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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 8 3756-3761
Copyright © 2003 by The Endocrine Society

Cross-Sectional and Prospective Relationships of Fasting Plasma Ghrelin Concentrations with Anthropometric Measures in Pima Indian Children

Joy C. Bunt, Arline D. Salbe, Matthias H. Tschöp, Angelo DelParigi, Pamela Daychild and P. Antonio Tataranni

Clinical Diabetes and Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (J.C.B., A.D.S., A.D., P.D., P.A.T.), Phoenix, Arizona 85016; and Department of Health and Human Services, German Institute of Human Nutrition (M.H.T.), 14558 Bergholz-Rehbrucke, Germany

Address all correspondence and requests for reprints to: Dr. Joy C. Bunt, Clinical Diabetes and Nutrition Section National Institutes of Health, 4212 North 16th Street, Room 541-A, Phoenix, Arizona 85016. E-mail: jbunt{at}mail.nih.gov.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Ghrelin, a recently discovered GH secretagogue with orexigenic effects, is proposed to be a regulator of energy balance. To test whether fasting plasma ghrelin concentrations predict future gain in body weight or adiposity, we measured weight, height, body mass index (BMI), percentage of body fat (by dual energy x-ray absorptiometry), and fasting plasma concentrations of ghrelin, insulin, and glucose in 10-yr-old Pima Indians (n = 40; 13 males and 27 females) and subsequent weight, height, and BMI 1.7 ± 0.6 yr later. At baseline, the fasting plasma ghrelin concentration was negatively associated with height (r = -0.52; P = 0.0006), weight, (r = -0.37; P = 0.02), percentage of body fat (r = -0.33, P = 0.04), and fasting plasma insulin concentration (r = -0.41; P = 0.01). In multiple regression models adjusting for gender and fasting plasma insulin, the fasting plasma ghrelin concentration was an independent determinant of height (ß = -13.9; P = 0.02), but not weight or BMI. Prospectively, the baseline fasting plasma ghrelin concentration was not an independent determinant of the relative rate of increase in weight, height, or adiposity. In conclusion, the fasting plasma ghrelin concentration was lower in taller and fatter Pima Indian children, but did not independently predict baseline weight, adiposity, or future growth rates. These data do not support a direct relationship between the fasting plasma ghrelin concentration and subsequent relative changes in height or weight in growing children.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GHRELIN, A HORMONE primarily secreted by the stomach, is a novel ligand for the GH secretagogue receptor (1). Although first identified as a potent stimulator of GH (2, 3, 4, 5), its potential role in the regulation of appetite and energy balance has been of much interest (6, 7, 8, 9, 10). Specifically, it has been observed that exogenous ghrelin administration in rodents leads to increased feeding behavior and decreased fat oxidation, with subsequent increases in adiposity (11). In humans, infusion of ghrelin increases appetite and food intake (12, 13), and endogenous plasma ghrelin concentrations increase shortly before meal initiation (14).

Despite the effect of ghrelin on increasing food intake, cross-sectional studies report that endogenous fasting plasma ghrelin concentrations are higher in anorexia nervosa (15, 16) and lower in obese compared with normal weight adults (17) and children (18, 19, 20). To explain this paradox it has been proposed that fasting plasma ghrelin concentrations decrease as an adaptive response to increases in weight or adiposity (9, 21). Indeed, studies have reported that fasting plasma ghrelin concentrations decrease with weight gain in patients with anorexia nervosa (15, 16) and increase with weight loss in obese subjects (22, 23). However, both children (20) and adults (24, 25) with Prader-Willi syndrome have very high levels of fasting plasma ghrelin concentrations despite high levels of adiposity, and Ravussin et al. (26) reported no relationship between baseline ghrelin concentrations and magnitude of weight change during interventions that induced a negative or a positive energy balance.

Cross-sectional and prospective data can lead to very different conclusions, as illustrated by an earlier study in Pima Indians (27). Whereas high metabolic and fat oxidation rates were identified as factors associated with obesity (cross-sectional), low metabolic and fat oxidation rates were predictors of weight gain (prospective). Therefore, it could be hypothesized that although low fasting plasma ghrelin concentrations are associated with higher weight or adiposity, high fasting plasma ghrelin concentrations might predict potential gains in weight or adiposity.

