AJCN Tufts Nutrition Symposium, Boston & Online Sept 2009
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Moran, L. J
Right arrow Articles by Norman, R. J
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Moran, L. J
Right arrow Articles by Norman, R. J
Agricola
Right arrow Articles by Moran, L. J
Right arrow Articles by Norman, R. J
American Journal of Clinical Nutrition, Vol. 86, No. 6, 1603-1610, December 2007
© 2007 American Society for Nutrition

ORIGINAL RESEARCH COMMUNICATION

Postprandial ghrelin, cholecystokinin, peptide YY, and appetite before and after weight loss in overweight women with and without polycystic ovary syndrome1,2,3

Lisa J Moran, Manny Noakes, Peter M Clifton, Gary A Wittert, Carel W Le Roux, Mohammed A Ghatei, Stephen R Bloom and Robert J Norman

1 From the Research Centre for Reproductive Health, Discipline of Obstetrics and Gynaecology, University of Adelaide, Adelaide, Australia (LJM and RJN); the Commonwealth Scientific and Industrial Research Organisation (CSIRO) Human Nutrition, Adelaide, Australia (LJM, MN, and PMC); the Discipline of Medicine, University of Adelaide, Adelaide, Australia (WG); and the Department of Metabolic Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom (WLRC, MAG, and SRB)

2 Supported by a National Health and Medical Research Council Program Grant (to RJN) and by The University of Adelaide Faculty of Health Sciences Small Research Grants Scheme, Colin Matthews Research Grants for Clinically Based Research, and CSIRO Human Nutrition. Unilever donated the meal replacements used in the weight-loss component of the study; McDonalds Australia donated the premeal tolerance test food.

3 Address reprint requests to RJ Norman, Discipline of Obstetrics and Gynaecology, University of Adelaide, 6th Floor, Medical School North, Adelaide, SA5005, Australia. E-mail: robert.norman{at}adelaide.edu.au.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background:Polycystic ovary syndrome (PCOS) is a common condition associated with obesity and with reproductive and metabolic dysfunction. Abnormalities in appetite regulation in PCOS patients may contribute to difficulties in weight management.

Objective:We aimed to examine appetite, appetite hormones, and ad libitum food consumption before and after weight loss in overweight women with and without PCOS.

Design:Overweight age- and weight-matched women with (n = 14) and without (n = 14) PCOS undertook an 8-wk energy-restricted diet (5185.3 ± 141.6 kJ/d). At baseline and study end, subjects consumed a test meal (936 kJ; 25% of energy from protein, 9% from fat, and 67% from carbohydrate). Subjective appetite and circulating glucose, insulin, ghrelin, cholecystokinin, and peptide YY were assessed at 0, 15, 30, 45, 60, 90, 120, and 180 min. A mixed buffet lunch was then offered to assess ad libitum food intake.

Results:Weight loss (4.2 ± 3.9 kg) did not differ significantly between the 2 groups. Women with PCOS had significantly (P = 0.023) lower ghrelin concentrations before and after weight loss than did women without PCOS. The degree of postprandial ghrelin suppression was lower at weeks 0 (P = 0.048) and 8 (P = 0.069) in women with PCOS than in women without PCOS. There were no significant differences between the 2 groups in appetite responses, buffet consumption, or fasting or postprandial peptide YY and cholecystokinin before or after weight loss.

Conclusions:PCOS was associated with lower fasting ghrelin and a smaller postprandial ghrelin suppression both before and after weight loss but was not associated with other postprandial gut peptides, subjective satiety, or food intake. It is not clear whether appetite regulation is impaired in PCOS.

Key Words: Appetite • obesity • polycystic ovary syndrome • weight loss • ghrelin • cholecystokinin • peptide YY


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Polycystic ovary syndrome (PCOS) is a common endocrine condition in women of reproductive age; it is associated with menstrual dysfunction, hyperandrogenism, a greater risk of developing type 2 diabetes, and an adverse cardiovascular disease risk profile. Insulin resistance (IR) is implicated in its development through the insulin stimulation of ovarian androgen production and the reduction in hepatic synthesis of sex hormone–binding globulin (SHBG) (1). Obesity—in particular, central obesity—is present in 10–65% of Western women with PCOS (2), and its presence worsens the associated IR and metabolic and endocrine features; weight loss reduces abdominal fat and IR and improves menstrual function (3).

We previously showed that overweight women with PCOS have lower postprandial satiety and higher postprandial hunger before and after weight loss than do weight-matched controls (4). There is some evidence that disturbances in appetite regulation in PCOS could account for these reported discrepancies in hunger and satiety. Ghrelin is proposed as an acute meal initiator; ghrelin concentrations increase preprandially and decrease postprandially (5), and ghrelin administration stimulates hunger and food intake (6). The reduction in postprandial ghrelin was less in obese than in lean subjects (7-9) and in overweight PCOS patients than in weight-matched persons without PCOS (4). Cholecystokinin is released from the small intestine postprandially, primarily in response to duodenal protein and fat, and it inhibits gastric emptying and reduces meal size and calorie intake in humans (10). Postprandial cholecystokinin has been reported either to be greater in obese than in lean subjects or to be unaffected by body weight status (11, 12). In overweight women with PCOS, a lower postprandial cholecystokinin response than in weight-matched controls was observed, which further supports impaired appetite regulation in PCOS (13). Peptide YY (PYY), a peptide that is synthesized in the gastrointestinal tract, increases postprandially, increases satiety, and reduces food intake. It has additional functions, including inhibition or reduction of gallbladder secretion, gut motility and pancreatic secretion (14, 15). Reductions in total fasting PYY or impaired postprandial PYY (15, 16) or no changes in fasting PYY (17, 18) have been observed in overweight subjects, and it is not known whether PYY is differentially regulated in PCOS.

