Obesity In Prader-Willi Syndrome Research Articles

Management of obesity in Prader–Willi syndrome

Prader–Willi syndrome (PWS) is associated with uncontrolled appetite and morbid obesity. Management of PWS is particularly challenging and requires the involvement of both the family and health-care providers, as well as the affected individual. In this Viewpoint the efficacy of the strategies currently used to control obesity in PWS is discussed.

Ghrelin levels in young children with Prader-Willi syndrome

To explore the hypothesis that high ghrelin levels contribute to obesity in Prader-Willi syndrome (PWS), we assessed whether the increased levels observed in older persons with PWS exist in very young children, before the onset of hyperphagia. We measured ghrelin levels in nine children with PWS (17-60 months of age) and eight healthy control subjects of equivalent body mass index (BMI), age, and sex. PWS and control groups had equivalent BMI (16.8 +/- 1.4 vs 16.1 +/- 0.9 kg/m(2), respectively; P = .24), age (37.8 +/- 15.4 vs 50.3 +/- 17.7 months; P = .14), and sex. PWS and control groups also had equivalent fasting levels of total ghrelin (787 +/- 242 vs 716 +/- 135 pg/mL, respectively; P = .24), bioactive ghrelin (102 +/- 35 vs 91 +/- 23 pg/mL; P = .45), insulin, and glucose. Ghrelin correlated negatively with BMI among controls (r = -0.760, P = .029) but not PWS (r = 0.015, P = .97). Children <5 years of age with PWS, who had not yet developed hyperphagia or excessive obesity, had normal ghrelin levels, in contrast with the hyperghrelinemia of older, hyperphagic people with PWS. It is possible that ghrelin levels increase suddenly before hyperphagia develops.

Postprandial Adiponectin Levels Are Unlikely to Contribute to the Pathogenesis of Obesity in Prader-Willi Syndrome

Aim:To investigate fasting and postprandial adiponectin levels in PWS patients as compared to obese and lean subjects and whether they could contribute to the pathogenesis of obesity in this syndrome. Methods: We studied 7 patients with PWS, 16 obese patients and 42 lean subjects for the fasting study. From this group, we evaluated 7 patients with PWS, 7 age-sex-BMI-matched obese non-PWS patients and 7 age-sex-matched lean subjects before and after the administration of 3,139.5 kJ (750 kcal) of a standard liquid meal (53.2% carbohydrate, 30% fat, 16.7% protein) after an overnight fast. Blood samples were obtained every 15 min for the first hour and every 30 min thereafter until 6 h. Adiponectin, IGF-I, glucose, triglycerides, cholesterol, and insulin were measured. Results:Fasting plasma adiponectin levels were lower in PWS than in lean subjects (5.24 ± 2.56 vs. 8.28 ± 4.63 µg/ml, p = 0.041) but higher than in obese patients (4.01 ± 1.27 µg/ml, p = 0.047). After the meal, adiponectin concentrations mildly decreased in PWS at time point 240 min, while in obese and lean subjects no changes were observed. However, 6-hour postprandial AUC for adiponectin was similar in all three groups. Conclusion: Fasting adiponectin levels are low in PWS, but they are so mildly modulated postprandially that these changes do not seem significant for the pathogenesis of obesity in this syndrome.

Hyperghrelinemia Is a Common Feature of Prader-Willi Syndrome and Pituitary Stalk Interruption: A Pathophysiological Hypothesis

Background: Elevated plasma ghrelin levels have recently been reported in adults and children with Prader-Willi syndrome (PWS). The aim of the study is to investigate the relationship between obesity, growth hormone (GH) deficiency (GHD) and ghrelinemia in PWS and to examine whether hyperghrelinemia is specific to PWS. Methods: We measured fasting ghrelinemia in children with PWS, idiopathic GHD (iGHD), obese children, controls and in 6 children presenting another congenital syndrome associated with GHD: pituitary stalk interruption (PSI). Results: Children with PWS exhibited significantly higher ghrelin levels (995 pg/ml (801/1,099, median 1st/3rd quartile)) than iGHD (517 pg/ml (392/775)), obese (396 pg/ml (145/610)) and control (605 ng/ml (413/753)) children. Similar to PWS hyperghrelinemia was found in PSI children (1,029 pg/ml (705/1,151)), and was not modified by GH treatment. Conclusion: We conclude that hyperghrelinemia in PWS and PSI is not related to GH secretion. We hypothesize that a major site of ghrelin action is at the hypothalamic level and that a ‘ghrelin resistance’ syndrome may be present in these patients, primarily due to a hypothalamic defect. Combined alterations such as impaired serotonin receptor regulation associated with abnormal ghrelin responsiveness are probably responsible for obesity in PWS.

High circulating ghrelin: a potential cause for hyperphagia and obesity in prader-willi syndrome.

