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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-0754
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 1 229-234
Copyright © 2007 by The Endocrine Society

Obestatin Is Not Elevated or Correlated with Insulin in Children with Prader-Willi Syndrome

Won Hah Park, Yoo Joung Oh, Gae Young Kim, Sang Eun Kim, Kyung-Hoon Paik, Sun Ju Han, An Hee Kim, Su Hyun Chu, Eun Kyung Kwon, Seon Woo Kim and Dong-Kyu Jin

Departments of Orthopedic Sports Medicine (W.H.P.) and Pediatrics (K.-H.P., E.K.K., D.-K.J.), Samsung Medical Center, Sungkyunkwan University School of Medicine, 135-710 Seoul, Korea; Department of Nuclear Medicine (S.E.K.), Seoul National University College of Medicine, 110-799 Seoul, Korea; and Clinical Research Center (Y.J.O., G.Y.K., S.J.H., A.H.K., S.H.C., S.W.K.), Samsung Biomedical Research Institute, 135-710 Seoul, Korea

Address all correspondence and requests for reprints to: Dong-Kyu Jin, M.D., Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Il-Won Dong, Gang-Nam Gu, 135-710 Seoul, Korea. E-mail: jindk{at}smc.samsung.co.kr.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Obestatin is a peptide hormone derived from the proteolytic cleavage of ghrelin preprohormone. In Prader-Willi syndrome (PWS), the levels of total ghrelin (TG) and acylated ghrelin (AG) are increased, and these hormones are regulated by insulin.

Objective: Our objective was to analyze the changes in the obestatin levels after glucose loading and to characterize the correlations of obestatin with TG, AG, and insulin.

Design: Plasma obestatin, TG, AG, and insulin levels were measured in PWS children (n = 15) and controls (n = 18) during an oral glucose tolerance test.

Setting: All subjects were admitted to the Samsung Medical Center.

Interventions: An oral glucose tolerance test was performed after an overnight fast.

Main Outcome Measures: The plasma levels of obestatin, TG, AG, and serum insulin were measured at 0, 30, 60, 90, and 120 min after glucose challenge, and areas under the curves (AUCs) were calculated.

Results: No significant difference in AUC of the plasma obestatin was found between the PWS children and normal obese controls (P = 0.885), although AUC of AG (P = 0.002) and TG (P = 0.003) were increased in the PWS children. Moreover, There was a negative correlation between the AUC of AG and AUC of insulin both in PWS (r = –0.432; P = 0.049) and in controls (r = –0.507; P = 0.016). However, AUC of obestatin was not significantly correlated with AUC of insulin (in PWS, r = 0.168 and P = 0.275; in controls, r = –0.331 and P = 0.09).

Conclusions: Our results indicate that plasma obestatin is not elevated in PWS children and is not regulated by insulin both in PWS children and in obese controls.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
OBESTATIN IS A hormone that has been recently discovered by a bioinformatics-based prediction of the typical enzymatic cleavage site of the ghrelin-producing preprohormone, similar to {alpha} - and ß-MSH and ß-endorphin that are cleaved from proopiomelanocortin (1). Human ghrelin, a 28-amino-acid peptide, is derived by the posttranslational cleavage of a prepropeptide of 117 residues (2). Likewise, the 23-amino-acid obestatin is derived from the same peptide precursor.

The pharmacological dose of ghrelin increases food intake and body weight in rodents (2, 3) and accelerates gastric emptying (4, 5), whereas obestatin decreases food intake and body weight in addition to decelerating gastric emptying (1). In this context, obestatin may function as a physiological counterpart of ghrelin.

There are several similarities between these two hormones. Similar to ghrelin, which requires posttranslational modification by acylation, the biological activity of obestatin depends on amidation at its carboxy terminus (1, 2). In addition, obestatin binds to and activates the orphan receptor G protein-coupled receptor 39, which is reminiscent of the binding of ghrelin to the GH secretagogue receptor 1a (1, 2).

It has been reported that the levels of acylated ghrelin (AG) and total ghrelin (TG), which comprises AG and desacylated ghrelin, are elevated in Prader-Willi syndrome (PWS) (6, 7, 8), although ghrelin levels are often normal in PWS, and no direct relationship of elevated ghrelin levels to the satiety defect has been shown (9, 10). However, it would be interesting to investigate whether plasma obestatin levels are elevated in PWS.