Although fasting ghrelin concentrations rise and the postprandial ghrelin response improves with weight loss, these changes may be impaired in women with PCOS (4). Fasting PYY increases (19) or decreases (17) after diet-induced weight loss, and fasting or postprandial cholecystokinin is unchanged by weight loss (20). The effect of weight loss on cholecystokinin and PYY has not yet been examined in persons with PCOS. The aim of this study was therefore to examine fasting and postprandial subjective appetite, appetite hormones (ie, ghrelin, PYY, and cholecystokinin), and ad libitum buffet meal consumption before and after weight loss in overweight women with and without PCOS.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects and recruitment
Overweight age- and weight-matched women with (n = 14) and without (n = 14) PCOS (age: 32.3 ± 5.9 and 36.2 ± 4.5 y, respectively; weight: 94.5 ± 19.8 and 94.9 ± 15.4 kg, respectively) were recruited through public advertisement. PCOS was diagnosed according to the Rotterdam consensus group as previously described (21, 22). Exclusion criteria were pregnancy, breastfeeding, body mass index (BMI; in kg/m2) < 25, type 2 diabetes mellitus, and the use of oral contraceptives, endocrine hormonal treatment, or insulin-sensitizing agents (subjects were required to cease oral contraceptives 4 wk and hormonal treatment or insulin-sensitizing agents 2 wk before commencement of the study). The PCOS patients and control subjects were matched for age, BMI, and smoking status.

All subjects gave written informed consent. We certify that all applicable institutional and governmental regulations concerning the ethical use of human volunteers were followed during this research. The study was approved by the human ethics committees of the Commonwealth Scientific and Industrial Research Organisation Division of Human Nutrition at The Royal Adelaide Hospital and of the Women's and Children's Hospital of South Australia.

Study design and dietary treatment
The study was conducted on an outpatient basis over a span of 8 wk. Subjects followed an energy-restricted diet in which 2 meals/d were replaced with commercially available meal replacements (Slimfast; Unilever Australasia, Epping, Australia), a supply of which was provided every 2 wk (21). The aim of the dietary intervention was to induce an energy deficit of {approx}30% through daily consumption of 2 meal replacements (1800 kJ), a low-fat evening meal, and ≥5 servings of fruit and vegetables (3500 kJ). The dietary composition of the intervention is described in Table 1Go. Nutrient intakes were calculated with the use of DIET 4/NUTRIENT CALCULATION software (version 4; Xyris Software, Highgate Hill, Australia) by using data from Australian food composition tables. Nutritional intake was assessed from 3-d consecutive dietary food records (1 weekday and 2 weekend days) collected every 2 wk and daily dietary checklists. Dietary compliance was determined by subject adherence to the meal replacement regimen. Subjects attended the clinic every 2 wk and were weighed while wearing light clothes but no shoes (model AMZ14 Mettler scales; A&D Mercury, Kinomoto, Japan). At weeks 0 and 8, waist circumference and total fat mass and total fat-free mass (determined by bioelectrical impedance analysis) were measured as previously described (21), and overnight fasting venous blood samples were taken for measurement of testosterone and SHBG. Dietary restraint, disinhibition, and hunger were measured at week 0 by using the Three-Factor Eating Questionnaire (TFEQ) (23). Prestudy dietary intake (the previous 6 mo) was assessed with the use of a food-frequency questionnaire from the Anti-Cancer Foundation. Exercise was assessed at weeks 0 and 8 by using a 7-d physical activity record (24). For the 2 wk before study commencement, subjects weighed themselves daily to ensure weight stability, defined as a weight change of ≤2% of initial body weight.


View this table:
[in this window]
[in a new window]

  		TABLE 1. Dietary intake data for subjects at baseline and during the study intervention1

 
At weeks 0 and 8, subjects underwent a meal tolerance test (MTT). All subjects consumed the same meal the evening before the test (3820 kJ; 20% of energy from protein, 17% from fat, and 62% from carbohydrate) and refrained from consuming alcohol for 24 h. A cannula was inserted into a forearm vein, and an overnight fasting venous blood sample was taken between 0800 and 1000 for measurement of plasma glucose and insulin concentrations and serum ghrelin, cholecystokinin, and PYY concentrations. Subjects then completed a validated visual analogue scale (VAS) questionnaire to assess subjective hunger as previously described (25). The change in ratings from baseline was quantified. Subjects consumed a liquid preload of Slimfast [325 mL, 936 kJ, 12 g protein (25% of energy from protein), 2 g fat (9% of energy from fat), and 35 g carbohydrate (67% of energy from carbohydrate)] within 5 min; additional blood samples were taken and VAS questionnaires were completed at 15, 30, 45, 60, 90, 120, and 180 min after meal consumption. At 180 min, subjects were given a mixed buffet-style lunch (12.1 MJ; 15% of energy from protein, 44% from fat, and 41% from carbohydrate); each subject served his or her own meal from designated portions of the foods and ate until satisfied over a 30-min period. Each food was weighed to the nearest gram with the use of digital scales before and after eating. Total (glucose, insulin, cholecystokinin, and PYY), incremental (ghrelin), and net (VAS) areas under the curve (AUCs) during the 3-h MTT were calculated geometrically by using the trapezoidal rule (26).

