Visceral and Truncal Subcutaneous Adipose Tissue Are Associated ...

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The Journal of Clinical Endocrinology & Metabolism 91(12):5100 –5106 Copyright © 2006 by The Endocrine Society doi: 10.1210/jc.2006-1103

Visceral and Truncal Subcutaneous Adipose Tissue Are Associated with Impaired Capillary Recruitment in Healthy Individuals Renate T. de Jongh, Richard G. Ijzerman, Erik H. Serne´, Jasper J. Voordouw, John S. Yudkin, Henriette A. Delemarre-van de Waal, Coen D. A. Stehouwer, and Mirjam M. van Weissenbruch Department of Internal Medicine, the Institute for Cardiovascular Research-Vrije Universiteit (R.T.d.J., R.G.I., E.H.S., J.J.V., C.D.A.S.), the Department of Paediatrics (R.G.I., J.J.V., H.A.D.-v.d.W., M.M.v.W.), VU University Medical Center, 1007 MB Amsterdam, The Netherlands; Department of Internal Medicine and the Cardiovascular Research Institute Maastricht (C.D.A.S.), University Hospital Maastricht, 6202 AZ Maastricht, The Netherlands; and Department of Medicine (J.S.Y.), University College London, London N19 5LW, United Kingdom Context: Central adiposity is associated with cardiovascular risk independently of total adiposity. Microvascular dysfunction is thought to contribute to obesity-associated insulin resistance and hypertension and may thus link central adiposity with cardiovascular risk. Objective: Our objective was to investigate how body fat distribution relates to microvascular function and the role of adipocytokines in these relationships. Design, Setting, and Participants: We cross-sectionally studied 51 healthy adults and 29 of their prepubertal children born at the VU University Medical Center in Amsterdam. Main Outcome Measures: We measured visceral and abdominal sc adiposity with magnetic resonance imaging and truncal and peripheral sc adiposity with skinfold thickness. Postocclusive skin capillary recruitment was assessed with videomicroscopy. Concentrations of C-reactive protein, IL-6, and TNF-␣ were combined in an inflammation score.

O

BESITY IS A leading cause of cardiovascular disease globally. Obesity-associated microvascular dysfunction has been proposed to play a role in relationships of obesity with cardiovascular risk factors such as insulin resistance and hypertension (1, 2). Recent studies support a pathophysiological role of microvascular dysfunction in insulin resistance by regulation of nutrient supply to muscle cells and in the development of hypertension by an increase in peripheral resistance (3, 4). This concept is supported not only cross-sectionally by relationships of microvascular dysfunction with insulin resistance, hypertension, and coronary heart disease risk as estimated by the Framingham risk score (5, 6) but also prospectively where arteriolar microvascular defects precede the occurrence of diabetes and hypertension (7, 8). Apart from and independent of overall obesity, body fat distribution determines cardiovascular disease risk. Large

First Published Online September 26, 2006 Abbreviations: BMI, Body mass index; CRP, C-reactive protein; FFA, free fatty acids; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MRI, magnetic resonance imaging; SAT, sc abdominal adipose tissue area; VAT, visceral abdominal adipose tissue area. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community.

Results: In adults, visceral adipose tissue and trunk/extremity skinfold ratio were inversely associated with capillary recruitment (partial correlation coefficients, ⫺0.32, P ⫽ 0.03, and ⫺0.37, P ⬍ 0.01, respectively). The inflammation score was inversely associated with capillary recruitment (r ⫽ ⫺0.50; P ⬍ 0.01) and statistically explained 41% of the association between visceral adipose tissue and capillary recruitment. In children, trunk/extremity skinfold ratio was inversely associated with capillary recruitment (r ⫽ ⫺0.49; P ⫽ 0.01), but other measures of adiposity were not. Conclusion: Our data in adults suggest a role for visceral adiposity and its associated proinflammatory state in capillary dysfunction and its possible sequelae such as hypertension and insulin resistance. Also, our findings in children and adults suggest that truncal sc adiposity is detrimental for capillary perfusion and that this process may start before puberty. (J Clin Endocrinol Metab 91: 5100 –5106, 2006)