To test this hypothesis we examined the cross-sectional and prospective relationships of fasting plasma ghrelin concentrations with measures of weight, height, and adiposity [body mass index (BMI)] in a group of 10-yr-old Pima Indians, a population known for a high prevalence of obesity (28). Assessment of ghrelinemia in growing children allowed us to investigate whether ghrelin is predictive of the magnitude of future weight gain in free-living conditions. We hypothesized that although baseline fasting plasma ghrelin concentrations would be negatively associated with weight and adiposity in cross-sectional analyses, for any given weight, those children with higher fasting plasma ghrelin concentrations would have greater subsequent increases in weight and BMI over the next 1–2 yr.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Children were participants in a longitudinal study of the pathophysiology of obesity and type 2 diabetes in the Pima Indian population (29, 30). The baseline data reported here (n = 40) were collected during the summer months of 2000 and 2001 when subjects were 10 yr old. Briefly, children were studied at the NIH field clinic located in the Gila River Indian Community in Sacaton, Arizona, about 40 miles southeast of Phoenix. Subjects were of full Indian and at least 75% Pima-Tohono O’Odham heritage. At baseline, children arrived at the clinic at 0800 h in the fasted state, accompanied by one of their parents, and their health status was determined by medical history and physical examination. Heights and weights at follow-up were measured in October 2002 at the same NIH field clinic in the morning hours (0900–1100 h) with children in a fasted state and accompanied by one of their parents. Before participation, volunteers and their parents were fully informed of the nature and purpose of the study, and written informed consent/assent was obtained. The experimental protocol was approved by the institutional review board of the NIDDK and the Tribal Council of the Gila River Indian Community.

Anthropometrics

Height was measured without shoes, and body weight was measured while the children were in light clothing. BMI was calculated as the ratio of body weight (kilograms) and squared height (meters). The percentage of body fat (PFAT) at baseline was determined using dual energy x-ray absorptiometry (31).

Analytical procedures7

Blood samples at baseline were drawn after an overnight fast for measurement of plasma ghrelin, insulin, and glucose concentrations. Plasma insulin concentrations were determined by an automated immunoassay (Access, Beckman Instruments, Fullerton, CA). Blood samples for the measurement of fasting plasma ghrelin concentrations were drawn and transferred into prechilled EDTA tubes and immediately placed on ice. All tubes were cold-centrifuged (4 C) and stored at -70 C until assayed. Fasting plasma ghrelin concentrations were measured with a commercial RIA (Phoenix Pharmaceuticals, Belmont, CA). The inter- and intraassay coefficients of variation of this assay were 13.6% and 5.3%, respectively.

Statistical methods

All statistical analyses were performed using SAS software (SAS Institute, Inc., Cary, NC). Data are expressed as the mean ± SD. Fasting plasma ghrelin and insulin concentrations were log transformed (log10) to approximate a normal distribution. Gender differences in anthropometric and metabolic variables at baseline and follow-up were evaluated by t test. Pearson correlation coefficients and general linear regression models were used to quantify the cross-sectional and prospective relationships between the anthropometric (weight, height, BMI, and PFAT) and hormonal (ghrelin and insulin) variables at baseline and measures of weight, height, and BMI at follow-up.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Subject characteristics (Table 1Go)

There were no significant gender differences in levels or changes in the anthropometric variables or in fasting plasma ghrelin, insulin, and glucose concentrations at 10 yr of age. As expected, all children increased in weight, height, and BMI from baseline to follow-up.


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  		TABLE 1. Subject characteristics at baseline (10 yr of age) and follow-up

 
Cross-sectional relationships

At baseline (10 yr of age), fasting plasma ghrelin concentrations were negatively associated with height, weight, PFAT, and fasting plasma insulin concentrations (Fig. 1Go). Fasting plasma insulin concentrations were positively associated with all anthropometric variables (all P < 0.0001). After adjustment for gender and fasting plasma insulin concentrations in general linear regression models, the fasting plasma ghrelin concentration was an independent negative determinant for height, but not for weight or adiposity, whereas the fasting plasma insulin concentration was an independent positive determinant for all anthropometric variables (Table 2Go).