Biochemical measurements
Blood for measurement of serum concentrations was collected in tubes with no additives and allowed to clot at room temperature for 30 min. Blood for measurement of plasma concentrations was collected in tubes containing sodium fluoride and EDTA (glucose) or potassium and EDTA and aprotinin (aprotinin concentration: 500 KIU/mL blood; Roche Diagnostics, Indianapolis, IN) (ghrelin, cholecystokinin, and PYY) and stored on ice. Serum and plasma were stored at –80 °C. Serum SHBG and total testosterone (bound and unbound) (3), total ghrelin (4), insulin and glucose (21), cholecystokinin (11), and total PYY (1–36 and 3–36) (16) were measured as described previously. The homeostatic model assessment (HOMA) was used as a surrogate measure from which to calculate insulin sensitivity according to the following equation (27):

Formula 1(1)
The free androgen index (testosterone/SHBG x 100) and equilibrium-binding equations were used for estimation of free testosterone (28). Biochemical assays were performed in a single assay at the completion of the study, and all samples for individuals were analyzed in the same assay.

Statistical analysis
Parametric data were presented as means ± SEMs except where specified. Nonparametric data (TFEQ) were presented as median, minimum, and maximum. When data were nonnormally distributed, data were log transformed for analysis. Results are presented for 28 subjects (n = 14 for both the PCOS patients and control subjects); for postprandial glucose, insulin, ghrelin, PYY, and cholecystokinin, the numbers differed slightly (n = 14 and 13 in the PCOS patients and control subjects, respectively) because of incomplete data. Two-tailed statistical analysis was performed with the use of SPSS for WINDOWS software (version 14.0; SPSS Inc, Chicago, IL) with statistical significance set at an {alpha} level of P < 0.05. Baseline data were assessed by using a one-factor analysis of variance for parametric data and a Kruskal-Wallis test for nonparametric data (TFEQ). Comparisons between time points were assessed by using a general linear model repeated-measures analysis of variance with PCOS diagnosis as the between-subject factor. In the event of an interaction, Bonferroni post hoc pairwise comparisons were performed. Relations between variables were examined by using bivariate and partial correlations and analysis of covariance after adjustment for weight, fasting and postprandial insulin, and total energy intake. This study had 80% power to detect a preweight-loss difference of 75.9 pmol/L in fasting ghrelin and a change of 31.3 pmol/L in fasting ghrelin during weight loss between subjects with and without PCOS (P < 0.05 for both) (4).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Subjects, physical activity, dietary intake, weight loss, body composition, and reproductive hormones
Baseline characteristic of the subjects are shown in Table 1Go. For the TFEQ data, there were no differences in the baseline scores for dietary restraint (median: 9.5; range: 3–16), disinhibition (10; 3–16), or hunger (7; 0–14) between the PCOS patients and the control subjects. Activity levels did not differ significantly between the 2 groups at week 0 and did not change throughout the study. There were no significant differences in energy or macronutrient intake between the 2 groups at baseline or during the study intervention (Table 2Go). Decreases in weight (Formula 1 ± SEM: 4.2 ± 3.9 kg or 4.3 ± 3.8%), waist circumference, total fat mass, total fat-free mass, free testosterone, free androgen index, and testosterone and increases in SHBG occurred in all subjects with no differential effect of PCOS status (Table 2Go).


View this table:
[in this window]
[in a new window]

  		TABLE 2. Weight, body composition, lipids, glucose, and reproductive hormones before and after 8 wk of energy restriction1

 
Insulin and glucose homeostasis
There was no effect of PCOS status on changes in fasting glucose and no change in fasting glucose over the study duration. There was an interaction between postprandial glucose and PCOS status (P = 0.017) so that the postprandial glucose response decreased significantly (P = 0.043) only in the PCOS patients, and no changes in postprandial glucose occurred with weight loss in the control subjects (Figure 1Go). Decreases in HOMA (13.6%; P = 0.010), fasting insulin (15.9%; P = 0.004), AUC insulin (20.0 ± 3.9%; P < 0.001), and postprandial insulin (P < 0.001) did not differ significantly between the 2 groups. There was no difference between the 2 groups in the magnitude of the change, although subjects without PCOS had lower fasting, AUC insulin, and postprandial insulin responses at all time points (Figure 1Go, Table 1Go).


Figure 1
View larger version (9K):
[in this window]
[in a new window]

  		FIGURE 1.. Mean (±SEM) glucose, insulin, and ghrelin concentrations at baseline and 15, 30, 45, 60, 90, 120, and 180 min after the ingestion of a test meal at weeks 0 (—) and 8 (---). Week 0 and week 8 data were compared by repeated-measures ANOVA with week and blood sampling time as within-subject factors and polycystic ovary syndrome (PCOS) status as the between-subject factor. {diamondsuit}, subjects with PCOS, n = 14; {square}, subjects without PCOS, n = 13. To convert glucose values from mmol/L to mg/dL, multiply by 18. To convert insulin values from mU/L to pmol/L, multiply by 6.95. To convert ghrelin values from pmol/L to pg/mL, multiply by 3.38. *Significant week x min x PCOS status effect, P = 0.017. **Significant effect of time from week 0 to week 8 for fasting (P = 0.004) and postprandial (P < 0.001) insulin. {dagger}Significant between-subject effect of PCOS status, P < 0.05. {dagger}{dagger}Significant difference at 0 min between subjects with and subjects without PCOS at week 0 (P = 0.042) and week 8 (P = 0.009). {ddagger}Significant min x PCOS status effect (P = 0.023).

