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Original Article |
Division of Endocrinology, Department of Pediatrics (A.M.H., S.H.L., R.G.R., K.L.P.) and Division of Endocrinology, Diabetes, and Clinical Nutrition, Department of Medicine (D.D.S., J.Q.P.), Oregon Health and Science University, Portland, Oregon 97201; and University Department of Medicine (I.S.F., S.O.), Addenbrooke’s Hospital, Cambridge, United Kingdom
Address all correspondence and requests for reprints to: Andrea M. Haqq, M.D., Duke University Medical Center, Department of Pediatrics, Division of Endocrinology and Diabetes, DUMC 3080, 306FA Bell Building, Durham, North Carolina 27710. E-mail: haqq0001{at}mc.duke.edu.
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Abstract |
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Introduction |
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Studies in rodents support the premise that ghrelin is involved in energy balance. In rats fed ad libitum, both intracerebroventricular and ip administration of ghrelin potently stimulates food intake (3). In mice, peripheral injection of ghrelin for 2 wk resulted in a significant increase in body weight that was attributed to an increase in fat mass (4). These mice also displayed an increased respiratory quotient, reflecting a reduced utilization of fat. However, neither energy expenditure nor locomotor activity significantly changed in these mice (4).
In humans, ghrelin was incidentally noted to increase appetite during a clinical study designed to evaluate the GH-releasing activity of pharmacological ghrelin injection in seven normal individuals. Three out of the seven subjects reported a subjective increase in hunger after ghrelin injection (5). An effect of more physiological levels of ghrelin on appetite and food intake in humans was studied recently. In a randomized, double-blind, cross-over study that examined the effects of iv ghrelin on appetite and food intake, energy consumption increased 28 ± 3.9% (P < 0.001) during ghrelin infusion (resulting in ghrelin levels approximately two times higher than fasting) compared with saline infusion (6). Although ghrelin levels are inversely related to body weight in humans (7, 8), ghrelin concentrations are higher during starvation (7, 8) and increase with weight loss (9). Therefore, ghrelin may signal conservation of energy to prevent further weight loss and restore usual body weight.
Prader-Willi Syndrome (PWS) is one of the most common genetic obesity syndromes and is caused by a lack of expression of paternal genes on the long arm of chromosome 15 (15q11-q13) (10). Hypothalamic dysfunction is thought to be the basis for many features of PWS including insatiable hunger and obesity, deficient GH secretion, hypogonadism, aberrant body temperature control, and sleep disturbances, although the underlying mechanisms remain unknown (11). A recent report by Cummings et al. (12) has shown increased plasma ghrelin levels in adults with PWS compared with lean and obese control groups. Therefore, we sought to determine if ghrelin may play a role in the pathogenesis of obesity in children with PWS. In addition to studying children with PWS, we measured endogenous fasting serum ghrelin concentrations in children who were healthy but obese (OC), children with other monogenic causes of obesity [melanocortin-4 receptor mutations (MC4), leptin deficiency (OB)] and children who were healthy and of normal weight (NC). We hypothesized that if circulating ghrelin concentrations were higher in children with PWS than the two control groups, then the orexigenic properties of this hormone may contribute to the obesity phenotype of PWS.
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Subjects and Methods |
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Thirteen children with PWS, 20 children of normal weight (NC) matched for sex and age, 17 healthy but obese children (OC), and 14 children with MC4 receptor (MC4-R) mutations (MC4) matched for age, sex, and body mass index (BMI) and 3 children with leptin deficiency (OB) were studied. This study was approved of by the Institutional Review Board of Oregon Health and Science University. A parent of each child gave written informed consent and when appropriate, each child provided assent before entry into the study.
Blood sample analysis
Blood samples were collected after an overnight fast between 0800 and 1000 into red-top vacutainer tubes. Following 30 min to allow clotting on ice, each sample was centrifuged and serum was removed and stored at -70 C until the time of the assay. All samples were measured in duplicate.
Ghrelin analysis
Serum samples were assayed for immunoreactive ghrelin concentration using a commercial RIA (Phoenix Pharmaceuticals, Belmont, CA). Three serum controls from common laboratory stocks were included in each assay to measure intraassay and interassay variability. Based on these controls, the intraassay and interassay coefficients of variation (CV) were 7.16% and 9.86%, respectively. The lower and upper limits of detection for this assay were 24 and 1516 pmol/liter.
Insulin analysis
Serum insulin concentrations were measured in all groups (PWS, NC, OC, MC4, and OB) by using a two-site immunoradiometric method (13). The intraassay and interassay CV were 3–5% and 5–7%. The normal range was 0–69.5 pmol/liter.
Leptin analysis
Serum leptin levels were determined in all groups (PWS, NC, OC, MC4, and OB) using a commercially available RIA (Linco, Inc., St. Charles, MO) with a detection limit of 0.5 ng/ml and intraassay and interassay CV of 2 and 5%, respectively.
