotein synthesis (10) have been noted. IL-6 has also been shown to promote synthesis of C-reactive protein (CRP) (11), an observation that is concordant with the high CRP levels and state of chronic inflammation often reported among abdominally obese individuals (12, 13). Furthermore, the detrimental effects of chronic inflammation on atherosclerosis and insulin resistance have been mainly attributed to two proinflammatory cytokines, namely IL-6 and TNF-α (14).

Although there is evidence linking abdominal obesity to increased TNF-α, IL-6, and CRP levels in the fasting state, few reports have examined changes in plasma cytokine levels after the consumption of a high-fat meal. Increased postprandial TNF-α and IL-6 levels have been reported in healthy subjects (15), which could be partly explained by the elevation of the number of monocytes expressing TNF-α within AT after a fat meal (16). Furthermore, rises in plasma CRP (17) and abdominal subcutaneous fat interstitial IL-6 concentrations (18) have been noted after food intake. However, none of these previous studies have reported the potential correlations among the above cytokines with adiposity indices and metabolic variables in the postprandial state. Thus, the aim of the present study was to measure postprandial variations in circulating TNF-α, IL-6, and CRP levels and to examine their relationships with adiposity and metabolic profile variables in abdominally obese men.

Research Methods and Procedures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Subjects

Thirty-eight men, 19 to 62 years old (mean age ± standard deviation, 44 ± 10 years) were recruited from the Quebec City metropolitan area by solicitation through the media to take part in a study on the characterization of the postprandial metabolic response to a fat-rich meal in abdominal obesity (2, 19, 20). Participants were selected to cover a wide range of adiposity values (BMI, 20.2–41.0 kg/m2) and gave their written consent to participate in the study, which was approved by the Medical Ethics Committee of Laval University. All subjects were asymptomatic, nonsmoking volunteers and were not under treatment for coronary heart disease, diabetes, dyslipidemias, or endocrine disorders. Apo E genotype was not assessed in subjects included in the study.

Anthropometric and Body Composition Measurements

Body weight, height (21), and waist circumference (22) were measured following standardized procedures. Abdominal AT accumulation was assessed by computed tomography, which was performed on a Siemens Somatom DRH scanner (Erlangen, Germany) using previously described procedures (23).

Oral Lipid Tolerance Test

Each participant was given a test meal containing 60 g fat/m2 body surface area as previously described (2). Briefly, the meal consisted of eggs, cheese, toast, peanut butter, peaches, whipped cream, and milk. Energy content of the meal was 64% fat, 18% carbohydrates, and 18% protein, and ranged from 1800 to 2200 kcal depending on body surface area. The test meal was well tolerated by all subjects. After the meal, subjects were not allowed to eat for the next 8 hours but were given free access to water. After a 12-hour overnight fast, an intravenous catheter was inserted into the subject's forearm vein for blood sampling before meal ingestion, and blood samples were drawn before the meal and again at 4 and 8 hours after the meal.

Fasting and Postprandial Plasma Lipoprotein Concentrations

Plasma was separated immediately after blood collection by centrifugation at 3000 rpm for 10 minutes at 4°C. Triglyceride (TG) and cholesterol concentrations in total plasma were determined enzymatically on a Technicon RA-500 (Bayer Corporation Inc., Tarrytown, NY) as previously described (24). Each plasma sample (4 mL) was then subjected to a 12-hour ultracentrifugation (50,000 rpm) in a Beckman 50.3 Ti rotor (Beckman, Palo Alto, CA) at 4°C in a 6-mL Beckman Quickseal tube, which yielded two fractions: the top fraction, containing TRL [(TG-rich lipoprotein), total TRLs; density (d) < 1.006 g/mL], and the bottom fraction (d > 1.006 g/mL), containing TG-poor lipoproteins. High-density lipoprotein particles were isolated from the bottom fraction (d > 1.006 g/mL) after precipitation of apo B-containing lipoproteins with heparin and MnCl2 (25). Fasting total apo B concentration was measured in plasma by the rocket immunoelectrophoretic method of Laurell (26). The lyophilized serum standard for apo B measurement was prepared in our laboratory and calibrated with reference standards obtained from the Centers for Disease Control and Prevention (Atlanta, GA). All lipoprotein isolation procedures were completed within 2 to 3 days of the fat load.