 
Fasting ghrelin
Fasting ghrelin was significantly higher in the PCOS patients than in the control subjects at week 0 (486.2 ± 41.1 and 318.1 ± 44.0 pg/mL, respectively; P = 0.01), and there was a trend for it to be higher at week 8 (463.5 ± 36.8 and 347.0 ± 56.0 pg/mL, respectively; P = 0.099). There was no change in fasting ghrelin after weight loss in either group. At weeks 0 and 8, fasting ghrelin in the PCOS patients and control subjects was correlated with fasting insulin (r = –0.518, P = 0.006 and r = –0.515, P = 0.006, respectively), HOMA (r = –0.488, P = 0.008 and r = –0.508, P = 0.007, respectively), free androgen index (r = –0.553, P = 0.003 and r = –0.489, P = 0.010, respectively), and free testosterone (r = –0.538, P = 0.004 and r = –0.471, P = 0.013, respectively). After control for weight, all of the above relations remained except fasting ghrelin and HOMA at week 0 (r = –0.369, P = 0.063).

Postprandial ghrelin
The PCOS patients had significantly lower ghrelin concentrations at all time points after preload consumption before and after weight loss than did the control subjects (P = 0.023 for between-subject effect of PCOS) (Figure 1Go). There was a trend for an effect of weight loss on changes in test meal ghrelin (P = 0.097) and a significant effect of PCOS status on test meal ghrelin (minute-by-PCOS status effect, P = 0.023). In the PCOS patients, the postprandial ghrelin response was more impaired (as indicated by a lesser postprandial decrease) at week 0 and tended to be more impaired at week 8 than in the control subjects (P = 0.048 and 0.069, respectively, for time-by-PCOS status effect). The above differences in ghrelin between subjects with and without PCOS were removed on adjustment for fasting or postprandial insulin at week 0 or 8.

Fasting and postprandial PYY and cholecystokinin
There was no significant effect of PCOS status on baseline cholecystokinin in either the PCOS patients or the control subjects (1.1 ± 0.3 and 0.7 ± 0.2 pmol/L, respectively; P = 0.276) and PYY (17.2 ± 1.6 and 14.0 ± 0.7 pmol/L, respectively; P = 0.091); on post-weight-loss cholecystokinin (1.0 ± 0.3 and 0.7 ± 0.2 pmol/L, respectively; P = 0.302) and PYY (15.9 ± 2.8 and 13.6 ± 1.0 pmol/L, respectively; P = 0.381); or on the changes in fasting cholecystokinin and PYY with weight loss. PCOS status had no significant effect on postprandial cholecystokinin or PYY or on changes in postprandial cholecystokinin or PYY with weight loss (Table 1Go). There was no significant effect of weight loss on fasting cholecystokinin (P = 0.919) or PYY (P = 0.404) or postprandial cholecystokinin (P = 0.440) or PYY (P = 0.210) in either group. Cholecystokinin and PYY increased in both groups after test meal consumption at both week 0 and week 8 (P < 0.001). The change in weight was significantly and negatively correlated with the change in AUC PYY (r = –0.453, P = 0.018) or CCK (r = –0.443, P = 0.021) with weight loss.

Visual analogue scores
PCOS patients and control subjects had an increase in their sensation of fasting fullness with weight loss (29.4 ± 3.5 and 38.4 ± 4.8 mm, respectively; P = 0.033) and a decrease in their sensation of postprandial fullness with weight loss (P = 0.005), as reflected in the AUC (3326.5 ± 630.0 and 1130.9 ± 686.4 mm/180 min, respectively; P = 0.009). No significant reduction in fullness after weight loss was observed with adjustment for the change in the total amount of energy consumed at the buffet meal. There were no other significant differences in fasting or postprandial VAS measures before or after weight loss or between the PCOS patients and control subjects (data not shown). None of the postprandial appetite hormones correlated with each other or with VAS.

Buffet dietary intake
The energy intake at the buffet meal did not differ significantly between the PCOS patients and control subjects before (4625.8 ± 458.6 and 5476.3 ± 354.6 kJ, respectively) or after (3921.4 ± 355.3 and 4314.6 ± 330.1 kJ, respectively) weight loss. Macronutrient intake and fatty acid profile also did not differ significantly before or after weight loss (data not shown). After weight loss, the amount of food eaten at the buffet meal decreased equivalently, by 919.0 ± 260.0 kJ, for all subjects (P = 0.002); there were consequent reductions in total macronutrient intake but no significant changes in proportional macronutrient intake. The amount of food eaten at the buffet correlated significantly with weight (r = 0.489, P = 0.008), BMI (r = 0.447, P = 0.017), total FFM (r = 0.498, P = 0.007), and total FM (r = 0.513, P = 0.005) at week 0 but not at week 8.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We have confirmed reports of lower fasting ghrelin concentrations (4, 29), and we also reported a smaller postprandial reduction in ghrelin in overweight women with PCOS than in control subjects. In contrast to previous findings (4), we observed no significant change in fasting ghrelin and only a trend for a change in postprandial ghrelin with weight loss. This discrepancy likely is due to the modest weight loss (4.2 kg), because no significant changes in ghrelin were observed after weight losses of 3% to 5% (30). Postmeal ghrelin suppression is related to the energy content of the meal (9), and it correlates with postmeal decreases in hunger and increases in satiety (31). The impairment in postprandial ghrelin secretion observed in obesity (7-9) may be related to the impairment of appetite regulation in overweight humans, which is consistent with reports of delayed satiation (32). Furthermore, positive energy balance may decrease the sensitivity of the central nervous system to ghrelin (33), which suggests that postprandial ghrelin and its regulatory role on appetite may be blunted in obesity. The improvement in postprandial ghrelin that follows weight loss suggests an improvement in appetite regulation, and this possibility is supported by the post-weight-loss reduction in food consumption observed here and by other investigators (34).

