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Reduction of Elevated Serum Retinol Binding Protein in Obese Children by Lifestyle Intervention: Association with Subclinical Inflammation

Nemours Children’s Clinic (P.B., A.A., V.F., D.G.) and Mayo Clinic College of Medicine (P.B.), Jacksonville, Florida 32207; and Division of Endocrinology, Diabetes, and Metabolism (T.E.G., B.B.K.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

Address all correspondence and requests for reprints to: Prabhakaran Balagopal, Ph.D., Nemours Children’s Clinic, 807 Children’s Way, Jacksonville, Florida 32207. E-mail: bbalagop{at}nemours.org.

	Abstract

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Context: Retinol binding protein (RBP4), secreted primarily from the liver and adipose tissues, was recently proposed as a link between obesity and insulin resistance. The role of RBP4 in pediatric obesity, its relationship with subclinical inflammation, and its response to lifestyle changes are not elucidated.

Objective: The objective of the study was to determine in children: 1) the status of RBP4 levels in lean vs. obese; 2) the relationship between RBP4 levels and subclinical inflammation; and 3) the effect of lifestyle-only intervention on RBP4 levels.

Design, Setting, and Patients: Lean and obese children (n = 21) matched for age (>14 yr to < 18 yr) and maturity stage (Tanner IV) were studied at baseline and with lifestyle intervention in obese subjects only (n = 15).

Intervention: Patients received 3 months of randomized and controlled physical activity-based lifestyle intervention.

Main Outcome Measure: RBP4 levels in children before and after intervention and the relationship between RBP4 and subclinical inflammation were measured.

Results: Higher RBP4 levels were found in the obese group vs. lean group (P = 0.005). RBP4 correlated with not only indices of obesity and insulin resistance but also inflammatory factors (r = 0.63 and 0.64 for C-reactive protein and IL-6, respectively, P < 0.01). Intervention reduced RBP4 levels by approximately 30% (P = 0.001), and RBP4 reduction was correlated with the magnitude of decrease in inflammatory factors (P = 0.01).

Conclusion: Alterations in serum RBP4 occur at an early age in the clinical course of obesity and appear to correlate with subclinical inflammation. Lifestyle intervention almost entirely reversed the raised RBP4 levels in obese children. Future studies should determine whether elevation of RBP4 is a direct trigger for the insulin resistance and subclinical inflammation implicated in the premature development of cardiovascular disease and diabetes.

	Introduction

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ALTHOUGH RETINOL BINDING protein (RBP4) was established as an adipokine in the 1990s (1, 2), a causal role for RBP4 in the pathogenesis of insulin resistance and type 2 diabetes has only recently been suggested (3). Elevating RBP4 in mice by transgenic overexpression or injection of purified RBP4 causes insulin resistance, whereas lowering RBP4 by genetic knockout or treatment with a synthetic retinoid that promotes RBP4 excretion improves insulin sensitivity (3). In adult human subjects of diverse ethnicities, elevated serum RBP4 is associated with insulin resistance, type 2 diabetes, and metabolic abnormalities such as obesity, glucose intolerance, dyslipidemia, and hypertension (3, 4, 5, 6, 7, 8, 9, 10, 11). However, serum RBP4 is not significantly higher in diabetic vs. nondiabetic insulin-resistant subjects, indicating that hyperglycemia is not a contributing factor (4). Interventions that improve insulin sensitivity (3) including exercise training and weight loss in adult subjects may lower serum RBP4 (4, 11). However, improvement in insulin sensitivity via modest weight reduction in overweight postmenopausal women did not alter serum RBP4 but did result in decreased RBP4 expression in subcutaneous adipose tissue in one study (12). Whether serum RBP4 is elevated in obese children or responds to physical activity-based lifestyle interventions in obese children are not known.

Rates of obesity are soaring in most parts of the world, predisposing children to type 2 diabetes with increased risk for cardiovascular disease (CVD) early in life (13). It has been proposed that type 2 diabetes and atherosclerotic CVD arise from common soil, and inflammation appears to be such a candidate (14). The presence of a state of obesity-related chronic inflammation, denoted by elevated levels of C-reactive protein (CRP) and proinflammatory cytokines has recently been reported in children (15, 16). In contrast, serum RBP4 levels are frequently found to be reduced in settings of inflammation or infection, and RBP4 is therefore regarded as a negative acute phase reactant (17, 18). Here we assessed the status of serum RBP4 levels in children with obesity and effects of a physical activity-based lifestyle intervention on serum RBP4 in relation to changes in obesity-related subclinical inflammation.

	Subjects and Methods

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The Nemours Children’s Clinic Research Review Committee and Baptist Medical Center/Wolfson Children’s Hospital Institutional Review Board approved the study. Written informed consents were obtained from subjects and parents.