epidemiological trials have shown that both visceral and truncal sc adiposity increase the risk of incident diabetes, hypertension, and coronary heart disease (9, 10). In contrast, peripheral sc adiposity has been proposed to have a protective effect against metabolic cardiovascular risk factors (9). Although previous studies have shown that obesity is characterized by microvascular dysfunction, these studies have not investigated the role of body fat distribution (1, 2). In the present study, we hypothesize that specifically visceral and/or truncal sc adiposity is related to microvascular dysfunction. Visceral adipocytes secrete so-called adipocytokines, of which many have a proinflammatory function (11). A proinflammatory state in itself increases cardiovascular risk, and several adipocytokines have been shown to contribute, either directly or indirectly, to the development of insulin resistance and hypertension (12, 13). In addition, visceral adiposity is characterized by dyslipidemia (14). Recent studies suggest that both adipocytokines and dyslipidemia have a detrimental effect on microvascular function (6, 15, 16). Therefore, we additionally examined whether adipocytokines and/or dyslipidemia explain associations between visceral adipose tissue and microvascular function. Growth and puberty may play an important role in the

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development of associations between measures of obesity and cardiovascular risk factors (17, 18). Thus, we also investigated whether associations between body fat distribution and microvascular function differ in prepubertal children as opposed to adults. Subjects and Methods Subjects This study is part of a larger project in which vascular and metabolic variables were studied in prepubertal children and their parents (16, 19). After exclusion of individuals taking vasoactive medication, having newly diagnosed diabetes mellitus, or with a history of recent vaccinations, anorexia nervosa, or rheumatoid arthritis, 51 healthy Caucasian adults and 29 prepubertal children participated (22 children with both parents, seven with one). Characteristics of participants are shown in Table 1. The study was undertaken with approval of the local ethics committee and performed in accordance with the Declaration of Helsinki. Informed consent was obtained from each participant. For the children, written informed consent was obtained from both parents and verbal informed consent was obtained from the children.

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and directly after release of the cuff were counted for, respectively, 15 and 30 sec. Postocclusive capillary recruitment was calculated as the relative increase in number of capillaries. Intrasubject coefficient of variation of capillary recruitment was 17.2 ⫾ 12.1%, as determined in seven individuals on two occasions. Endothelium-dependent and -independent vasodilation were evaluated by iontophoresis of acetylcholine and sodium nitroprusside, respectively, in combination with laser Doppler fluxmetry as previously described (5, 16). Acetylcholine (1%, Miochol; Bournonville Pharma, The Hague, The Netherlands) was delivered using an anodal current (seven doses of 0.1 mA for 20 sec with a 60-sec interval). Sodium nitroprusside (0.1%, Nipride; Roche, Mydrecht, The Netherlands) was delivered using a cathodal current (9 doses of 0.2 mA for 20 sec with a 90-sec interval). Acetylcholine- and sodium nitroprusside-dependent vasodilation was measured on the middle phalanx of the third and fourth finger, respectively. The responses were calculated as relative increase from baseline to plateau phase, which is reached during the final two iontophoretic deliveries. Intrasubject coefficients of variation of acetylcholine- and sodium nitroprusside-dependent vasodilation were 13.5 ⫾ 7.7 and 18.7 ⫾ 23.4%, respectively, as determined in seven individuals on two occasions. In the present study, iontophoresis data are lacking in one adult and one child because of technical problems.

Microvascular measurements

Anthropometric measurements

The microvascular measurements were conducted in the morning after 30 min of acclimatization in a quiet, temperature-controlled room (23.4 ⫾ 0.4 C), with the investigated, nondominant hand at heart level. All individuals had abstained from caffeine-containing drinks overnight. Nailfold and iontophoresis studies were performed on the same day by a single experienced investigator (R.G.I.). Nailfold capillaries in the dorsal skin of the third finger were visualized by a capillary microscope, as described previously (5, 16). Briefly, capillaries were recorded before and after 4 min of arterial occlusion with a digital cuff. Baseline capillary density was defined as the number of continuously erythrocyte-perfused capillaries. The numbers of capillaries at baseline

Anthropometric measurements were performed twice, and the mean of two measurements was used for analyses. All measurements were performed by one trained investigator (J.J.V.).Weight and height were determined barefoot and wearing underwear. Waist and hip circumference were measured with a soft plastic measure tape as the horizontal circumference at the level of the umbilicus and both great trochanters, respectively. Skinfold thickness was measured with a Harpenden skinfold caliper (Baty International, Burgess Hill, UK) at the biceps, triceps, subscapular, and suprailiac sites using standard methods (20). The ratio of subscapular and suprailiac to biceps and triceps skinfold was calculated as an estimate of the ratio between sc trunk and extremity adipose