We observed an impaired postprandial ghrelin response in women with PCOS that was partially normalized by weight loss; this same observations was previously made by our group in conjunction with increased postprandial hunger (4). One proposed regulator of ghrelin is insulin, which could acutely suppress ghrelin secretion postprandially (35) and could chronically suppress it in hyperinsulinemic conditions such as obesity or PCOS (4, 36). A recent study found that, in obese children, postprandial ghrelin decreases were positively correlated with insulin sensitivity and negatively correlated with postprandial insulin (35). A dose-dependent suppression of total ghrelin by hyperinsulinemia was also observed in subjects without type 2 diabetes, whereas supraphysiological insulin concentrations were required to suppress ghrelin concentrations in subjects with type 2 diabetes (37). The ability of insulin to suppress ghrelin may thus be altered by IR. This possibility is consistent with the lower ghrelin concentrations observed in the present study in persons with PCOS and in all subjects before weight loss and with amelioration of the differences in ghrelin between women with and without PCOS after adjustment for insulin concentrations. Furthermore, women with PCOS but without IR have fasting ghrelin concentrations similar to those of control subjects and higher than those of women with PCOS and IR (29). Thus, it is possible that abnormalities in appetite regulation will be more prevalent in women with PCOS and IR than in women with PCOS but not IR. Conversely, our previous study showed lower fasting ghrelin concentrations in women with PCOS than in weight- and insulin-matched control subjects, which suggests a role for PCOS independent of IR in regulating ghrelin (4). A variety of contributory factors to ghrelin regulation in PCOS—including adiponectin (38), fat–free mass (39), and androgens (40)—also warrant investigation. A greater degree of weight loss may be necessary to reduce insulin, androgen, or other factors sufficiently to induce changes in ghrelin.

We report for the first time that fasting and postprandial PYY do not differ significantly in age- and weight-matched women with or without PCOS before or after weight loss. Postprandial PYY profiles are proposed to play a role in regulating both acute satiation and longer-term satiety (16, 41), and the similar postprandial PYY may account for the similar food intake between women with and without PCOS. We also report for the first time that postprandial PYY is not altered after diet-induced weight loss. Lower fasting and postprandial PYY concentrations observed previously in obese persons—potentially caused by decreased PYY synthesis or release—could cause reduced postprandial satiety and therefore potentially contribute to obesity (15, 16). Fasting total PYY increases with weight loss, and the increase is positively related to the degree of weight loss (19). The lack of a change in fasting or postprandial PYY with weight loss seen in the present study was unexpected; however, the intervention duration and degree of weight loss (4.2 kg) may have been inadequate to induce changes. Alternatively, this lack of a change may reflect increased central nervous system sensitivity to the effects of PYY or an adaptive response to attempts to restore energy balance. Food intake is similarly reduced after PYY 3–36 infusions in obese and lean subjects (15), which indicates that obese subjects may not suffer PYY resistance. The negative correlation between the degree of weight loss and a change in AUC PYY could also indicate that subjects with the greatest degree of weight loss potentially had a relative compensatory decrease in postprandial PYY; this possibility is supported by recent studies showing decreases in fasting (17) or postprandial (42) PYY after diet- or gastric bypass–induced weight loss.

Unlike other investigators (13), we observed no differences in fasting or postprandial cholecystokinin between women with and without PCOS either before or after weight loss. It is not clear whether the similar cholecystokinin profiles of the women with and without PCOS are related to the consequent buffet meal energy intake, because the primary effects of cholecystokinin are an inhibition of gastric emptying, an increase in satiation, and a reduction in meal size (43). However, a recent study suggested a potential role of cholecystokinin in satiety through a prolonged postprandial elevation of cholecystokinin and the possibility that cholecystokinin is a significant predictor of late postprandial appetite (44). Although we observed a significant negative correlation between the degree of weight loss and the change in AUC cholecystokinin in all subjects, fasting and postprandial cholecystokinin did not change with weight loss. This is consistent with previous reports of similar postprandial cholecystokinin profiles between aged-matched lean and obese subjects (11), no changes in postprandial cholecystokinin with diet-induced weight loss (20), and similar satiating effects of cholecystokinin infusions in lean and obese subjects (43). Conversely, postprandial cholecystokinin was higher in overweight than in lean males and females (12). Cholecystokinin is released postprandially from the small intestine, predominantly in response to duodenal protein and fat (10). The relatively low amount of protein or fat in our preload may not have provided a sufficient stimulus (25% of energy from protein, 67% from carbohydrate, and 9% from fat compared with 17% of energy from protein, 54% from carbohydrate, and 28% from fat) (13). The lack of observed differences in PYY may also be affected by the preload macronutrient composition, because postprandial PYY is stimulated more strongly by protein than by fat or carbohydrate (45). Furthermore, PYY is released in proportion to calories ingested (14), and the energy content of the preload (936 kJ) may not have been adequate to allow detection of subtle differences.