Among the 21 subjects studied, 15 were obese [body mass index (BMI) > 95th percentile for age and sex] and six were lean (BMI < the 85th percentile). All subjects were matched for age and pubertal status (Tanner stage IV), determined by physical examination by a pediatrician according to the criteria of Tanner. Study subjects were admitted to the Clinical Research Center (CRC) at Wolfson Children’s Hospital on the evening before the study. Anthropometric and body composition (by dual-energy x-ray absorptiometry using a QDR 4500-A instrument; Hologic, Waltham, MA) were performed under uniform conditions. Some aspects of this study were previously reported (16, 19), and the current study was undertaken, retrospectively, in the context of recent data on RBP4 (3, 4, 6, 7, 8, 9, 10, 12). Pertinent characteristics of study subjects are included in Table 1.

All obese subjects were sedentary and were randomly assigned to either the obese intervention group or the obese control group after stratification by age and pubertal status, and researchers were blind to metabolic parameters. The intervention group was enrolled in a weight management program previously described (16). Briefly, obese subjects were advised to perform aerobic activities involving mainly brisk walking with movement of the total body to ensure maximum caloric expenditure for 45–60 min three times per week for 3 months. One session each week was monitored at the clinic and at least one parent participated in these sessions. The physical activity regimen was supplemented with other lifestyle changes that included calorie restriction by exchanging high-calorie snacks with low-calorie and low-fat snacks; cutting down meal portions and frequency of snack consumption; limiting sugar-based carbonated drinks and limiting the duration of television watching. Compliance with the lifestyle changes was enhanced by a combination of good dietary practices, behavioral counseling (in consultation with a clinical psychologist) and active involvement of the family. Obese control subjects were given advice on basic lifestyle changes but were not supervised or coached during the 3-month study period. Biological measurement protocol was repeated in obese subjects at 3 months. Lean control subjects were studied only at baseline.

Data analysis

Baseline data were analyzed initially using an independent-sample t test and a one-way ANOVA. Multivariate regression analysis was performed to identify independent correlations for RBP4. Intervention data were analyzed by Student’s two-tailed paired t test or ANOVA for repeated measures. Significance levels less than 5% were considered significant. The calculations were performed using a standard statistical package, the SAS program (SAS Institute, Cary, NC). Nonnormally distributed values of CRP concentration were transformed logarithmically.

	Results

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Baseline serum RBP4 levels were elevated approximately 36% in obese vs. lean subjects (Fig. 1A) and correlated with fat mass (r = 0.64; P < 0.01; Fig. 1B), HOMA-IR (r = 0.64; P = 0.007); fasting insulin levels (r = 0.70; P = 0.002); CRP (r = 0.63 and P = 0.008; Fig. 1C), and IL-6 (r = 0.65 and P = 0.002) and inversely with adiponectin (r = –0.55 and P = 0.01; Fig. 1D). Multivariate regression analysis showed an independent correlation between RBP4 and CRP levels at baseline (P = 0.002).

View larger version (16K): [in this window] [in a new window]   FIG. 1. A, Baseline fasting serum RBP4 concentration (grams per liter) in lean and obese adolescents. B, Relationship between serum RBP4 and fat mass in children. Correlation coefficient (r) and P values are included in the respective panels. C, Relationship between serum RBP4 and log CRP in children. Correlation coefficient (r) and P values are included in the respective panels. D, Relationship between serum RBP4 and adiponectin in children. E, In the obese intervention group, the individual concentrations of serum RBP4 before and after the 3-month lifestyle-only intervention are shown. F, In the obese control group, the individual concentrations of serum RBP4 before and after the 3-month control are shown. Correlation coefficient (r) and P values are included in the respective panels.

View this table: [in this window] [in a new window]   TABLE 2. Intervention studies: Correlation (r) between -decrease in the fasting serum RBP4 level and -changes in insulin and circulating levels of inflammatory factors (CRP and IL-6)

	Discussion

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The current study indicates that alterations in RBP4 are evident at an early age in obesity, and the results are in agreement with previous studies in adult human subjects (3, 4, 5, 6, 7, 8, 9, 10, 11). However, the relationship between inflammatory factors and serum RBP4 that we observed in the current study is somewhat unexpected because serum RBP4 is found to be reduced in many clinical settings associated with inflammation, such as acute illness, burns, surgery, infection, or trauma (17, 18). Therefore, the obesity-related proinflammatory state in children (15, 16, 20) appears to be fundamentally different from illness- or injury-related inflammation with regard to effects on serum RBP4 levels. In addition, levels of the RBP4-binding protein, transthyretin (TTR), are lower in states of illness- or injury-related inflammation, frequently in association with some degree of negative protein balance, but not in obesity-related inflammation (5). Binding of RBP4 to TTR in serum is crucial for preventing RBP4 excretion through the kidney. Therefore, the reduced serum TTR levels occurring in illness/injury-related inflammation, unlike in obesity-related inflammation, may indirectly promote increased clearance of RBP4 from circulation.