TABLE 1. Characteristics of both study groups

n (male/female) Age (yr) BMI (kg/m2) Waist (cm) Hip (cm) WHR Subscapular skinfold (mm) Suprailiac skinfold (mm) Biceps skinfold (mm) Triceps skinfold (mm) Trunk/extremity skinfold ratio Total body fat (%) VAT (cm2) Total SAT (cm2) Deep SAT (cm2) (n ⫽ 40) Superficial SAT (cm2) (n ⫽ 40) VAT/SAT ratio Total cholesterol (mmol/liter) LDL-cholesterol (mmol/liter) HDL-cholesterol (mmol/liter) Triglycerides (mmol/liter) FFA (mmol/liter) Leptin (ng/ml) CRP (mg/liter) L-6 (pg/ml) TNF-␣ (pg/ml) General inflammatory score (SD) Capillary density in the resting state (n/mm2) Capillary recruitment during PRH (%) Acetylcholine-mediated vasodilation (%) Sodium nitroprusside-mediated vasodilation (%) Data are presented as mean ⫾

SD

Adults

Children

51 (28/23) 44.0 ⫾ 4.9 25.2 ⫾ 3.8 88.4 ⫾ 11.2 100.9 ⫾ 7.3 0.87 ⫾ 0.07 15.9 (11.8 –20.4) 15.9 (12.2–20.9) 10.9 (8.0 –14.7) 19.0 (13.1–24.6) 1.26 (0.83–1.55) 24.5 ⫾ 7.3 72 (52–105) 234 (191–281) 105 (88 –130) 126 (100 –154) 0.35 ⫾ 0.16 5.3 ⫾ 1.0 3.7 ⫾ 1.1 1.2 ⫾ 0.3 1.1 (0.7–1.7) 0.55 ⫾ 0.22 6.4 (4.0 –10.6) 0.80 (0.32–2.27) 1.4 (1.1–2.4) 1.7 (1.3–2.4) 0.00 ⫾ 0.64 45 ⫾ 12 36 ⫾ 24 427 ⫾ 294 389 ⫾ 463

29 (14/15) 8.9 ⫾ 1.3 16.5 ⫾ 2.9 58.1 ⫾ 8.3 71.0 ⫾ 7.9 0.82 ⫾ 0.04 5.9 (5.3– 8.9) 6.0 (4.8 –9.6) 6.4 (5.1–9.0) 10.2 (8.2–13.0) 0.79 (0.66 – 0.95) 20.1 ⫾ 10.1 21 (14 –26) 69 (51–122)

or as median (interquartile range). PRH, Postocclusive reactive hyperemia.

0.28 ⫾ 0.10 4.0 ⫾ 1.0 2.5 ⫾ 1.0 1.3 ⫾ 0.3 0.6 (0.5– 0.8) 0.64 ⫾ 0.25 2.8 (2.1– 6.3) 0.12 (0.09 – 0.52) 1.5 (0.9 –1.9) 3.3 (2.4 –5.5) ⫺0.01 ⫾ 0.61 38 ⫾ 7 29 ⫾ 23 310 ⫾ 257 283 ⫾ 156

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tissue. Fat-free mass was measured using a four-terminal bioimpedance analyzer (RJL Spectrum Bioelectrical Impedance, BIA 101/S Akern; RJLSystem, Detroit, MI). Fat percentage was calculated as percentage of total body weight. Magnetic resonance imaging (MRI) was used to calculate visceral adipose tissue area (VAT) and sc abdominal adipose tissue area (SAT) as described previously (21). Processing of MRI data and calculations of VAT and SAT were performed by a single experienced investigator (J.J.V.). Briefly, sagittal and coronal slices were used to localize anatomic sites for image acquisition (L4 –L5). Three transverse images (spacing, 10 mm) were obtained. Quantitation of visceral and sc fat areas was performed using an image-analyzing program, based on a seedgrowing procedure. After a seed point is placed in a fat depot on a Sparc10 workstation (Sun Microsystems, Palo Alto, CA), this fat depot can be circumscribed by selection of a pixel intensity range. The area of the circumscribed fat depot is then calculated by converting the number of pixels to square centimeters. The average of three images was used for statistical analyses. In 40 participants, the circumferential abdominal fascia could be identified. The sc adipose tissue deeper than this fascia is referred to as deep sc abdominal adipose tissue and that superficial to the fascia as superficial sc abdominal adipose tissue.