Insulin has been reported to be a physiological and dynamic modulator of plasma ghrelin levels (11, 12), and it has an inhibitory effect on ghrelin secretion. Moreover, this regulation of ghrelin by insulin is independent of the plasma glucose level (13, 14). Inverse relationships have been reported between fasting ghrelin and insulin levels and insulin resistance indexes (15, 16, 17). In addition, postmeal ghrelin suppression has been reported to correlate with a rise in serum insulin level (16).

To our knowledge, no report has been issued on the changes in plasma obestatin levels after glucose challenge in PWS children or a healthy population. Furthermore, the dynamics of obestatin in relation to insulin have not been evaluated.

Previously, we have reported on the dynamics of AG and insulin by performing the oral glucose tolerance test (OGTT) in PWS children and normal obese children, who served as controls (18). In this study, to understand the dynamics of obestatin after glucose challenge and the relationship between obestatin and insulin, we investigated the responses of plasma obestatin, AG, TG, and serum insulin to glucose loading in PWS children and normal obese non-PWS children.


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

The study population comprised 15 PWS children [median age, 11.2 yr (interquartile range, 10.0–12.0 yr); body mass index (BMI), 24.8 kg/m2 (20.2–26.3 kg/m2)] and 18 normal obese controls [median age, 12.0 yr (11.0–12.2 yr); BMI, 26.3 kg/m2 (22.5–29.2 kg/m2)]. Subjects with diabetes mellitus (fasting plasma glucose of >126 mg/dl with a 2-h OGTT value of >200 mg/dl) were excluded. The 15 PWS subjects were those who were invited and agreed to participate in this study, from a pool of approximately 100 PWS children followed at our medical center.

All children were prepubertal, and their clinical characteristics are presented in Table 1Go. For recruiting controls, we visited several elementary and middle schools located in southern Seoul. The purpose of the study was explained to the teachers, and a written study protocol was sent to all parents. For the PWS children, informed consent was obtained from parents or guardians, and for the controls, it was obtained from the study participants as well as the parents or guardians. None of the study subjects were receiving GH therapy or any other medications. Monetary compensation was not provided to the subjects. The study design was reviewed and approved by the Samsung Medical Center Institutional Review Board.


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  		TABLE 1. Clinical characteristics of the study subjects

 
Experimental design

All children were admitted to the Pediatric Ward at the Samsung Medical Center. After overnight fasting for 10–12 h, the children received OGTT (1.75 g/kg, maximum 75 g). Blood samples were drawn at 0, 30, 60, 90, and 120 min to determine the plasma glucose, obestatin, AG, TG, and serum insulin levels. Samples were collected on ice, centrifuged immediately at 4 C, and stored at –70 C until required for assay.

To prepare the plasma samples for AG and TG analysis, whole blood was drawn directly into a centrifuge tube containing 500 U aprotinin and 1.25 mg EDTA-2Na per milliliter of whole blood collected and centrifuged immediately at 4 C. Next, 100 µl of 1 mol/liter HCl per milliliter of collected plasma was immediately added for AG analysis and stored at –70 C until required for assay. The body fat percentages of all the children were assessed by Lunar Prodigy dual energy x-ray absorptiometry (GE-Lunar, Madison, WI).

Hormonal assay

The plasma glucose levels were measured using a YSI 2300 dual analyzer (Yellow Springs Instrument Co., Yellow Springs, OH), and the serum insulin levels were measured using a commercially available immunoradiometric assay kit (BioSource Europe SA, Nivelles, Belgium) with a detection limit of 1 µU/ml and intra- and interassay coefficients of variation of less than 10%.

The plasma obestatin levels were measured using a commercial RIA kit (Phoenix Pharmaceuticals, Belmont, CA) after extracting peptides by using the kits provided by the manufacturer. Briefly, 1 ml plasma collected in the aprotinin-containing EDTA tube was loaded onto an SEP-column containing 200 mg C18 (Phoenix Pharmaceuticals), and the eluted sample was evaporated and dissolved in 250 µl RIA buffer. Thus, 1 ml plasma sample was concentrated to 250 µl; thereafter, this sample was diluted. The percent recovery of obestatin after the extraction was 86.0–89.1% when measured with diluted standard obestatin. According to the manufacturer, there was no cross-reactivity with other peptides derived from the ghrelin gene; the inter- and intraassay coefficients of variance were less than 10%, and the lower and upper detection limits of the RIA kit assay were 0.05 and 6.4 ng/ml, respectively. The plasma AG levels were measured in duplicate by using a commercial ELISA kit (Linco Research, Inc., St. Charles, MO); the inter- and intraassay coefficients of variance were less than 10%, and the lower and upper detection limits for this assay were 8.4 and 540 pg/ml, respectively, according to the manufacturer.