Insulin and Glucose Concentrations

Fasting and postprandial plasma glucose was measured enzymatically (27), whereas plasma insulin was measured by radioimmunoassay with polyethylene glycol separation (28). The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated according to the equation of Matthews et al. (29).

Determination of CRP, IL-6, and TNF-α Concentrations

Circulating CRP, IL-6, and TNF-α levels were measured in frozen (−80°C) plasma samples of fasting (0 hours) and postprandial (4 and 8 hours) conditions. Concentrations of CRP levels were measured with a highly sensitive immunoassay that used a monoclonal antibody coated with polystyrene particles; the assay was performed with a BN-ProSpec nephelometer (Dade Behring, Mississauga, Ontario, Canada) according to the methods described by the manufacturer (30). The run-to-run coefficient of variation at CRP concentrations ranging from 1.0 to 10 μg/mL was <5%. Plasma IL-6 and TNF-α were quantified by commercially available high-sensitivity enzyme-linked immunosorbent assay kits (R&D Systems Inc., Minneapolis, MN), according to the manufacturer's instructions. The minimum detectable concentrations by these methods were estimated to be 0.039 pg/mL for IL-6 and 0.12 pg/mL for TNF-α.

Statistical Analyses

Data are expressed as means ± standard deviation unless indicated otherwise. Area under the curve of different metabolic variables were determined by the trapezoid method. Significance of changes in plasma variables during the postprandial period was tested by ANOVA for repeated measures, whereas difference between individuals’ postprandial time-points was tested with paired Student's t tests. For some analyses, subjects were divided according to the 50th percentile of the HOMA-IR into insulin-sensitive (<2.27, n = 19) vs. -resistant (>2.27, n = 19) individuals. Spearman correlation coefficients were computed to quantify relationships among variables. We used p < 0.01 for significance of correlations and differences to decrease the possibility of false positives (type I error) and because the Bonferroni correction (p value of 0.05/n tests) would have been overly conservative. All statistical procedures were performed with the SAS statistical package (version 8.2; SAS Institute, Cary, NC).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Subjects’ physical and metabolic variables are presented in Table 1. As a group, subjects were overweight (BMI > 25 kg/m2) (31) and characterized by a high visceral AT accumulation with a mean value above the proposed cut-off point of 130 cm2 (32), which has been reported to be associated with an increased likelihood of finding the peculiar metabolic disturbances of visceral obesity. Accordingly, subjects had mildly elevated TG (>1.7 mM) and low high-density lipoprotein cholesterol levels (<1.04 mM), which are used as markers for the presence of the metabolic syndrome (33).

Table 1.  Physical characteristics and fasting metabolic profile of the sample of 38 men
VariablesMeans ± SD25th to 75th Percentiles
  • SD, standard deviation; AT, adipose tissue; HDL, high density lipoprotein; TG, triglyceride; Apo, apolipoprotein, TNF, tumor necrosis factor; IL, interleukin; CRP, C-reactive protein.

  • *

    Median values.

Age (years)44 ± 10(40 to 49)
BMI (kg/m2)29.1 ± 4.1(26.7 to 31.5)
Waist circumference (cm)98.1 ± 10.1(91.3 to 105.0)
Waist-to-hip ratio0.95 ± 0.06(0.90 to 0.98)
Visceral AT (cm2)148 ± 64(104 to 174)
Subcutaneous AT (cm2)286 ± 106(193 to 384)
Cholesterol (mM)5.18 ± 0.82(4.60 to 5.68)
Low-density lipoprotein-cholesterol (mM)3.50 ± 0.71(2.95 to 3.90)
HDL-cholesterol (mM)0.99 ± 0.18(0.88 to 1.10)
Cholesterol/HDL cholesterol5.39 ± 1.35(4.30 to 6.55)
TGs (mM)1.89 ± 1.01(1.21 to 2.15)
Apo B (g/L)1.09 ± 0.22(0.88 to 1.27)
Insulin (pM)97.5 ± 56.3(63 to 118)
Glucose (mM)4.99±.53(4.65 to 5.33)
TNF-α (pg/mL)*1.73(1.34 to 2.13)
IL-6 (pg/mL)*1.94(1.43 to 2.97)
CRP (mg/L)*1.27(0.48 to 2.73)