Statistical analysis
Outcome variables were compared among the subgroups (PWS, OC, MC4, OB, and NL) using t tests. The correlation between fasting serum ghrelin concentrations and sex, age, BMI, and leptin and insulin concentrations were examined by linear regression and Pearson product moment correlation analyses. All statistical analyses were performed using SigmaStat software (SPSS, Inc., Chicago, IL).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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1.5-fold) in PWS compared with NC (mean ± SD; 429 ± 374 vs. 270 ± 102 pmol/liter; P = 0.18), although it did not reach statistical significance. PWS demonstrated significantly higher fasting ghrelin concentrations compared with the OC group (mean ± SD; 429 ± 374 vs. 146 ± 75 pmol/liter; P = 0.003), MC4 group (mean ± SD; 429 ± 374 vs. 119 ± 40 pmol/liter; P < 0.001) or OB group (mean ± SD; 429 ± 374 vs. 135 ± 15.5 pmol/liter; P = 0.03). Removal of the PWS with the outlying ghrelin (see Fig. 4) did not change the statistical significance of these results. In addition, we found no significant difference in ghrelin concentrations for those PWS subjects who had maternal disomy vs. a deletion of chromosome 15 as the etiology for their syndrome. No difference in ghrelin concentrations was seen in subjects with MC4-R or leptin deficiency compared with obese controls (Fig. 1).
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, 3, and 4
, respectively). On multiple linear regression analysis, significant independent relationships between fasting serum ghrelin concentrations and BMI and insulin were demonstrated (P = 0.03 and 0.01, respectively) (Table 2). In PWS, however, no significant correlation was seen between fasting ghrelin concentrations and age, BMI, leptin, or insulin.
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Discussion |
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The regulation of ghrelin secretion is poorly understood. Ghrelin secretion is inhibited by ingestion of nutrients (4), which in turn stimulate secretion of a number of gut and pancreatic hormones that might be candidate regulators of ghrelin. It is also possible that ghrelin is inversely regulated by leptin, given ghrelin’s proposed role in body weight regulation. In the present study, the relationship between ghrelin concentrations and age, BMI, leptin, and insulin was examined in the normal control subjects. Whereas age was inversely related to ghrelin levels in normal control subjects by simple regression analysis, only BMI and insulin (not age or leptin) independently predicted ghrelin levels on multiple linear regression analysis. The finding that ghrelin levels in subjects with leptin deficiency were appropriate for their degree of obesity provides evidence that leptin does not have a regulatory role in ghrelin secretion. Therefore, although our data support a role for insulin (or insulin resistance, of which increased insulin levels are a marker) in ghrelin regulation, we cannot be sure that the lower ghrelin levels associated with increasing BMI and insulin levels is independent of other confounding variables such as a higher energy intake.
The mechanism by which ghrelin stimulates appetite has not been fully determined. Evidence now points to ghrelin’s effects in the hypothalamus being mediated through the agouti-related protein (AGRP)/neuropeptide Y (NPY) pathway. Studies demonstrate the presence of ghrelin receptors in multiple hypothalamic nuclei that may be involved in energy homeostasis (14, 15, 16). By immunohistochemistry, ghrelin is located in several regions of the hypothalamus (17). Ghrelin when administered centrally, leads to induction of c-fos, a measure of neuronal activation, in the medial arcuate nucleus where NPY/AGRP cells are located (18). Other experiments show that ghrelin is able to induce expression of fos protein in both NPY neurons and AGRP neurons; antibodies and antagonists of NPY and AGRP abolished ghrelin-induced feeding (19). Finally, within the arcuate nucleus itself, there is significant coexpression of GH secretagogue-receptor and NPY mRNA (20). It is plausible that both stomach and hypothalamic-derived ghrelin modulate these hypothalamic centers. For example, stomach-derived ghrelin may interact with the arcuate nucleus, which is less protected by a blood-brain barrier and has some direct connection with the bloodstream. Alternatively, hypothalamic-derived ghrelin may modulate hypothalamic centers located within the blood-brain barrier, such as the paraventricular nucleus.