Whereas altered ghrelin regulation in PCOS potentially indicates impaired appetite regulation and difficulty with weight management, these possibilities are not supported by the findings of similar cholecystokinin and PYY concentrations, subjective appetite, and buffet food intake in women with and without PCOS. In addition to its proposed role in appetite regulation, ghrelin has a variety of functions—including endocrine pancreatic function, glucose metabolism, inflammation, vasodilation, and ovarian function (46-48). It is possible that the lower ghrelin concentrations commonly observed in persons with PCOS represent the increased metabolic, diabetic, and reproductive dysfunction associated with the condition rather than abnormalities in appetite regulation. The preprandial increase in ghrelin also may occur as an anticipatory response to feeding rather than as a physiologic meal initiator (49, 50); this possibility is supported by a later onset of the postprandial ghrelin decrease in obese than in lean males, but similar energy intakes in the 2 groups (11). The observed differences in ghrelin may induce subtle alterations in appetite, which would be more detectable in a free-living environment with ad libitum energy intake. Selection of subjects with similar eating behaviors and performance of the MTT at defined stages of the menstrual cycle would further strengthen our observations, because variations in appetite or food intake, appetite hormones (specifically, cholecystokinin), insulin sensitivity, or glucose homeostasis have been reported over the course of the menstrual cycle (51-53) or between restrained and unrestrained eaters (54). Other potential limitations of the current study include the measurement of total ghrelin, which comprises biologically active (Ser3 octanolyated) and inactive ghrelin and which may not be optimal for the assessment of ghrelin regulation in diverse conditions such as obesity, weight loss, and PCOS (55).

In conclusion, we observed no differences in postprandial subjective appetite, PYY and cholecystokinin concentrations, and ad libitum food consumption, but we confirmed alterations in fasting and postprandial ghrelin concentrations in women with PCOS. Ad libitum buffet consumption was decreased after modest weight loss in conjunction with an improved postprandial ghrelin profile, but no changes were seen in subjective appetite or circulating cholecystokinin or PYY concentrations. It is not clear whether women with PCOS have abnormal regulation of energy homeostasis or appetite hormones, and, despite improving some aspects of appetite regulation, the effect of weight loss on postprandial anorexigenic hormones is unclear in overweight women with or without PCOS.


   ACKNOWLEDGMENTS
 
We thank Julia Weaver, Vanessa Courage, Rosemary McArthur, Ruth Pinches, Sue Evans, Deborah Roffe, Mark Mano, Candita Sullivan, Paul Orchard, Cathryn Seccafien and Michael Mular for their assistance.