Although reversal of hypoadiponectinemia in response to lifestyle intervention (19) and a negative association between RBP4 and adiponectin levels at baseline were observed, there was no significant association between the magnitude of changes in RBP4 and adiponectin levels in response to the intervention. Somewhat surprisingly the magnitudes of change in fat mass and fat-free mass (Table 3) were also not correlated to the magnitude of decrease in RBP4 levels. In contrast, lifestyle-induced -decreases in factors of inflammation (CRP and IL-6) and insulin were correlated with the -decrease in serum RBP4 level. Prior observation in adults also showed that changes in insulin sensitivity in response to exercise training, and not changes in BMI or fat mass, were the strongest determinant of serum RBP4 (4). Although the increased baseline level of serum RBP4 in obese children might be a consequence of its increased expression, increased fat mass, or alterations in its secretion and/or clearance from circulation, the lack of association between the -decreases in RBP4 and fat mass suggests that a primary reduction in fat mass alone is not sufficient to determine the serum RBP4 level. Therefore, it appears that although RBP4 is produced in adipose tissue, simply reducing fat mass per se may not be the sole mechanism for the change in the serum RBP4 levels.

The current study does not identify a precise mechanism for the lifestyle-induced reduction in serum RBP4; however, it raises the possibility that the changes in circulating RBP4 levels may be related to changes in subclinical inflammation and/or vice versa. Previous studies have also shown that exposure to inflammatory factors down-regulates GLUT4 expression in adipocytes (21) and that adipose tissue-specific GLUT4 knockout results in increased RBP4 expression in adipocytes (3). Furthermore, exercise training up-regulates GLUT4 expression in adipocytes and skeletal muscle (22). Therefore, the coordinated reduction of markers of inflammation and serum RBP4 by lifestyle intervention observed in this study may reflect an amelioration of inflammation along with restoration of GLUT4 expression in adipose tissue. Conversely, lifestyle intervention in obese children may decrease RBP4 production and/or secretion from the liver. It is also not known whether these observations are unique to the pediatric population.

Alterations in serum RBP4 early in the clinical course of obesity, its relationship with inflammatory factors, and its reduction in response to lifestyle intervention observed in the current study have not only physiological relevance but also clinical implications. Together with previous data in animals and adult humans, the current study suggests a potentially important role for RBP4 in childhood obesity and the early development of diabetes with increased risk for CVD. Further studies will be necessary to determine whether the relationship between RBP4 and subclinical inflammation is causal or whether RBP4 is primarily a marker for insulin resistance.

	Acknowledgments

 
We thank the volunteers for participating in this study. We are grateful to Linda Russell and Leslie Berry for excellent support in conducting the study; Burnese Rutledge, Sheila Smith, and the nursing staff of the CRC at the Wolfson Children’s Hospital for their superb assistance; Stacey Boatright for excellent secretarial help; and as always the skilled technical assistance of Shawn Sweeten, Brenda Sager, and Lynda Everline. We thank Dr. Hossien Yarandi for statistical help, Dr. William Roberts for the measurement of CRP, and Drs. Edward Bayne and Norman Patton for help with the study.

	Footnotes

 
This work was supported by a grant from Nemours Research Programs, a Scientist Development Award from the American Heart Association, and National Institutes of Health Grants RO1 DK 43051 and K08 DK69624.

P.B., A.A., V.F., and D.G., have nothing to declare; T.E.G. is an inventor on patent application (pending, United States) and received royalties from the licensor of the patent (Takeda Pharmaceutical Co. Ltd.); B.B.K. is an inventor on patent application (pending, United States), received royalties from the licensor of the patent (Takeda Pharmaceutical Co. Ltd.), and received lecture fees from Merck and grant support from Takeda Pharmaceutical Co. Ltd. (January 2003 to June 2007).

First Published Online March 6, 2007

Abbreviations: %BF, Percent body fat; BMI, body mass index; CRP, C-reactive protein; CVD, cardiovascular disease; HOMA-IR, homeostasis model assessment of insulin resistance; %LM, percent non-bone lean mass; RBP4, retinol binding protein; TTR, transthyretin.

Received December 8, 2006.

Accepted February 27, 2007.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Balagopal, P. Articles by George, D. Search for Related Content PubMed PubMed Citation Articles by Balagopal, P. Articles by George, D. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Obesity Related Collections Pediatric Endocrinology Diabetes and Insulin Metabolism