The increased concentrations of ghrelin found in children with PWS may lead to stimulation of appetite through the hypothalamic NPY/AGRP signaling pathways. Because the human ghrelin gene on chromosome 3p26–25 is not located within the known deleted gene sequence that causes PWS, it is not yet clear how or why this elevation in circulating ghrelin occurs in this syndrome. Because ghrelin is thought to regulate GH secretion, and the majority of PWS children are GH deficient, one might speculate that the increase in ghrelin concentration found in PWS children reflects a lack of feedback inhibition from GH. However, this theory is unlikely given the finding that ghrelin concentrations are not elevated in subjects with GH deficiency and GH therapy in these same individuals does not alter their levels of ghrelin (21). It would be important to know whether most of the increase in ghrelin concentration in PWS is derived from the stomach or from other sources, such as the hypothalamus. Furthermore, because the assay used to measure ghrelin in this study captures all ghrelin-like immunoreactive proteins, it is plausible that the increase in ghrelin concentration is attributable not only to active acylated ghrelin protein, but also to an increase in circulating fragments of ghrelin-derived from degradation or alternative splicing or mutations of the ghrelin gene product, which presumably would be inactive. For instance, it is possible that PWS children may have altered processing of preproghrelin by prohormone convertase 2 into the mature active peptide as supported by previous work that postulates a processing defect of vasopressin in some PWS subjects (22). Therefore, it is possible that the increased ghrelin concentrations demonstrated in PWS children reflect mostly inactive hormone, which may explain why higher levels of GH are not observed in PWS children. A second possibility is that the defect in GH secretion in PWS children is not affected by GH secretagogues such as ghrelin (23, 24). A final speculative explanation is that the elevated ghrelin levels in PWS may lead to lower GH levels through a paradoxical override inhibition, similar to that described before with continuous GH-releasing hormone stimulation of GH (12, 25).
In conclusion, we have found markedly elevated concentrations of ghrelin in children with PWS compared with obese controls and children with monogenic obesity defects in MC4-R or leptin. The absence of increased ghrelin concentrations in children with monogenic obesity defects in MC4-R or leptin suggests that ghrelin may be a unique candidate mediator of the obesity in PWS through mechanisms that include ghrelin’s known ability to increase food intake and decreasing energy expenditure (as demonstrated in rodents). Future studies will need to address the functional activity of the circulating ghrelin in subjects with PWS and whether ghrelin antagonists effectively reduce food intake in PWS and thereby prevent the expression of obesity and its complications.
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Acknowledgments |
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Footnotes |
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Abbreviations: AGRP, Agouti-related protein; BMI, body mass index; CV, coefficients of variation; MC4, melanocortin-4; MC4-R, MC4 receptor; NC, normal weight children; NPY, neuropeptide Y; OB, children with leptin deficiency; OC, obese children; PWS, Prader-Willi Syndrome.
Received July 8, 2002.
Accepted October 3, 2002.
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G. Marchesini, U. Pagotto, E. Bugianesi, R. De Iasio, R. Manini, E. Vanni, R. Pasquali, N. Melchionda, and M. Rizzetto Low Ghrelin Concentrations in Nonalcoholic Fatty Liver Disease Are Related to Insulin Resistance J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5674 - 5679. [Abstract] [Full Text] [PDF]
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 B. Horsthemke, H. Nazlican, J. Husing, L. Klein-Hitpass, U. Claussen, S. Michel, C. Lich, G. Gillessen-Kaesbach, and K. Buiting Somatic mosaicism for maternal uniparental disomy 15 in a girl with Prader-Willi syndrome: confirmation by cell cloning and identification of candidate downstream genes Hum. Mol. Genet., October 16, 2003; 12(20): 2723 - 2732. [Abstract] [Full Text] [PDF]
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U. Pagotto, A. Gambineri, C. Pelusi, S. Genghini, M. Cacciari, B. Otto, T. Castaneda, M. Tschop, and R. Pasquali Testosterone Replacement Therapy Restores Normal Ghrelin in Hypogonadal Men J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4139 - 4143. [Abstract] [Full Text] [PDF]
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J. Farquhar, M. Heiman, A. C. K. Wong, R. Wach, P. Chessex, and J.-P. Chanoine Elevated Umbilical Cord Ghrelin Concentrations in Small for Gestational Age Neonates J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4324 - 4327. [Abstract] [Full Text] [PDF]
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J. M. Zigman and J. K. Elmquist Minireview: From Anorexia to Obesity--The Yin and Yang of Body Weight Control Endocrinology, September 1, 2003; 144(9): 3749 - 3756. [Abstract] [Full Text] [PDF]
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A. M. Haqq, D. D. Stadler, R. G. Rosenfeld, K. L. Pratt, D. S. Weigle, R. S. Frayo, S. H. LaFranchi, D. E. Cummings, and J. Q. Purnell Circulating Ghrelin Levels Are Suppressed by Meals and Octreotide Therapy in Children with Prader-Willi Syndrome J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3573 - 3576. [Abstract] [Full Text] [PDF]
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J. C. Bunt, A. D. Salbe, M. H. Tschop, A. DelParigi, P. Daychild, and P. A. Tataranni Cross-Sectional and Prospective Relationships of Fasting Plasma Ghrelin Concentrations with Anthropometric Measures in Pima Indian Children J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3756 - 3761. [Abstract] [Full Text] [PDF]
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