The authors' responsibilities were as follows—LM, MN, PMC, GAW, and RJN: conceived and designed the study and contributed to data analysis and manuscript writing; CWL, MAG, and SRB: contributed to data analysis and manuscript writing; LM: coordinated the study, collected the data, wrote the manuscript, and contributed to the design and implementation of the study dietary protocol; and MN: contributed to the design of the study dietary protocol. None of the authors had a personal or financial conflict of interest.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 1997;18:774–800.[Abstract/Free Full Text]
  2. Kiddy DS, Sharp PS, White DM, et al. Differences in clinical and endocrine features between obese and non-obese subjects with polycystic ovary syndrome: an analysis of 263 consecutive cases. Clin Endocrinol (Oxf) 1990;32:213–20.[Medline]
  3. Huber-Buchholz MM, Carey DG, Norman RJ. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. J Clin Endocrinol Metab 1999;84:1470–4.[Abstract/Free Full Text]
  4. Moran LJ, Noakes M, Clifton PM, et al. Ghrelin and measures of satiety are altered in polycystic ovary syndrome but not differentially affected by diet composition. J Clin Endocrinol Metab 2004;89:3337–44.[Abstract/Free Full Text]
  5. Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 2001;50:1714–9.[Abstract/Free Full Text]
  6. Druce MR, Neary NM, Small CJ, et al. Subcutaneous administration of ghrelin stimulates energy intake in healthy lean human volunteers. Int J Obes (Lond) 2006;30:293–6.[Medline]
  7. English PJ, Ghatei MA, Malik IA, Bloom SR, Wilding JP. Food fails to suppress ghrelin levels in obese humans. J Clin Endocrinol Metab 2002;87:2984–87.[Abstract/Free Full Text]
  8. Moran LJ, Luscombe-Marsh ND, Noakes M, Wittert GA, Keogh JB, Clifton PM. The satiating effect of dietary protein is unrelated to postprandial ghrelin secretion. J Clin Endocrinol Metab 2005;90:5205–11.[Abstract/Free Full Text]
  9. le Roux CW, Patterson M, Vincent RP, Hunt C, Ghatei MA, Bloom SR. Postprandial plasma ghrelin is suppressed proportional to meal calorie content in normal-weight but not obese subjects. J Clin Endocrinol Metab 2005;90:1068–71.[Abstract/Free Full Text]
  10. Liddle RA, Goldfine ID, Rosen MS, Taplitz RA, Williams JA. Cholecystokinin bioactivity in human plasma. Molecular forms, responses to feeding, and relationship to gallbladder contraction. J Clin Invest 1985;75:1144–52.[Medline]
  11. Bowen J, Noakes M, Clifton PM. Appetite regulatory hormone responses to various dietary proteins differ by body mass index status despite similar reductions in ad libitum energy intake. J Clin Endocrinol Metab 2006;91:2913–9.[Abstract/Free Full Text]
  12. French SJ, Murray B, Rumsey RD, Sepple CP, Read NW. Preliminary studies on the gastrointestinal responses to fatty meals in obese people. Int J Obes Relat Metab Disord 1993;17:295–300.[Medline]
  13. Hirschberg AL, Naessen S, Stridsberg M, Bystrom B, Holtet J. Impaired cholecystokinin secretion and disturbed appetite regulation in women with polycystic ovary syndrome. Gynecol Endocrinol 2004;19:79–87.[Medline]
  14. Adrian TE, Ferri GL, Bacarese-Hamilton AJ, Fuessl HS, Polak JM, Bloom SR. Human distribution and release of a putative new gut hormone, peptide YY. Gastroenterology 1985;89:1070–7.[Medline]
  15. Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ, Frost GS, et al. Inhibition of food intake in obese subjects by peptide YY3–36. N Engl J Med 2003;349:941–8.[Abstract/Free Full Text]
  16. le Roux CW, Batterham RL, Aylwin SJ, Patterson M, Borg CM, Wynne KJ, et al. Attenuated peptide YY release in obese subjects is associated with reduced satiety. Endocrinology 2006;147:3–8.[Abstract/Free Full Text]
  17. Pfluger PT, Kampe J, Castaneda TR, Vahl T, D'Alessio DA, Kruthaupt T, et al. Effect of human body weight changes on circulating levels of peptide YY and peptide YY3–36. J Clin Endocrinol Metab 2007;92:583–8.[Abstract/Free Full Text]
  18. Stock S, Leichner P, Wong AC, Ghatei MA, Kieffer TJ, Bloom SR, et al. Ghrelin, peptide YY, glucose-dependent insulinotropic polypeptide, and hunger responses to a mixed meal in anorexic, obese, and control female adolescents. J Clin Endocrinol Metab 2005;90:2161–8.[Abstract/Free Full Text]
  19. Roth CL, Enriori PJ, Harz K, Woelfle J, Cowley MA, Reinehr T. Peptide YY is a regulator of energy homeostasis in obese children before and after weight loss. J Clin Endocrinol Metab 2005;90:6386–91.[Abstract/Free Full Text]
  20. Lieverse RJ, van Seters AP, Jansen JB, Lamers CB. Relationship between hunger and plasma cholecystokinin during weight reduction with a very low calorie diet. Int J Obes Relat Metab Disord 1993;17:177–9.[Medline]
  21. Moran LJ, Noakes M, Clifton PM, Wittert GA, Williams G, Norman RJ. Short-term meal replacements followed by dietary macronutrient restriction enhance weight loss in polycystic ovary syndrome. Am J Clin Nutr 2006;84:77–87.[Abstract/Free Full Text]
  22. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004;19:41–7.[Abstract/Free Full Text]
  23. Stunkard AJ, Messick S. The three-factor eating questionnaire to measure dietary restraint, disinhibition and hunger. J Psychosom Res 1985;29:71–83.[Medline]
  24. Bouchard C, Tremblay A, Leblanc C, Lortie G, Savard R, Theriault G. A method to assess energy expenditure in children and adults. Am J Clin Nutr 1983;37:461–7.[Abstract/Free Full Text]
  25. Luscombe-Marsh ND, Noakes M, Wittert GA, Keogh JB, Foster P, Clifton PM. Carbohydrate-restricted diets high in either monounsaturated fat or protein are equally effective at promoting fat loss and improving blood lipids. Am J Clin Nutr 2005;81:762–72.[Abstract/Free Full Text]
  26. Wolever TM, Jenkins DJ, Jenkins AL, Josse RG. The glycemic index: methodology and clinical implications. Am J Clin Nutr 1991;54:846–54.[Abstract/Free Full Text]
  27. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412–9.[Medline]
  28. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 1999;84:3666–72.[Abstract/Free Full Text]