Biochemical methods Serum total cholesterol, high-density lipoprotein (HDL)-cholesterol and triglyceride concentrations were measured using standard methods. Low-density lipoprotein (LDL)-cholesterol was calculated by the Friedewald formula, except for one person with triglycerides of 10.8 mmol/ liter. Plasma free fatty acids (FFA) concentrations were determined by an enzymatic colorimetric method (ELAN; Merck, Darmstadt, Germany). Leptin was determined by RIA (Linco Research Inc., St. Charles, MO). C-reactive protein (CRP) was measured with a highly sensitive in-house ELISA. IL-6 and TNF-␣ were measured by sandwich enzyme immunoassay (Quantikine High Sensitivity; R&D Systems, Oxon, UK). The intra- and interassay coefficients of variation of these measurements were less than 12%, as established in our laboratory.

Statistical analyses Variables are presented as mean ⫾ sd or, in the case of a nonparametric distribution, as median and interquartile range. Nonparametric distributed data were log-transformed, and the log-transformed data were used in statistical analyses. Partial correlation analyses were used to investigate associations. Multiple regression analyses were performed to examine determinants of the association between visceral adiposity and capillary recruitment. All analyses were adjusted for age and sex. A two-tailed P value of ⬍0.05 was considered significant. Statistical testing was performed on a personal computer with the statistical software package SPSS version 11.0 (SPSS, Chicago, IL) Our study of 51 adults comprised 21 couples, and measurements within couples may not be independent of each other. Consequently, all analyses were also carried out using multilevel models with adjustment for possible correlations among spouses. These analyses lead to similar conclusions as the unadjusted analyses and, therefore, are not shown separately. Interaction analyses were performed to exclude effects of gender on associations between body fat distribution and inflammatory markers. In the present study, these associations did not differ significantly between men and women (P ⬎ 0.2). Therefore, data are presented in the total study population and not in men and women separately. Concentrations of inflammatory markers were measured once in the present study, and thus these measurements may display considerable biological variability. This may lead to an underestimation of associations of separate inflammatory markers with outcome measures. To reduce this variability and to create a standardized summary measure of inflammatory status, we constructed an inflammation score with combined information on CRP, IL-6, and TNF-␣ as previously described (22). In short, for every individual, each variable was expressed as a sd score, i.e. [(value in the individual minus the mean value in the population) divided by the sd]. The composite inflammation score was the mean of the sd scores of the individual variables, i.e. (CRP ⫹ IL-6 ⫹ TNF-␣)/3.

de Jongh et al. • Fat Distribution and Capillary Function

Results Associations of skin microvascular function with adipose tissue area and anthropometric measures

In the adults, capillary recruitment was significantly associated with VAT but not total SAT (Table 2 and Fig. 1). In the subgroup (n ⫽ 40) in which the circumferential abdominal fascia on MRI was identified, capillary recruitment was not significantly associated with either deep SAT or superficial SAT (partial correlation coefficient r ⫽ ⫺0.07, P ⫽ 0.70; and r ⫽ ⫺0.22, P ⫽ 0.19, respectively). Neither VAT nor total SAT was associated with capillary density in the resting state (r ⫽ ⫺0.04, P ⫽ 0.80; and r ⫽ ⫺0.08, P ⫽ 0.59, respectively). Greater truncal skinfolds and trunk/extremity skinfold ratio were associated with less capillary recruitment (Table 2 and Fig. 1). The association between VAT and capillary recruitment did not change materially after correction for total SAT or total body fat (data not shown). The association between trunk/extremity skinfold ratio and capillary recruitment was not affected by adjustment for VAT or total body fat (data not shown). VAT, SAT, and anthropometric measures were not associated with microvascular endothelium-dependent or -independent vasodilation (data not shown). In the children, suprailiac skinfold and trunk/extremity skinfold ratio were negatively associated with capillary recruitment (r ⫽ ⫺0.47, P ⫽ 0.02; and r ⫽ ⫺0.49, P ⫽ 0.01, respectively). These associations did not decrease after adjustment for VAT or total body fat (data not shown). Other associations between microvascular function and measures of body fat distribution were not significant (P ⬎ 0.2). Interaction analyses demonstrated that all investigated associations were not significantly different between adults and children (P ⬎ 0.4). Associations of capillary recruitment and adipose tissue area with adipocytokines and lipoproteins