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  		FIG. 1. Relationships of fasting plasma ghrelin concentrations with height (A), fasting plasma insulin concentration (B), weight (C), and PFAT (D) at 10 yr of age (baseline).

 

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  		TABLE 2. General linear regression models for determinants of anthropometry at baseline (10 yr old)

 
Prospective relationships

Fasting plasma ghrelin concentrations at baseline were negatively associated with height and weight at follow-up as well as with rate of increase in weight and BMI (all P < 0.05). Fasting plasma insulin concentrations at baseline were positively associated with height, weight, and BMI at follow-up as well as with rate of increase in weight and BMI (all P < 0.01). However, once fasting plasma ghrelin and insulin concentrations were adjusted for either baseline weight or BMI, ghrelin was not a predictor of future growth rates in these variables, whereas insulin was an independent positive predictor for weight at follow-up (Table 3Go).


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  		TABLE 3. General linear regression models for determinants of anthropometry at follow-up

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
At baseline, fasting plasma ghrelin concentrations were negatively associated with weight, height, PFAT, and fasting plasma concentrations of insulin. After adjusting for the effect of insulin, fasting plasma ghrelin was an independent determinant for height, but not for weight or adiposity. In contrast to our hypothesis, the fasting plasma ghrelin concentration did not predict future growth in weight, height, or BMI once adjusted for baseline measures of these anthropometric variables.

The significant negative association of the fasting plasma ghrelin concentration with height is a new finding not previously observed in adults (17) or reported in other children’s studies to date (18, 19, 20). The association of ghrelin with a variable such as height may be more apparent during childhood than adulthood, because childhood is a dynamic period of growth for both height and weight. One of the possible explanations for this finding is that peripheral plasma ghrelin concentrations may be under direct negative feedback regulation from GH, as recently demonstrated in rats (32). In humans, Cappiello et al. (33) reported lower levels of circulating ghrelin levels (and higher levels of insulin) in adults with active acromegaly (a condition of GH hypersecretion). A negative association between human cord blood concentrations of GH and ghrelin has also been reported in male (but not female) neonates (34). Although ghrelin repeatedly has been shown to be a potent stimulator of GH release in both animals (35) and humans (2, 3, 4, 5), the physiological interactions between ghrelin and the GH-IGF-I axis are not well understood. It is possible that the hypothalamic source of ghrelin, rather than the peripheral, gastric source, influences GH release from the pituitary, which, in turn, suppresses ghrelin secretion from the stomach (11, 36, 37). Although we did not measure GH levels in our cohort, the lower ghrelin levels in the taller children may be a consequence of higher concentrations of GH that are routinely observed in children as they approach puberty (38, 39, 40). Low fasting plasma ghrelin concentrations may, therefore, be a consequence of greater GH release in taller children.

The present study shows that fasting plasma ghrelin concentrations are inversely associated with weight and adiposity in 10-yr-old Pima Indian children. These results are in agreement with previous observations in adults (10, 17, 33, 41, 42) as well as recent reports on children (18, 19, 20) and female neonates (34). Although this inverse association initially might seem paradoxical considering the effect that exogenous ghrelin has in increasing food intake and reducing fat utilization (7, 8, 11, 21, 43), it has been proposed that changes in plasma ghrelin reflect an adaptive response to chronic as well as acute changes in energy balance (9, 21).

It has also been proposed that the negative relationship of fasting plasma ghrelin concentrations with adiposity is secondary to higher insulin levels. Our results would support this hypothesis. The exact nature of the relationship between insulin and ghrelin, however, is unclear. In vitro studies have reported that ghrelin stimulates insulin release from pancreatic ß-cells in both diabetic and normal rats (44), and ghrelin from pancreatic {alpha}-cells also stimulates insulin (45). In humans, Broglio et al. (46) demonstrated that ghrelin injection resulted in both an increase in glucose and a decrease in insulin levels. In contrast to an earlier study (47), Saad et al. (48) as well as Möhlig et al. (49) demonstrated a direct acute decrease in ghrelin levels during a hyperinsulinemic euglycemic clamp. Although specific mechanisms are not known, there appears to be a reciprocal relationship between insulin and ghrelin.