  29. Schofl C, Horn R, Schill T, Schlosser HW, Muller MJ, Brabant G. Circulating ghrelin levels in patients with polycystic ovary syndrome. J Clin Endocrinol Metab 2002;87:4607–10.[Abstract/Free Full Text]
  30. Weigle DS, Cummings DE, Newby PD, et al. Roles of leptin and ghrelin in the loss of body weight caused by a low fat, high carbohydrate diet. J Clin Endocrinol Metab 2003;88:1577–86.[Abstract/Free Full Text]
  31. Lejeune MP, Westerterp KR, Adam TC, Luscombe-Marsh ND, Westerterp-Plantenga MS. Ghrelin and glucagon-like peptide 1 concentrations, 24-h satiety, and energy and substrate metabolism during a high-protein diet and measured in a respiration chamber. Am J Clin Nutr 2006;83:89–94.[Abstract/Free Full Text]
  32. Delgado-Aros S, Cremonini F, Castillo JE, et al. Independent influences of body mass and gastric volumes on satiation in humans. Gastroenterology 2004;126:432–40.[Medline]
  33. Tung YC, Hewson AK, Carter RN, Dickson SL. Central responsiveness to a ghrelin mimetic (GHRP-6) is rapidly altered by acute changes in nutritional status in rats. J Neuroendocrinol 2005;17:387–93.[Medline]
  34. Doucet E, St-Pierre S, Almeras N, Tremblay A. Relation between appetite ratings before and after a standard meal and estimates of daily energy intake in obese and reduced obese individuals. Appetite 2003;40:137–43.[Medline]
  35. Maffeis C, Bonadonna RC, Consolaro A, et al. Ghrelin, insulin sensitivity and postprandial glucose disposal in overweight and obese children. Eur J Endocrinol 2006;154:61–8.[Abstract/Free Full Text]
  36. Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML. Circulating ghrelin levels are decreased in human obesity. Diabetes 2001;50:707–9.[Abstract/Free Full Text]
  37. Anderwald C, Brabant G, Bernroider E, et al. Insulin-dependent modulation of plasma ghrelin and leptin concentrations is less pronounced in type 2 diabetic patients. Diabetes 2003;52:1792–8.[Abstract/Free Full Text]
  38. Vrbikova J, Dvorakova K, Hill M, et al. Determinants of circulating adiponectin in women with polycystic ovary syndrome. Gynecol Obstet Invest 2005;60:155–61.[Medline]
  39. Purnell JQ, Cummings D, Weigle DS. Changes in 24-h area-under-the-curve ghrelin values following diet-induced weight loss are associated with loss of fat-free mass, but not with changes in fat mass, insulin levels or insulin sensitivity. Int J Obes (Lond) 2007;31:385–9.[Medline]
  40. Panidis D, Farmakiotis D, Koliakos G, et al. Comparative study of plasma ghrelin levels in women with polycystic ovary syndrome, in hyperandrogenic women and in normal controls. Hum Reprod 2005;20:2127–32.[Abstract/Free Full Text]
  41. Batterham RL, Cowley MA, Small CJ, et al. Gut hormone PYY(3–36) physiologically inhibits food intake. Nature 2002;418:650–4.[Medline]
  42. Morinigo R, Moize V, Musri M, et al. Glucagon-like peptide-1, peptide YY, hunger, and satiety after gastric bypass surgery in morbidly obese subjects. J Clin Endocrinol Metab 2006;91:1735–40.[Abstract/Free Full Text]
  43. Lieverse RJ, Jansen JB, Masclee AM, Lamers CB. Satiety effects of cholecystokinin in humans. Gastroenterology 1994;106:1451–4.[Medline]
  44. Bowen J, Noakes M, Trenerry C, Clifton PM. Energy intake, ghrelin, and cholecystokinin after different carbohydrate and protein preloads in overweight men. J Clin Endocrinol Metab 2006;91:1477–83.[Abstract/Free Full Text]
  45. Batterham RL, Heffron H, Kapoor S, et al. Critical role for peptide YY in protein-mediated satiation and body-weight regulation. Cell Metab 2006;4:223–33.[Medline]
  46. Murata M, Okimura Y, Iida K, et al. Ghrelin modulates the downstream molecules of insulin signaling in hepatoma cells. J Biol Chem 2002;277:5667–74.[Abstract/Free Full Text]
  47. Li WG, Gavrila D, Liu X, et al. Ghrelin inhibits proinflammatory responses and nuclear factor-kappaB activation in human endothelial cells. Circulation 2004;109:2221–6.[Abstract/Free Full Text]
  48. Skommer J, Katulski K, Poreba E, et al. Gherlin expression in women with polycystic ovary syndrome–a preliminary study. Eur J Gynaecol Oncol 2005;26:553–6.[Medline]
  49. Drazen DL, Vahl TP, D'Alessio DA, Seeley RJ, Woods SC. Effects of a fixed meal pattern on ghrelin secretion: evidence for a learned response independent of nutrient status. Endocrinology 2006;147:23–30.[Abstract/Free Full Text]
  50. Natalucci G, Riedl S, Gleiss A, Zidek T, Frisch H. Spontaneous 24-h ghrelin secretion pattern in fasting subjects: maintenance of a meal-related pattern. Eur J Endocrinol 2005;152:845–50.[Abstract/Free Full Text]
  51. Escalante Pulido JM, Alpizar Salazar M. Changes in insulin sensitivity, secretion and glucose effectiveness during menstrual cycle. Arch Med Res 1999;30:19–22. (Published erratum appears in Arch Med Res 1999;30:265.)[Medline]
  52. Dye L, Blundell JE. Menstrual cycle and appetite control: implications for weight regulation. Hum Reprod 1997;12:1142–51.[Abstract/Free Full Text]
  53. Frick G, Bremme K, Sjogren C, Linden A, Uvnas-Moberg K. Plasma levels of cholecystokinin and gastrin during the menstrual cycle and pregnancy. Acta Obstet Gynecol Scand 1990;69:317–20.[Medline]
  54. De Castro JM. How can eating behavior be regulated in the complex environments of free-living humans? Neurosci Biobehav Rev 1996;20:119–31.[Medline]
  55. Marzullo P, Verti B, Savia G, et al. The relationship between active ghrelin levels and human obesity involves alterations in resting energy expenditure. J Clin Endocrinol Metab 2004;89:936–9.[Abstract/Free Full Text]
Received for publication May 30, 2007. Accepted for publication August 8, 2007.





This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Moran, L. J
Right arrow Articles by Norman, R. J
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Moran, L. J
Right arrow Articles by Norman, R. J
Agricola
Right arrow Articles by Moran, L. J
Right arrow Articles by Norman, R. J

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS