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Is There a Role for Ghrelin and Peptide-YY in the Pathogenesis of Obesity in Adults with Acquired Structural Hypothalamic Damage?

Diabetes and Endocrinology Research Group (C.D., I.A.M., J.P.H.W., J.H.P.), University Hospital Aintree, Clinical Sciences Center, Liverpool L9 7AL, United Kingdom; Department of Diabetes and Endocrinology (P.J.E.), Derriford Hospital, Plymouth PL6 8DH, United Kingdom; Department of Metabolic Medicine (M.P., M.A.G.), Imperial College School of Medicine, Hammersmith Hospital, London W12 0HS, United Kingdom; and Kissilef Laboratory (T.M.D., J.C.G.H.), Department of Psychology, University of Liverpool, Liverpool L69 7ZB, United Kingdom

Address all correspondence and requests for reprints to: Dr. C. Daousi, University Hospital Aintree, Diabetes and Endocrinology Research Group, Clinical Sciences Center, Longmoor Lane, Liverpool L9 7AL, United Kingdom. E-mail: c.daousi{at}ntlworld.com.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Obesity is a common sequel to hypothalamic tumors and their treatment, but the underlying mechanisms are not fully established.

Objective: Our objective was to evaluate the role of ghrelin and peptide-YY (PYY) in human hypothalamic obesity.

Setting: The study took place at a University Medical Center.

Participants: Subjects included 14 adult patients (six male, eight female) with tumors of the hypothalamic region and 15 healthy controls (six male and nine female) matched for age, body mass index, and percentage of body fat.

Interventions: Plasma ghrelin and total PYY were measured using RIAs after an overnight fast and 15, 30, 60, 120, and 180 min after a mixed meal.

Main Outcome Measures: We assessed ghrelin, PYY, and appetite ratings.

Results: The fall in ghrelin levels after the test meal was similar in the two groups. There was no statistically significant change postprandially in circulating PYY in the patients with hypothalamic damage. Fasting leptin levels and postprandial insulin responses were also similar in the two groups. Patients with hypothalamic damage reported higher hunger ratings at 3 h after the meal (P = 0.01) and a stronger desire to eat at 2 h (P = 0.01) and 3 h (P = 0.02) compared with the control group.

Conclusions: Adult patients with structural hypothalamic damage show impaired satiety, but the changes observed in circulating ghrelin and PYY concentrations in response to a test meal do not indicate a central role for these gut hormones in the control of appetite and the pathogenesis of obesity in these patients.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
WEIGHT GAIN AND obesity after hypothalamic insults have been described in both children and adults (1, 2, 3). Although some potential mechanisms contributing to the development of obesity in children with hypothalamic damage have been explored (4, 5, 6), far fewer data exist in the adult population with acquired structural hypothalamic damage (7).

In recent years, the hypothalamus has emerged as an important control center of energy homeostasis. Ghrelin, peptide-YY (PYY), leptin, and insulin are only a few of the hormonal signals that have been implicated in the coordination of energy balance. Plasma ghrelin has recently been shown to be raised in patients with Prader-Willi syndrome (PWS) (8), a genetic form of hypothalamic obesity. Obesity and hyperphagia are cardinal features of this syndrome and a causal link with the known hyperghrelinemia in these patients has been postulated. Recent work has also shown that PYY inhibits appetite in the fasting state at physiological concentrations, and obese subjects have lower endogenous levels of PYY, suggesting that PYY deficiency may contribute to the pathogenesis of obesity (9). Hyperleptinemia was found to be associated with hyperphagia in obese children with craniopharyngioma (4), and hyperinsulinemia has previously been found in a small group of four adults with hypothalamic obesity (7) and in children with hypothalamic tumors (5). The aim of the present study was to identify possible alterations in some of the critical neurohormonal pathways known to influence energy balance that may be linked etiologically to the development of obesity in adults with acquired structural hypothalamic damage.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

We studied 14 obese patients with tumors of the hypothalamic-pituitary region and radiological evidence of hypothalamic destruction and 15 healthy controls of similar age, gender, body mass index (BMI), and percent body fat (Table 1). The patients with hypothalamic tumors were recruited from a neuroendocrine clinic at the Walton Center for Neurology and Neurosurgery in Liverpool, UK. In brief, nine of these patients had a diagnosis of a hypothalamic craniopharyngioma, four patients had pituitary macroadenomas with suprasellar extension and hypothalamic involvement, one patient had a hypothalamic glioma, and another one had an extensive chordosarcoma. Ten of these patients had undergone a craniotomy, in four patients their tumor was removed via a transphenoidal approach, nine patients underwent radiotherapy, and five patients had been inserted with a ventriculo-peritoneal shunt. The criteria for exclusion were uncontrolled diabetes mellitus, any current inflammatory or malignant disease, or diseases or treatment likely to impact body weight and body composition, apart from replacement for anterior pituitary hormone deficiencies. They were all on stable and optimized replacement therapies with thyroid hormone, hydrocortisone, desmopressin, and sex steroids as appropriate. Twelve patients with hypothalamic tumors were currently receiving GH replacement (GHR), and two others with severe GH deficiency (defined as a peak GH response < 9 mU/liter to provocative testing) were not receiving this treatment (one patient declined to have GHR, and another one did not have significant impairment of quality of life, which in the United Kingdom is a prerequisite for a trial of GHR). The 15 healthy controls with simple obesity were recruited from the local population. The exclusion criteria were the same as for the patients with hypothalamic tumors. The study was carried out in accordance with the principles of the Declaration of Helsinki of the World Medical Association, and all subjects gave written informed consent. The study was approved by the South Sefton Research Ethics Committee (project registration number E.C.74.2002).

Subjects attended the investigational unit at 0830 h, having fasted overnight from 2200 h. The patients on GHR received their last GH injection at approximately 2200 h the day before the study.

Anthropometric assessments included BMI, waist-hip ratio, and estimation of percent body fat by whole-body bioelectrical impedance analysis (Tanita Systems, Tanita Corp., Tokyo, Japan).

An iv cannula was then inserted in a distal forearm or hand vein for collection of samples in the fasted state, and then subjects consumed a mixed meal calculated to provide approximately 600 kcal. The energy load was 23% fat, 13% protein, and 64% carbohydrate.

Assays

Ghrelin. All samples were assayed in duplicate and in one assay to eliminate the effect of interassay variation. Ghrelin-like immunoreactivity was measured with a specific and sensitive RIA. The assay measures both octanoyl and des-octanoyl ghrelin and did not cross-react with any known gastrointestinal or pancreatic peptide hormones. The antisera (SC-10368) was obtained from Santa Cruz Biotechnology (Santa Cruz, CA) and used at a final dilution of 1:50,000. The ¹²⁵I-labeled ghrelin was prepared by Bolton & Hunter reagent (Amersham International, Little Chalfont, UK) and purified by reverse-phase HPLC using a linear gradient from 10 to 40% acetonitrile, 0.05% TFA over 90 min. The specific activity of ghrelin label was 48 Bq/fmol. The assay was performed in a total volume of 0.7 ml of 0.06 M phosphate buffer (pH 7.2) containing 0.3% BSA and incubated for 3 d at 4 C before separation of free and antibody-bound label by charcoal absorption. The assay detected changes of 25 pmol/liter plasma ghrelin with a 95% confidence limit, with an intraassay coefficient of variation of 5.5%.

PYY. Plasma PYY-like immunoreactivity was measured using an established RIA (10). Briefly, antibody (Y21) was raised in a rabbit against synthetic porcine PYY and used at a final dilution of 1:50,000. This antibody cross-reacted fully (100%) with rat and human PYY and also with PYY (3–36). It cross-reacted less than 0.01% with neuropeptide-Y (NPY) and NPY (3–36) and did not cross-react with any other gastrointestinal peptides including glucagon-like peptide-1 and pancreatic polypeptide. ¹²⁵I human PYY label was prepared using the Iodogen method and purified by HPLC using a C-18 (Waters, Milford, CT) column. The assay was capable of detecting changes of 1.5 pM between adjacent tubes. The intra- and interassay variations were less than 15% and less than 9%, respectively.

Leptin, IGF-I, insulin, and glucose were assayed using commercially available kits. Leptin was determined by ELISA (BioSource International, Inc., Camarillo, CA), insulin by a chemiluminescence assay on the IMMULITE 2000 system (Diagnostic Products Corp., Llanberis, Gwynedd, UK) and glucose by the glucose hexokinase method using the ADVIA 1650 system (Bayer UK Ltd., Newbury, UK).

Paired measurements of fasting glucose and insulin were used to derive estimates of insulin resistance using the homeostasis model assessment 2 (HOMA2) computer model (11).

Assessment of eating behavior and appetite

The subjects’ appetitive behavior was assessed by means of the Three Factor Eating Questionnaire (TFEQ) (12). A series of motivational (hunger, fullness, urge to eat, prospective consumption of food, and preoccupation with food) and mood visual analog scale (VAS) ratings (possible scores, 0–100 mm) were given to all subjects before, immediately after, and hourly after the test meal.