Table 2 shows postprandial changes in different metabolic variables. As expected, there were significant increases in plasma TG (p < 0.0001), glucose (p < 0.0001), and insulin (p < 0.0001) concentrations after the meal. We also noted a significant step-wise increase (p < 0.0001) in circulating IL-6 levels after the fat meal. On the other hand, a slight yet significant reduction in postprandial plasma TNF-α levels (p < 0.01) was observed that was mostly explained by a significant decrease at 4 hours (p < 0.0005 vs. 0 hours) after meal ingestion. Plasma TNF-α concentrations slightly increased back toward fasting values at 8 hours (p = 0.1102 vs. 0 hours). No variation was noted in mean plasma CRP concentrations after consumption of the test meal (Table 2).

Table 2.  Postprandial changes in plasma TGs, insulin, glucose, and inflammatory cytokines in the 38 men
 Time after fat meal 
Variables0 hours2 hours4 hours6 hours8 hoursTime effect
  • TG, triglyceride; IL, interleukin; TNF, tumor necrosis factor; CRP, C-reactive protein.

  • *

    Significantly different from 0 hours, p < 0.01.

  • Significantly different from 2 hours, p < 0.01.

  • Significantly different from 4 hours, p < 0.01.

  • §

    Significantly different from 6 hours, p < 0.01.

TGs (mM)1.89 ± 1.013.36 ± 1.61*4.69 ± 2.74*4.93 ± 3.11*4.02 ± 2.94*0.0001
Insulin (pM)97.5 ± 56.3428.3 ± 327.1*348.2 ± 276.7*199.3 ± 129.7*137.6 ± 87.7*§0.0001
Glucose (mM)4.99 ± 0.535.34 ± 0.61*5.58 ± 0.54*5.30 ± 0.53*5.11 ± 0.410.0001
IL-6 (pg/mL)2.42 ± 1.37 2.85 ± 1.68 4.34 ± 2.24*0.0001
TNF-α (pg/mL)1.74 ± 0.51 1.56 ± 0.52* 1.63 ± 0.590.02
CRP (mg/L)2.08 ± 2.31 2.05 ± 2.03 1.92 ± 2.030.3

We also examined univariate associations between postprandial changes in plasma inflammatory cytokine levels and those of plasma glucose and insulin concentrations. There was no correlation between postprandial circulating glucose level variations and plasma TNF-α, IL-6, or CRP concentrations before or after the meal. However, we noted that higher circulating TNF-α concentrations throughout the postprandial period were associated with a larger increment (increase above fasting level) in plasma insulin levels after the meal (Figure 1).

image

Figure 1. Univariate association between postprandial plasma TNF-α concentrations and the increase in plasma insulin levels after the meal in the sample of 38 men.

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To further investigate the relationships between postprandial inflammatory marker and insulin levels, we compared changes in plasma TNF-α, IL-6, and CRP concentrations after the fat meal in men separated on the basis of the HOMA-IR, an index of insulin resistance (Figure 2). Ingestion of the fat meal did not lead to any significant variation in plasma CRP concentrations in men irrespective of their insulin resistance status. On the other hand, we found that plasma IL-6 levels significantly rose after the meal (p < 0.0001) in both subjects with a low or high HOMA-IR. We, however, also noted that in men with a low HOMA-IR, plasma IL-6 concentrations were significantly higher than fasting values only at 8 hours, whereas in those in men with a high HOMA-IR, concentrations were significantly increased at 4 and 8 hours after the meal. Figure 2 also illustrates that there was significant reduction of plasma TNF-α concentrations at 4 hours after the meal in insulin-sensitive men (low HOMA-IR), which contrasts with the lack of a significant response in men with a high HOMA-IR.

image

Figure 2. Postprandial variations in TNF-α (top), IL-6 (middle), and CRP (bottom) in men separated on the HOMA-IR (50th percentile, 2.36) into men with low (white bars, n = 19) vs. high (black bars, n = 19) insulin resistance. (1) Significantly different from 0 hours. (2) Significantly different from 4 hours. p Value above bars is for time effect.