The plasma TG levels were measured in duplicate using a commercial ELISA kit (Linco); the inter- and intraassay coefficients of variance were less than 10%, and the lower and upper detection limits for this assay were 40.6 and 2595 pg/ml, respectively, according to the manufacturer.

Statistical analysis

Homeostasis model assessment for insulin resistance (HOMA-IR) and whole-body insulin sensitivity index (WBISI) was calculated as insulin sensitivity indexes. The validity of WBISI has been described in the report of Matsuda and DeFronzo (19).

All values are expressed as median and interquartile ranges in the tables and as means ± SE in the figures. The t test with Bonferroni’s correction was used when the samples were normally distributed; in other cases, the Mann-Whitney U test with Bonferroni’s correction was used to compare the hormone levels between the PWS and control groups.

Two-way ANOVA with repeated measures was used to compare these two groups with regard to the changes in the hormone levels with time. Correlations were determined using Spearman’s correlation analysis. P values of <0.05 were considered statistically significant. All statistical analyses were performed using SAS version 8.2 (SAS Corp., Cary, NC).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The clinical characteristics of the study subjects are described in Table 1Go. The PWS and control groups did not differ significantly with respect to age or sex ratio. However, the PWS children were more insulin sensitive than the obese controls, as demonstrated by HOMA-IR [PWS vs. contro, 3.53 (2.41–5.33) vs. 5.5 (4.67–7.53); P = 0.033], although the BMI, BMI SDS, and percent body fat were similar in the two groups. The fasting glucose levels and those throughout OGTT were not significantly different between the two groups (Fig. 1aGo). Compared with the control group, the PWS group showed lower plasma insulin levels after glucose loading, particularly at 60 min [PWS vs. control: 398.5 pmol/liter (176.5–897.9) vs. 740.4 pmol/liter (486.3–1061.6); P = 0.045], 90 min [384.3 pmol/liter (233.1–816.4) vs. 842.5 pmol/liter (332.6–1324.8); P = 0.025], and 120 min [309.8 pmol/liter (131.8–514.1) vs. 953.6 pmol/liter (523.4–1394.5); P = 0.003] (Fig. 1bGo). However, the baseline insulin levels were not significantly different between the two groups [PWS vs. control: 107.3 pmol/liter (79.2–176.1) vs. 165.3 pmol/liter (136.5–217.4); P = 0.113].


Figure 1
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  		FIG. 1. Left, Fasting glucose levels were not significantly different in PWS patients and controls at baseline or any time during OGTT. All values were expressed as mean ± SE. Right, Plasma insulin levels were significantly lower in PWS especially at 60, 90, and 120 min post glucose loading. *, P < 0.05.

 
Comparison of plasma obestatin, TG, and AG levels between PWS children and normal obese controls

The plasma obestatin levels reached a nadir at 60 min after glucose loading in the PWS children and at 90 min in the controls (Fig. 2aGo). However, the difference in the changes in the obestatin levels from baseline (0 min) to 60 min in the PWS group and that from baseline to 90 min in the control group was not statistically significant (P = 0.108 and P = 0.188, respectively). Importantly, no significant difference in the obestatin levels was observed between the PWS and control groups at any time after glucose loading. Their AUCs for obestatin were calculated, and no significant difference was observed (control: 0.16 ± 0.095 ng/ml/120 min; PWS: 0.025 ± 0.013 ng/ml/120 min; P = 0.885).


Figure 2
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  		FIG. 2. Left, Plasma obestatin levels post glucose loading. No significant difference in obestatin levels was observed between PWS children and normal obese controls at any time post glucose loading. Middle, Plasma AG levels post glucose loading. Right, The levels of total ghrelin were always higher in PWS than in the normal obese controls.