Statistical analyses

Ghrelin, PYY, glucose, and insulin data were skewed and therefore log transformed for statistical analyses. Comparison between groups was made using unpaired sample t test or Mann-Whitney U test, as appropriate. Statistical significance was defined as P < 0.05 (two-tailed). Group by time interaction for ghrelin, PYY, insulin, and glucose was analyzed using ANOVA for multiple comparisons with baseline (Dunnett’s method). Areas under the curve (AUC) for ghrelin, PYY, insulin, and glucose responses were calculated by trapezoidal integration. Data were analyzed using SPSS version 10.0 (SPSS, Inc., Chicago, IL).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Baseline

Patients with hypothalamic damage were closely matched for age, BMI, and percent body fat with healthy controls (Table 1). They had similar fasting glucose levels [median (interquartile range; IQR), 5.6 (4.8–6.2) mmol/liter in the hypothalamic group vs. 5.3 (5.1–5.8) mmol/liter in the controls; P = 0.37] and similar degrees of insulin resistance (IR) as assessed by HOMA2-IR index. Fasting ghrelin was significantly lower in the group of patients with hypothalamic damage [median (IQR), 432.8 (305.9–568.9) pmol/liter vs. 564.7 (383.2–824.7) pmol/liter in healthy controls; P = 0.03]. Two patients with hypothalamic tumors were not currently receiving GHR despite having severe GH deficiency, and their fasting ghrelin levels were 340.3 and 389.1 pmol/liter, respectively. Fasting PYY was higher in the hypothalamic group, but this difference did not attain statistical significance (P = 0.06). Fasting leptin was also similar in the two groups (Table 1).

Responses to the test meal

The insulin and glucose responses to the test meal displayed similar patterns in the patients with hypothalamic damage and the healthy controls (Fig. 1). Although the AUC for the glucose response was significantly higher in the hypothalamic group [median (IQR) 1,515 (609) mmol/min·liter vs. 1,253.2 (172.5) mmol/min·liter in the controls; P = 0.003], the total AUC for plasma insulin did not differ [17,034.7 (15,216.9) mU/min·ml vs. 9,803.2 (7,716.7) mU/min·ml in the healthy obese controls; P = 0.15]. Because of the biphasic nature of insulin secretion, we also calculated separately the AUC for the insulin responses at 15, 30, and 60 min, which were similar in both groups.

View larger version (12K): [in this window] [in a new window]   FIG. 1. Postprandial responses of glucose (A) and insulin (B) in patients with hypothalamic damage () and healthy obese controls (•). To convert glucose from mmol/liter to mg/dl, multiply by 18.

View larger version (13K): [in this window] [in a new window]   FIG. 2. Postprandial responses of ghrelin (A) and total PYY (B) in patients with hypothalamic damage () and healthy obese controls (•). To convert hormone levels from pmol/liter to pg/ml, multiply ghrelin by 3.4 and PYY by 4.3.

When the analyses of fasting levels and postprandial ghrelin, PYY, insulin, and glucose responses were performed separately for the male and female patients with hypothalamic damage and controls, no significant differences emerged compared with the results obtained when not taking into account the subjects’ gender.

The serum IGF-I levels of the patients with hypothalamic damage (12 of whom were currently on GHR) were not different from the obese healthy subjects [mean (SEM) IGF-I, 26.14 ± 4.72 nmol/liter in the hypothalamic damage group vs. 18.0 ± 3.7 nmol/liter in the controls; P = 0.18], and IGF-I levels did not correlate with ghrelin levels in the two groups. Similar results were obtained when the two patients with documented severe GH deficiency currently not on GHR were excluded from the calculations [mean (SEM) IGF-I, 28.2 ± 5.25 nmol/liter in the hypothalamic damage group vs. 18.0 ± 3.7 nmol/liter in the controls; P = 0.1]; IGF-I levels again did not correlate with ghrelin levels in the two groups.

Analysis of the TFEQ showed significantly lower levels of hunger and disinhibition in the group of patients with hypothalamic damage compared with controls [hunger score (mean ± SEM), 0.25 ± 0.04 in the hypothalamic damage group vs. 0.48 ± 0.07 in the control group (P = 0.01); disinhibition score, 0.26 ± 0.04 in the hypothalamic group vs. 0.52 ± 0.07 in the controls (P = 0.004)]. Analysis of motivational and mood VAS ratings during the period of the test revealed significant changes in hunger scores over time compared with baseline in both groups, and the hunger ratings at 3 h after the meal in the hypothalamic group were significantly higher than the control group, whose hunger ratings had yet to return to baseline (P = 0.01) (Fig. 3). The patients with hypothalamic damage were also reporting a stronger desire to eat at 2 h (P = 0.01) and 3 h after the meal (P = 0.02) and lower mood levels at 2 h (P = 0.03) compared with controls.