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Finally, to further investigate the relationship between postprandial TNF-α variations and insulin sensitivity, we compared plasma glucose and insulin levels in individuals separated on the basis of the HOMA-IR index (low vs. high according to the 50th percentile, Figure 3) but showing either a negative or positive plasma TNF-α response after the test meal. As expected, irrespective of their postprandial TNF-α response, insulin-resistant men displayed a postprandial hyperinsulinemic response compared with insulin-sensitive men. However, plasma insulin concentrations peaked at 2 hours after the test meal in insulin-resistant men with a negative postprandial TNF-α response, whereas the highest insulin levels were noted 4 hours after the meal in men with a high HOMA-IR but displaying a positive postprandial TNF-α response.

image

Figure 3. HOMA-IR (A), postprandial plasma TNF-α (B), insulin (C), and glucose (D) concentrations in insulin-sensitive men (HOMA-IR < 50th percentile; white circles, n = 19) and in insulin-resistant individuals (HOMA-IR > 50th percentile) displaying either a decrease (white squares, n = 12) or increase (black squares, n = 7) in plasma TNF-α levels after the high-fat meal. (1) Significantly different from insulin-sensitive men. (2) Significantly different from insulin-resistant men with a negative TNF-α postprandial response.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Results of the present study suggest that the consumption of a high-fat meal, sufficient to cause postprandial hypertriglyceridemia as previously shown (2), is associated with a significant increase in plasma IL-6 and transient decrease in TNF-α concentrations but had no effect on circulating CRP levels in overweight men. Our findings are concordant with previous results showing that the consumption of a fat-rich meal was associated with an increase in AT interstitial fluid IL-6 levels, whereas TNF-α concentrations remained practically unchanged (18). Similar findings to those we present in this paper were also reported for plasma TNF-α and IL-6 concentrations in trained and untrained men (34). However, significant increases in both plasma TNF-α and IL-6 levels were noted in normal and type 2 diabetes patients (15), who share metabolic characteristics with abdominally obese individuals, although TNF-α concentrations were practically returned to fasting values 4 hours after the meal (15). The discrepancies between the TNF-α data from this previous study and ours could be explained by the timing of blood sampling, which may have prevented us from noting an early increase in plasma TNF-α concentrations after the fat load. Recent observations suggest that the increase in postprandial plasma TNF-α levels may be resulting from a higher percentage of TNF-α producing monocytes in circulation after a fat meal, although the impact of such a change on circulating TNF-α levels was not investigated (16). Unfortunately, these measures were not performed in our study. Furthermore, differences in population under study and composition of the meal given to the subjects could also partly explain the apparent contradictions between these previous studies and results presented herein.

There are numerous interactions between inflammatory cytokines and lipoprotein metabolism. For instance, the inflammatory response of endothelial cells and macrophages has been shown to be induced by the presence of TRLs (35, 36). Furthermore, the proinflammatory condition that prevails during the postprandial period has been recently associated with a TG-specific activation of monocytes and neutrophils (37). These observations are concordant with the association that has been reported between the postprandial areas under the curve of IL-6 and remnant-like lipoprotein cholesterol concentrations in men with adult-onset growth hormone deficiency (38). However, this association was not seen in normal subjects. The role of IL-6 in postprandial TRL metabolism is not supported by our data because we found no relationship between the postprandial plasma IL-6 and TG responses. Although our results do not support a major effect of postprandial hypertriglyceridemia on the proinflammatory condition of abdominally obese men, the postprandial rise in plasma IL-6 levels could reflect the possible dissociation between fat ingestion and TG metabolism on postprandial inflammation as previously suggested (34). Furthermore, the role of endothelial cell damage after the consumption of a high-fat meal (39) in the postprandial inflammatory response will also be needed to be further investigated.

There is increasing evidence that postprandial changes in plasma glucose could be associated more closely with circulating inflammatory cytokine concentrations (40). Our results are, in appearance, in contrast, with these previous observations because we found no association between fasting or postprandial plasma glucose concentrations and changes in either TNF-α or IL-6 levels after the meal. However, it must be pointed out that mean postprandial glucose concentrations in the present study (∼5.5 mM) did not reach the levels (∼10.0 mM) that were previously found to lead to increases in circulating IL-6, IL-18, and TNF-α in both healthy and glucose-intolerant individuals (40). Studies should, however, be undertaken to further investigate the role of mild and severe hyperglycemia in the regulation of plasma inflammatory cytokines within the abdominally obese population.