In the adults, higher concentrations of triglycerides, leptin, CRP, and IL-6 and higher values of the inflammation score were associated with lower capillary recruitment (Table 3). Levels of HDL-cholesterol were positively associated with capillary recruitment. Higher levels of total cholesterol and TNF-␣ tended to be associated with lower capillary recruitTABLE 2. Partial correlations between capillary recruitment, area of visceral and sc adipose tissue, and different anthropometric measures in 51 adults

VAT Total SAT VAT/SAT ratio Total body fat BMI Waist circumference Hip circumference WHR Subscapular skinfold Suprailiac skinfold Biceps skinfold Triceps skinfold T/E skinfold ratio

r

P

⫺0.32 ⫺0.17 ⫺0.19 ⫺0.16 ⫺0.47 ⫺0.37 ⫺0.26 ⫺0.33 ⫺0.43 ⫺0.38 ⫺0.19 ⫺0.13 ⫺0.37

0.03 0.24 0.18 0.27 ⬍0.01 ⬍0.01 0.07 0.02 ⬍0.01 ⬍0.01 0.20 0.39 ⬍0.01

All correlations are adjusted for age and sex. T/E, Trunk/extremity; WHR, waist-to-hip ratio.

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FIG. 1. Associations of quartiles of visceral adipose tissue area (left) and trunk/extremity skinfold ratio (right) with capillary recruitment in 51 adults. Values are means ⫾ SE. P values represent significance of partial correlation coefficients.

ment. VAT was positively associated with total cholesterol, LDL-cholesterol, triglycerides, FFA, leptin, CRP, and the inflammation score and negatively associated with HDL-cholesterol (Table 3). In the children, adipokines or lipoproteins were not significantly associated with capillary recruitment. Visceral adipose tissue area tended to be positively associated with LDL-cholesterol and leptin (r ⫽ 0.35, P ⫽ 0.08 for both associations). Contribution of adipocytokines and lipoproteins to the association between visceral adipose tissue area and capillary recruitment

In the adults, we investigated to what extent the relationship between VAT and capillary recruitment could be explained by circulating adipocytokines (Table 4). Model 1 demonstrates that VAT was related to capillary recruitment. Addition of the inflammation score to this model reduced the regression coefficient by 41% and the coefficient was no longer statistically significant (Table 4; model 2). Separate introduction of CRP, IL-6, and TNF-␣ into the model did reduce the regression coefficient by 30, 11, and 11%, respecTABLE 3. Partial correlations between capillary recruitment, area of visceral adipose tissue, lipoproteins, and adipocytokines in 51 adults Capillary recruitment

Total cholesterol LDL-cholesterol HDL-cholesterol Triglycerides FFA Leptin CRP IL-6 TNF-␣ Inflammation score

Discussion

VAT

r

P

r

P

⫺0.26 ⫺0.22 0.30 ⫺0.48 ⫺0.23 ⫺0.30 ⫺0.38 ⫺0.33 ⫺0.27 ⫺0.50

0.08 0.14 0.04 ⬍0.01 0.11 0.04 ⬍0.01 0.02 0.06 ⬍0.01

0.29 0.28 ⫺0.38 0.54 0.38 0.54 0.30 0.11 0.15 0.29

0.04 0.05 ⬍0.01 ⬍0.01 ⬍0.01 ⬍0.01 0.03 0.43 0.29 0.04

All correlations are adjusted for age and sex.