View larger version (15K): [in this window] [in a new window]   FIG. 3. Mean VAS (mm) for perceived hunger during the test meal in patients with hypothalamic damage () and healthy obese controls (•).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

The recently discovered gut-brain peptide ghrelin, apart from its potent GH stimulatory effect, also has other important roles, one of which appears to be the regulation of appetite. Ghrelin, a powerful orexigen, exerts its effects, at least in part, via activation of neurons in the arcuate nucleus of the hypothalamus that coexpress NPY and agouti-related protein (AgRP), both neuropeptides known to increase food intake and body weight (13, 14, 15). In humans, the preprandial rise in ghrelin (16), the enhancement of appetite, and the subsequent increase in food intake that follow iv administration of ghrelin (17) suggest that this enteric hormone may be a physiological meal initiator and may play a role as a feeding signal. Hyperghrelinemia has been shown to be consistently present in obese patients with PWS (8, 18), a genetic form of hypothalamic obesity. Some of the cardinal features of this syndrome include GH deficiency, hypogonadotrophic hypogonadism, insatiable hunger, and uncontrolled compulsive eating. It has been postulated that the inappropriately raised ghrelin levels in these patients may be responsible for their insatiable hunger drive (18). Therefore, it appeared tempting to speculate that hyperghrelinemia could play a pivotal role in the development of obesity in patients with structural hypothalamic damage.

In apparent contrast to the previous observations in PWS, we observed that circulating ghrelin is suppressed in these patients to levels lower than those observed in common obesity, indicating that ghrelin is down-regulated in the presence of positive energy balance in adults with hypothalamic damage. In simple obesity, circulating ghrelin levels have also been found to be decreased (19) and do not exhibit the decline that is seen after a meal in the lean (20). The pathophysiological significance, if any, of the suppressed circulating ghrelin levels in obesity is still a matter of debate. This difference in ghrelin levels between our two study groups cannot be accounted for by differences in measures of adiposity because they both shared similar characteristics in terms of BMI and percent body fat, which have previously been shown to inversely correlate with circulating ghrelin (21). It should be noted, however, that the method of bioelectrical impedance analysis we used to assess body composition in our patients has not been fully validated in subjects at the extremes of BMI ranges; therefore, a possible influence of this on the measurements of adiposity obtained from our patients cannot be excluded.

What physiologically modulates plasma ghrelin levels is still a matter of speculation. Insulin has been proposed to be a candidate for the role of a dynamic ghrelin regulator. It has been postulated that sustained insulinemia mediates the effect of nutritional status and energy balance on plasma ghrelin (22), although others have claimed that acute plasma glucose increases, independently from the insulin response, regulate plasma ghrelin (23). Insulin has also been implicated in the pathogenesis of obesity in children with hypothalamic damage (5). In our patients with hypothalamic damage compared with their controls we did not observe a difference in the circulating levels of insulin pre- and postprandially, but the postprandial glucose response in the hypothalamic patients was significantly higher than the controls. Whether exposure to higher circulating glucose concentrations in the postprandial period could have negatively influenced ghrelin secretion in the hypothalamic group compared with their controls remains to be clarified. It has been previously proposed (24) that there may be a system in ghrelin-producing cells of the oxyntic glands of the stomach that responds to plasma glucose concentrations.

Another candidate for the role of ghrelin modulator is leptin. We observed no difference in fasting leptin between our two study groups to account for the observed difference in their fasting ghrelin levels. The nature of the relationship between ghrelin and leptin remains controversial. Although ghrelin has been portrayed as a downstream mediator of leptin’s action in one study (25), others have demonstrated that ghrelin increases in states of negative energy balance and vice versa (26, 27, 28) but shows no consistent relationship with leptin levels (29).

Another area of controversy is the effect of the GH/IGF-I axis on the regulation of ghrelin. All of our hypothalamic patients had documented severe GH deficiency, and 12 of 14 were currently receiving GHR aiming for IGF-I levels in the upper half of the age- and sex-adjusted reference range. There was a trend for serum IGF-I levels to be higher in the hypothalamic group compared with the obese controls, but this did not reach statistical significance. Therefore, we do not believe that over-replacement with GH could have influenced the difference in ghrelin levels between the two groups, but it is difficult to draw any further conclusions based on these cross-sectional data. Some have found no effect of GH on peripheral ghrelin levels in GH-deficient adults after 1 yr of GHR (30), whereas others have demonstrated a decrease in systemic ghrelin after GHR (31), which was strongly correlated with changes in IGF-I, concluding that a negative feedback influence exists on ghrelin secretion by the GH/IGF-I axis (31).