We also found significant differences in the pattern of response of TNF-α and IL-6 in response to the fat load, with insulin-resistant individuals displaying a greater inflammatory response during the postprandial period compared with more insulin-sensitive subjects. Indeed, the increase in plasma IL-6 levels after the high-fat meal was found to be delayed in insulin-sensitive individuals (low HOMA-IR) compared with subjects with a higher index of insulin resistance in which plasma IL-6 rose steadily from fasting to 4 and 8 hours after the meal. Furthermore, in men with a low HOMA-IR, plasma TNF-α concentrations were significantly lower than fasting values at 4 hours after the meal, whereas circulating TNF-α levels were not statistically different from fasting values throughout the entire postprandial period in men with a high HOMA-IR. These latter observations are concordant with results reported in diet-controlled type 2 diabetes individuals showing a significant reduction in plasma TNF-α concentrations after consumption of a high-fat meal (41). Although the hypothesis will need to be further examined, it has been suggested that a decrease in plasma TNF-α could minimize the interference of this proinflammatory cytokine with insulin signaling at a time when the maximal sensitivity of tissues to insulin is important for the uptake of glucose and TG by the cells (41). Some of our own results tend to support this hypothesis because within insulin-resistant individuals, those displaying a significant postprandial decrease in TNF-α concentrations after the high-fat meal seem to have a less pronounced postprandial plasma insulin response compared with those with a similar level of insulin resistance but who showed an increase in circulating TNF-α concentrations after consumption of the high-fat meal.

We are aware of the speculative level of our study but feel that the exploratory nature of association studies such as the present one requires that some speculations be made to explain our observations on the postprandial variations in plasma inflammatory cytokine levels. Further studies will certainly need to be conducted to investigate the role of postprandial inflammation in insulin resistance. For instance, nutritional interventions aimed at reducing the acute inflammatory response to a meal in abdominally obese, insulin-resistant individuals seem to be relevant in this endeavor.

In summary, our results support the previously reported changes in plasma IL-6 concentrations noted after a fat challenge and extend these observations to the abdominally obese population. In addition, results from our study also suggest that in insulin-resistant individuals, high circulating postprandial TNF-α levels seem to be associated with a greater insulinemic response to the meal. Because our study is mostly descriptive, additional studies are clearly needed to better understand the relationships between postprandial variations in circulating inflammatory cytokines and glucose-insulin homeostasis and their respective role, if any, in the risk of developing cardiovascular disease.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

This work was supported by the Canadian Institutes of Health Research (Grant MOP-14014), by the Quebec Heart and Stroke Foundation, and by the Canadian Society of Atherosclerosis, Thrombosis, and Vascular Biology. P.B. is the recipient of a studentship from the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada. B.L. holds a Canada Research Chair in Nutrition, Functional Foods, and Cardiovascular Health. A.T. holds a Canada Research Chair in Physical Activity, Nutrition, and Energy Metabolism. J.B. and C.C. are research scholars from the Fonds de la Recherche en Santé du Québec. C.C. is also supported by the Chair in Human Nutrition, Lipidology, and Cardiovascular Disease funded by Pfizer Canada, Montreal, Quebec, Canada and Provigo, Montreal, Quebec, Canada. We thank the staff of the Physical Activity Sciences Laboratory for the data collection and the staff of the Lipid Research Center for excellent and dedicated work. Finally, we acknowledge the contribution of the men who participated in this project without whom no clinical studies would be possible.

Footnotes
  • 1

    Nonstandard abbreviations: AT, adipose tissue; apo, apolipoprotein; TNF, tumor necrosis factor; IL, interleukin; CRP, C-reactive protein; TG, triglyceride; TRL, TG-rich lipoprotein; HOMA-IR, homeostasis model assessment of insulin resistance.

  • The costs of publication of this article were defrayed, in part, by the payment of page charges. This article must, therefore, be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
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