 
In contrast to obestatin, changes in the AG levels from baseline to any of the time points after glucose loading were significant (control group: P = 0.0001 at 30 min, P = 0.0001 at 60 min, P = 0.0001 at 90 min, and P = 0.001 at 120 min vs. PWS group: P = 0.004 at 30 min, P = 0.004 at 60 min, P = 0.004 at 90 min, and P = 0.004 at 120 min). Moreover, the baseline (fasting) AG level was significantly higher in the PWS group than in the control group [PWS vs. control: 0.039 ng/ml (0.026–0.072) vs. 0.028 ng/ml (0.018–0.032); mean ± SD: 0.060 ± 0.053 ng/ml vs. 0.028 ± 0.01 ng/ml; P = 0.011], and it decreased from baseline to a nadir at 30 min after glucose loading in the PWS group. The AG levels at 120 min were higher in the PWS children than in the controls [PWS vs. control: 0.025 ng/ml (0.016–0.041) vs. 0.018 ng/ml (0.014–0.020); P = 0.039] (Fig. 2bGo). The AUC for AG was calculated, and a significant difference was observed between the control and PWS groups (0.027 ± 0.005 ng/ml/120 min vs. 0.081 ± 0.0195 ng/ml/120 min; P = 0.002).

Moreover, the TG levels were always higher in the PWS children than in the controls (P = 0.007 at 0 min, P = 0.003 at 30 min, P = 0.009 at 60 min, P = 0.007 at 90 min, and P = 0.01 at 120 min) (Fig. 2cGo). In addition, the AUC for TG was calculated, and a significant difference was observed between the control and PWS groups (12.795 ± 1.593 ng/ml/120 min vs. 7.2127 ± 1.4407 ng/ml/120 min; P = 0.003). Finally, when the two groups were compared with regard to obestatin/AG and obestatin/TG ratios, no significant difference was observed at any time point during OGTT.

Correlation between plasma obestatin and AG, TG, and serum insulin levels

The obestatin and AG levels showed a correlation at 30 min (r = 0.498, P = 0.018), 60 min (r = 0.424, P = 0.043), and 120 min (r = 0.527, P = 0.015) after glucose challenge in the control group (Fig. 3aGo) and at 60 min (r = 0.465, P = 0.040) in the PWS group (Fig. 3bGo). Likewise, when the AUC of obestatin was compared with the AUC of AG, a positive correlation was observed in the control group (r = 0.461, P = 0.028) but not in the PWS group (r = 0.182, P = 0.258).


Figure 3
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  		FIG. 3. Correlation between obestatin levels and AG levels. Obestatin levels at 60 min post glucose loading were found to be correlated with AG levels at 60 min in controls (r = 0.424; P = 0.043) and in PWS (r = 0.465; P = 0.040).

 
In addition, the obestatin levels were found to correlate with the TG levels at 60 min only in the controls (r = 0.499, P = 0.017). However, significant correlation was not observed between these levels at any other time point in either group. No correlation was observed between the AUC of TG and the AUC of insulin (PWS: r = 0.179, P = 0.262; control: r = –0.226, P = 0.184) in both the groups.

To understand the correlation between obestatin, AG, and insulin in terms of the total secreted amount of each hormone, the correlations of their AUCs were evaluated. A negative correlation was observed between the AUC of AG and AUC of insulin in both PWS (r = –0.432, P = 0.049) and control groups (r = –0.507, P = 0.016). However, the AUC of obestatin did not show a significant correlation with the AUC of insulin in both the groups (PWS: r = 0.168, P = 0.275; control: r = –0.331, P = 0.09).

Insulin sensitivity index vs. obestatin or ghrelin

No correlation was found between the insulin sensitivity index and obestatin. The following were the observations: HOMA-IR in the PWS group: r = 0.025, P = 0.465; HOMA-IR in the control group: r = –0.132, P = 0.319; WBISI in the PWS group: r = 0.054, P = 0.425; and WBISI in the control group: r = 0.096, P = 0.366. The obestatin levels at 0 min were found to correlate with the BMI SD score (SDS) (r = 0.749; P = 0.001) and with the levels at 120 min (r = 0.398; P = 0.012) after glucose challenge in the PWS children (Fig. 4Go) but not in the controls.


Figure 4
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  		FIG. 4. Basal obestatin levels were found to be correlated with BMI SDS at 0 min (r = 0.749; P = 0.001) post glucose loading in PWS.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
To our knowledge, this is the first clinical investigation on plasma obestatin profiles in relation to ghrelin and insulin levels in human subjects, and our findings provide the first evidence that plasma obestatin levels are not correlated to plasma insulin levels in human subjects. Moreover, a negative correlation was observed between the AUC of AG and AUC of insulin in both PWS and control groups. However, the AUC of obestatin was not significantly correlated with the AUC of insulin.