PYY is secreted by the endocrine L cells of the small and large intestine with the highest concentrations found in the terminal ileum, colon, and rectum (10). It appears to mediate its effects through its action as a selective agonist of the NPY2-receptor, a presynaptic inhibitory receptor that is abundantly expressed on the NPY neurons in the arcuate nucleus of the hypothalamus (32). Recently, it has been demonstrated that PYY levels are low in simple human obesity (9) and that peripherally administered PYY inhibits appetite and food intake in both lean and obese subjects (9, 33), making it a possible mediator of postprandial satiety. In our current study, patients with hypothalamic damage had fasting levels of total PYY similar to controls and failed to exhibit postprandially an immediate and sustained rise, in contrast to previous reports in lean and obese subjects (9, 10). It has been postulated that the initial phase of PYY release, which occurs within 15 min of ingestion of a meal, is dependent on a neurohormonal mechanism, because it occurs before the nutrients come in contact with the lumen of distal parts of the intestine, where normally higher concentrations of this gut peptide are found (9, 34). The sustained postprandial release appears to occur in proportion to the calorie content of the ingested meal (35). In patients with hypothalamic tumors, the vulnerably situated ventromedial and paraventricular hypothalamic nuclei, which are known to give rise to descending autonomic projections, can be easily damaged and lead to autonomic imbalance (36, 37, 38). One can speculate that if the neurohormonal pathway that controls at least the initial phase of PYY release involves the autonomic nervous system, then this pathway would be anticipated to be interrupted in patients with hypothalamic damage. It is also possible that the postprandial release of PYY, after the contact of the intraluminal gut contents with the L cells, is more neurally mediated than previously thought, which could explain the lack of increase in circulating levels observed in this group of patients. The delayed rise at 180 min after the meal in circulating PYY in the healthy obese controls in our study is certainly in contrast to previous findings in healthy obese subjects (9). Differences in macronutrient and energy content of the test meals may account for this disparity. The postprandial AUC for PYY was similar in both groups; therefore, exposure to the anorectic effects of this gut-brain peptide over a period of 3 h in patients with hypothalamic damage was equivalent to that seen in their healthy obese counterparts, indicating that this particular gut hormone probably does not play a pivotal role in human hypothalamic obesity.

Patients’ subjective appetite sensations during the test meal were assessed by VAS, which have previously been shown to have high reproducibility, power, and validity in single test meal studies (39). There was an increase in the VAS ratings of hunger in both groups over time after the test meal, but the group of patients with hypothalamic damage reported significantly higher levels of hunger and a stronger desire to eat earlier than the controls. This suppression of post-ingestive satiety did not coincide with a rise in ghrelin or with a decrease in circulating PYY in these patients. It is possible that changes in other meal-stimulated, short-acting satiety factors such as cholecystokinin, glucagon, glucagon-like peptide-1, amylin, or bombesin-related peptides may account for the observed difference. So far, these factors have not been recognized as regulators of long-term energy homeostasis (40). Although these results suggest that in patients with hypothalamic damage post-ingestive satiety is not maintained as long as in the healthy obese controls, they do not prove that these patients increase the amount of energy they consume on subsequent eating occasions, because motivational ratings are not necessarily a good proxy measure of subsequent food intakes. These results contradict the findings from the assessment of the patients’ eating behavior by means of the TFEQ. Patients with hypothalamic damage reported fewer feelings of hunger and food cravings and less disinhibition of dietary restraint compared with controls. Although the TFEQ is extensively used in appetite research, its validity and reproducibility has not been demonstrated in patients with brain damage; therefore, caution should be exercised in interpreting these results.

In summary, impaired satiety may be an etiological factor of obesity in adult patients with hypothalamic damage, but the changes in the circulating levels of ghrelin, PYY, insulin, and leptin in response to a standard test meal do not indicate a central role for these gut-brain peptides in the control of appetite and the pathogenesis of obesity in this particular patient group. The mechanisms underlying this form of obesity require additional investigation, including direct measurement of energy intake, energy expenditure, and autonomic function.

	Footnotes

 
First Published Online June 21, 2005

Abbreviations: AUC, Area under the curve; BMI, body mass index; GHR, GH replacement; HOMA2, homeostasis model assessment 2; IQR, interquartile range; IR, insulin resistance; NPY, neuropeptide-Y; PWS, Prader-Willi syndrome; PYY, peptide-YY; TFEQ, Three Factor Eating Questionnaire; VAS, visual analog scale.

Received September 23, 2004.

Accepted June 14, 2005.

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