tively (analyses not shown). This suggests that inflammatory markers could, at least statistically, explain part of the relationship between VAT and capillary recruitment. To examine the hypothesis that dyslipidemia mediates the relationship between VAT and capillary recruitment, we added triglycerides and HDL-cholesterol to model 1. The regression coefficient decreased by 75% (Table 4; model 3) and 25% (␤ ⫽ ⫺15.6; 95% confidence interval ⫽ ⫺35.2 to 4.1; P ⫽ 0.12), respectively. However, VAT-associated impaired capillary recruitment may also contribute to dyslipidemia. After adjustment for capillary recruitment, the regression coefficient of the association between VAT and triglycerides decreased by 60% [from 1.6 (0.4 –2.7) (P ⬍ 0.01) to 1.1 (⫺0.02 to 2.3) (P ⫽ 0.06)], and the regression coefficient of the association between VAT and HDL-cholesterol decreased by 17% [from ⫺0.32 (⫺0.54 to ⫺0.09) (P ⬍ 0.01) to ⫺0.26 (⫺0.50 to ⫺0.03) (P ⫽ 0.03)]. Finally, the inflammation score is positively associated with triglycerides (r ⫽ 0.32; P ⫽ 0.02), and both variables may influence each other in the association between VAT and capillary recruitment. Model 4 demonstrates that if both were added to the model the association between VAT and capillary further decreased, but the contribution of both variables separately remained significant. This indicates that the role of the inflammatory score in the association between VAT and capillary recruitment is at least in part independent of triglycerides.

In the present study, we report several findings: 1) in adults, visceral adiposity as measured with MRI is inversely associated with capillary recruitment; 2) in adults and children, truncal sc adipose tissue using skinfold measurements is inversely associated with capillary recruitment; and 3) in adults, the association between visceral adiposity and capillary recruitment could, at least statistically, be partly explained by increased circulating inflammatory markers. In the present study, in adults, we extend previous findings of relationships between visceral adiposity and large artery properties unfavorable for cardiovascular risk (23, 24)

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de Jongh et al. • Fat Distribution and Capillary Function

TABLE 4. Regression analysis with capillary recruitment as dependent variable in 51 adults Model

1

␤ (95% CI)

P

R2

P model

Log visceral adipose tissue

⫺0.9 (⫺39.3 to ⫺2.5)

0.03

0.13

Log visceral adipose tissue Inflammation score

⫺12.3 (⫺29.7 to 5.2) ⫺16.2 (⫺25.7 to ⫺6.6)

0.16 ⬍0.01

0.31

⬍0.01

Log visceral adipose tissue Triglycerides

⫺5.2 (⫺25.6 to 15.1) ⫺18.3 (⫺31.1 to ⫺5.5)

0.61 ⬍0.01

0.22

0.02

Log visceral adipose tissue Inflammation score Triglycerides

⫺1.4 (⫺20.4 to 17.7) ⫺13.8 (⫺23.1 to ⫺4.3) ⫺14.3 (⫺26.5 to ⫺2.1)

0.16 ⬍0.01 0.02

0.38

⬍0.01

2 3 4

0.082

All models are adjusted for age and sex. CI, Confidence interval; R2, the proportion of variation in the dependent variable explained by the regression model.

to the capillary level. In addition, we show that truncal sc adiposity as measured by skinfolds may have adverse effects on capillary recruitment independently of total body fat. Previous studies have shown similar detrimental associations of truncal sc adipose tissue, independently of body mass index (BMI) or total body fat, on large vessel properties such as arterial stiffness (25) and on cardiovascular risk factors such as insulin resistance and dyslipidemia (26 –29). Also, truncal skinfolds independently predict the development of coronary heart disease (30, 31). Thus, our study demonstrates that not only visceral adiposity but also truncal sc adiposity may have adverse effects on capillary function. Recent experimental and prospective studies suggest a pathophysiological role for capillary recruitment in the development of insulin resistance and hypertension (3, 4, 7, 8). Therefore, defects in capillary recruitment may partly explain associations of visceral and truncal obesity with these cardiovascular risk factors. However, additional prospective studies in large populations remain necessary to establish and quantify the true contribution of capillary recruitment to obesity-associated cardiovascular risk. It should be noted that although truncal sc adiposity measured with skinfolds was inversely associated with capillary recruitment, abdominal sc adiposity as measured with MRI was not. This parallels earlier studies demonstrating strong associations of insulin sensitivity with truncal skinfolds and weaker or absent associations with sc adipose tissue as measured with MRI (26, 27). In previous studies, the variation in truncal skinfolds explained by the amount of sc adipose tissue assessed by imaging techniques varies between 16 and 85% (26, 27, 32) and is approximately 50% in the present study (analyses not shown). Moreover, the correlation between truncal site-specific MRI and skinfold measurements within subjects is poor (33). Thus, sc adipose tissue area and skin-fold measurements do not represent a reliable estimate of each other. The explanation for this discordance remains unclear. Previous findings that increased visceral obesity is associated with impaired endothelium-dependent vasodilation in large vessels (34, 35) are not paralleled by similar findings in the microvasculature in the present study. Defects in endothelium-dependent vasodilation at the precapillary level have been suggested to contribute to defects in postocclusive capillary recruitment (16). This hypothesis is not supported