When interpreting the association between fasting plasma ghrelin concentrations and adiposity in cross-sectional studies, it must be remembered that obese individuals can be in a state of energy balance when their weight is stable. Although experimental studies in adults have found increases in fasting plasma ghrelin concentrations with weight loss (22, 23, 26), decreases with overfeeding (26), and weight gain in individuals with anorexia nervosa (15, 16), Ravussin et al. (26) reported no relationship between baseline ghrelin concentrations and the magnitude of body weight change during interventions that induced negative or positive energy balance. It was noted that these interventions were in a controlled setting and that free-living conditions needed to be explored.

To our knowledge this is the first prospective study to examine the relationship between fasting plasma ghrelin concentrations in children and subsequent growth rates in weight, height, and adiposity in free-living conditions. We hypothesized that children with higher fasting plasma ghrelin concentrations at baseline would have greater gains in weight and adiposity. Our data did not support this hypothesis. Instead, unadjusted fasting plasma ghrelin concentrations at baseline were negatively associated with height and weight at follow-up as well as changes in weight or BMI per year. However, once fasting plasma ghrelin concentrations at baseline were adjusted for weight, height, or BMI, there was no relationship between fasting plasma ghrelin concentrations and growth rates in any of these variables. Indeed, those children who were heavier and taller at baseline continued to be heavier and taller at follow-up. A recent study by Iniguez et al. (50) reported that fasting plasma concentrations of ghrelin at 1 yr of age were not related to weight, length, or prior rates of growth from birth to 1 yr of age in infants born either adequate or small (SGA) for gestational age. Instead, those infants who had a smaller decrease in plasma ghrelin concentrations after a glucose infusion had shown a greater weight gain from birth to 1 yr, suggesting that diminished postprandial decreases in ghrelin (rather than fasting concentrations) may be more indicative of potential weight gain. This relationship, however, was only observed in the SGA infants and not in the adequate for gestational age infants. It is possible that ghrelin concentrations affect energy homeostasis only in certain clinical conditions, such as SGA (50), Prader-Willi syndrome (20, 24, 25), anorexia nervosa (15, 16), GH deficiency (41, 51), and acromegaly (33), and are not predictive of future gains in weight or adiposity within normal physiological ranges or circumstances. Because the majority of our cohort was already significantly overweight at baseline (30 of 40 subjects had BMI values above the 85th percentile), future prospective and longitudinal studies in lean or malnourished children are needed to explore this hypothesis. Finally, it must be acknowledged that the current assay for ghrelin measures the total plasma concentration, which may or may not correlate with biological activity.

In summary, despite its role in stimulating GH release and its reported orexigenic actions, fasting plasma ghrelin concentrations were lower in taller and fatter Pima Indian children; moreover, fasting plasma ghrelin concentrations did not predict future growth rates. The negative relationship between fasting plasma ghrelin concentration and obesity might be explained by an inhibitory effect of insulin on ghrelin. In conclusion, these data do not support a direct relationship between fasting plasma ghrelin concentration and subsequent relative changes in height or weight in growing children.


   Acknowledgments
 
We gratefully acknowledge the help of the staff of the NIH Field Clinic, recruiters, and many NIH-supported summer interns. We thank Dr. Martin Bidlingmaier for critical review of the technical and conceptual aspects of the manuscript. We also thank the technical staff of the NIH Clinical Diabetes and Nutrition Section in Phoenix and Eli Lilly & Co. for assisting with the laboratory analyses. We are grateful to the members and leaders of the Gila River Indian Community for their continuing cooperation in our studies. Most of all, we thank the children and their families for their participation in this study.


   Footnotes
 
Abbreviations: BMI, Body mass index; PFAT, percentage of body fat; SGA, small for gestational age.

Received February 12, 2003.

Accepted April 30, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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