Since the regulation of ghrelin by insulin has been reported (13, 14, 15, 16), it is rather unexpected that this regulation by insulin is independent of the plasma glucose level. Regarding the effect of insulin on ghrelin regulation, our data on ghrelin clearly revealed that the AUC of AG was negatively correlated with the AUC of insulin in both PWS and control groups. It is noteworthy that a negative correlation was found between the AG levels and the insulin levels at all times after the glucose challenge. These results are consistent with that of our previous report as well as other reports showing that the suppression or negative regulation of ghrelin is related to insulin (18, 20, 21). Thus, the regulations of ghrelin and obestatin differ.

Consequently, a question arises. What would be the possible mechanisms underlying these different regulations? Although the process of production and secretion of ghrelin and obestatin is still unveiling, several steps of this process might be potentially influenced by insulin. A recent report elaborated the transcription and RNA processing as well as the posttranslational cleavage and modifications of the preproghrelin mRNA in detail (22). The ghrelin gene encodes 117 amino acids. This preproghrelin contains a 23-amino-acid signal peptide and a 94-amino-acid proghrelin, and the latter includes the 28-amino-acid mature ghrelin and a 66-amino-acid tail (2); this implies that there are several cleavage steps in the process of ghrelin production. In addition, Jeffery et al. (23) reported that exon 4-deleted proghrelin was expressed in the examined mouse tissue. Moreover, desQ 14-ghrelin is produced by alternative splicing. Therefore, isoforms of ghrelin exist, and there might be several levels of regulation. Likewise, obestatin can be produced from either preproghrelin (117 amino acids) or prepro-desQ14-ghrelin, and amidation is mandatory for the receptor binding. To date, neither the enzyme responsible for the propeptide cleavage nor the enzyme responsible for ghrelin acylation has been identified, although potential candidates for ghrelin desacylation as well as N-terminal proteolysis have been proposed (24). Therefore, these peptides or enzymes could be potential candidates influenced by insulin. Especially, our results showed a negative correlation between AUC of AG and AUC of insulin both in PWS and in control and this relationship was not observed between TG and insulin or between obestatin and insulin. This implies that the regulation of insulin may involve the acylation step or occurs after the acylation process of ghrelin. However, we believe that more information is required to put forth a concrete hypothesis on the different effects of insulin on ghrelin and obestatin.

In addition to the above-mentioned results, our study confirms several previously reported findings in PWS subjects. A sustained increase in the TG level was observed during OGTT, and the nadir of TG in the PWS group was always higher than that in the control group; this is in agreement with our previous 24-h monitoring data findings (8). Furthermore, the suppression of AG after the glucose challenge was more remarkable in the PWS group than in the control group, and relative hypoinsulinemia was prominent in the PWS group despite the comparable BMI percentiles and fat percentages in the two groups (18).

One of the findings of the present study, which requires further investigation, is the positive correlation observed between baseline obestatin level and BMI SDS in the PWS children and not in the obese controls. Previously, we reported that plasma ghrelin levels were inversely correlated with the percentage of ideal weight for age and BMI (8). Therefore, this positive correlation between the baseline obestatin level and BMI SDS cannot be explained based on the correlation between obestatin and ghrelin. In fact, the correlation between obestatin and BMI SDS was independent of ghrelin. This finding should be further investigated using a larger PWS patient cohort.

We must mention the lack of apparent difference in the percent body fat between the PWS children and controls. In our study, the BMI and BMI SDS in the PWS children tended to be rather lower than those in the obese controls; this relatively low BMI in the PWS children might have resulted in the lack of apparent difference in the percent body fat between the two groups. Previously, we reported that there was a relative increase in the percent body fat in PWS subjects when compared with age-, sex-, and BMI-matched controls (8, 18, 25).

In conclusion, the present study shows that unlike ghrelin levels, the plasma obestatin levels are not increased in PWS children. Moreover, plasma obestatin is not regulated by insulin both in PWS children and obese controls. Additional studies are required to determine the specific role of obestatin based on the evaluation of the active obestatin levels.


   Footnotes
 
This research was supported by a Samsung Medical Center Clinical Research Development Program grant (CRS 104-67-3) and by the IN-SUNG Foundation for Medical Research.

Disclosure Statement: The authors have nothing to disclose.

First Published Online October 17, 2006

Abbreviations: AG, Acylated ghrelin; BMI, body mass index; HOMA-IR, homeostasis model assessment for insulin resistance; OGTT, oral glucose tolerance test; PWS, Prader-Willi syndrome; SDS, SD score; TG, total ghrelin; WBISI, whole-body insulin sensitivity index.

Received April 6, 2006.

Accepted October 5, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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