by the present study, and therefore, we propose that there is a direct association between (visceral) adiposity and functional or structural characteristics of the capillary network. In the present study, inflammatory markers were associated with impaired capillary recruitment and partly determined the relationship between visceral adipose tissue and capillary recruitment. In parallel, others have shown that CRP and IL-6 largely determine the association between visceral adipose tissue and carotid stiffness (24). The mechanisms by which circulating cytokines link visceral adipose tissue with (micro)vascular function are unknown and not investigated in the present study. However, it is generally acknowledged that increased circulating inflammatory markers represent a state of low-grade inflammation that contributes to structural and functional defects in (large) vessels (36). Alternatively, it may be hypothesized that increased visceral adiposity is accompanied by increased perivascular fat depots (37). Although visceral adipocytes stimulate production of CRP by the liver leading to higher circulating CRP levels, the perivascular adipocytes concomitantly may secrete adipocytokines in the local downstream circulation where they can affect arteriolar and capillary function (37). A limitation of the present study is that the role of the adipocytokine adiponectin was not studied, because there was a shortage of material. In agreement with previous studies (6, 15), our data demonstrate an inverse association between capillary recruitment and dyslipidemia. On the one hand, dyslipidemia may mediate the association between visceral adiposity and capillary recruitment. This is supported by the predictive value of triglycerides for the development and progression of retinal and renal microvascular complications in type 1 diabetes mellitus (38). On the other hand, visceral adiposity-associated impairment of capillary recruitment may contribute to dyslipidemia. From a pathophysiological point of view this might seem a more plausible hypothesis because a reduction of functional capillaries may lead to higher concentrations of lipoproteins through impaired clearance by loss of diffusion surface and by reduced lipoprotein lipase activity by loss of endothelial surface (15, 39). Unfortunately, because of the cross-sectional design of the present study, causal relationships cannot be inferred and regression analyses show that statistically both hypotheses are possible. Thus, additional (prospective) studies are necessary to clarify the role of cap-

de Jongh et al. • Fat Distribution and Capillary Function

illary function in relationships between visceral adipose tissue and dyslipidemia. Given the small number of children in the present study, the statistical power to find significant associations was limited. Nevertheless, we demonstrate an inverse association of truncal sc adiposity with capillary recruitment. Previous studies in children have shown associations between truncal sc adiposity and cardiovascular risk factors such as hyperinsulinemia, dyslipidemia, and elevated blood pressure (40 – 43). However, total body fat may largely determine these associations. Our results demonstrate that the inverse association with capillary recruitment is independent of total body fat. This indicates that a truncal distribution of body fat may be harmful in childhood and may contribute to microvascular dysfunction and, consequently, to increased cardiovascular risk in adulthood. In conclusion, our data in adults suggest a role for visceral adiposity and its associated proinflammatory state in capillary dysfunction and its possible sequelae such as hypertension and insulin resistance. Interventions directed at preservation or amelioration of capillary function may prevent the development of these obesity-associated cardiovascular risk factors. Also, our findings in children and adults suggest that not only visceral but also truncal sc adiposity is detrimental for capillary perfusion and that this process may start before puberty. These observations underline the necessity for interventions in childhood to prevent truncal obesity and its associated cardiovascular risk. Acknowledgments Received May 22, 2006. Accepted September 20, 2006. Address all correspondence and requests for reprints to: Renate T. de Jongh, Department of Internal Medicine, VU University Medical Center, De Boelelaan 1117, PO Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail: [email protected]. R.T.d.J. was supported by a grant from The Netherlands Organization for Health Research and Development (ZonMw 940-37-025). Author disclosure summary: R.G.I., E.H.S., J.J.V., H.A.D.-v.d.W., C.D.A.S., and M.M.v.W. have nothing to declare. R.T.d.J. received grant support from The Netherlands Organization for Health Research and Development (ZonMw 940-37-025). J.S.Y. received a lecture fee by Serono Pharmaceutical Co. (American Diabetes Association and American Heart Association meetings).

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