Prader-Willi syndrome (PWS) is a genetic disorder occurring in 1 of 10,000-16,000 live births and is characterized by excessive appetite with progressive massive obesity as well as short stature and mental retardation. Most patients have GH deficiency and hypogonadotropic hypogonadism. The causes of the hyperphagia and abnormal GH secretion are unknown. To determine whether ghrelin, a novel GH secretagogue with orexigenic properties, is elevated in PWS, we measured fasting plasma ghrelin concentration; body composition (dual-energy x-ray absorptiometry); and subjective ratings of hunger (visual analog scale) in seven subjects (6 males and 1 female; age, 26 +/- 7 yr; body fat, 39 +/- 11%, mean +/- SD) with PWS (diagnosis confirmed by genetic test) and 30 healthy subjects (reference population, 15 males and 15 females; age, 32 +/- 7 yr; body fat, 36 +/- 11%) fasted overnight. All subjects were weight stable for at least 6 months before admission to the study. The mean plasma ghrelin concentration was higher in PWS than in the reference population (307 +/- 164 vs. 109 +/- 24 fmol/ml; P < 0.001), and this difference remained significant after adjustment for percentage body fat (P < 0.001). Plasma ghrelin was also higher (P = 0.0004) in PWS than in five healthy subjects fasted for 36 h. A positive correlation was found between plasma ghrelin and subjective ratings of hunger (r = 0.71; P = 0.008). Furthermore, in subjects with PWS, the concentration of the hormone was not different before and after ingestion of 2 ml and a satiating amount of the same liquid meal (ghrelin concentrations: 307 +/- 164 vs. 306 +/- 205 vs. 260 +/- 134 fmol/ml, respectively; ANOVA for repeated measures, P = 0.56). This is the first evidence that ghrelin, a novel orexigenic hormone, is elevated in subjects with PWS. Our finding suggests that ghrelin may be responsible, at least in part, for the hyperphagia observed in PWS.

Resting metabolic rate, plasma leptin concentrations, leptin receptor expression, and adipose tissue measured by whole-body magnetic resonance imaging in women with Prader-Willi syndrome

Obesity in Prader-Willi syndrome (PWS) may be related to abnormalities in the adipocyte-leptin-hypothalamic pathway and may be exacerbated by reductions in the resting metabolic rate (RMR). We compared body composition, body-composition- adjusted RMR, and adiposity-adjusted plasma leptin between women with PWS and control women. We also examined leptin receptor expression in the PWS group. We studied body composition using whole-body magnetic resonance imaging and measured plasma leptin by radioimmunoassay in 45 control women aged 18-56 y and in 13 women with PWS aged 20-38 y. RMR was measured by indirect calorimetry in 41 control women and in 8 women with PWS. Age, body composition, and regional adipose tissue (AT) depots were corrected for by multiple regression analysis. Messenger RNA expression of the leptin receptor was examined by reverse transcriptase-polymerase chain reaction in lymphocytes. In the PWS group, fat mass was greater after correction for fat-free mass, and RMR was normal after correction for both fat-free mass and fat mass. Leptin was influenced primarily by subcutaneous AT volume in both subject groups. Leptin concentrations were not significantly different between the 2 groups after adjustment for age and AT content or distribution. Full-length leptin receptor messenger RNA was expressed in the lymphocytes of the PWS group. Differences in RMR in women with PWS are explained by abnormal body composition, suggesting that energy expenditure is normal at the tissue level in PWS. There is no evidence that defective leptin production causes obesity in PWS, and leptin receptor deficiency is not a primary consequence of the gene defects leading to leptin resistance.

Energy expenditure at rest and during sleep in children with Prader-Willi syndrome is explained by body composition

Obesity in Prader-Willi syndrome (PWS) seems to be related to a low basal metabolic rate (BMR). In addition, abnormal sleep patterns reported in PWS might affect sleeping metabolic rate (SMR). Our objective was to assess BMR and SMR adjusted for fat-free mass in young PWS patients. Subjects were 17 PWS patients (10 females and 7 males aged 7.5-19.8 y) and 17 obese control subjects matched for sex and bone age. SMR was measured in a respiratory chamber, BMR with a ventilated-hood system, and body composition by deuterium dilution. BMR and SMR were significantly lower in the PWS group than in the control group (5.36 +/- 1.18 and 4.62 +/- 1.08 MJ/d compared with 6.38 +/- 1.55 and 5.60 +/- 1.52 MJ/d, respectively; P < 0.05). When fat-free mass was included in the analysis, multiple regression showed no differences in BMR and SMR between groups. When weight was included in the analysis instead of fat-free mass, SMR was lower in the PWS group. Fat-free mass was lower in the PWS group both as an absolute value and when adjusted for height. BMR and SMR are low in young patients with PWS because of a low fat-free mass.

Development and validation of a measurement system for assessment of energy expenditure and physical activity in Prader-Willi syndrome.

The morbid obesity associated with Prader-Willi syndrome (PWS) may result from either excessive energy intake or reduced energy expenditure (EE). In this report, we describe the development and validation of an Activity-Energy Measurement System (AEMS) to measure EE and physical activity components in an environment approximating free-living conditions. The AEMS consists of a live-in, whole-room indirect calorimeter equipped with a novel force platform floor system to enable simultaneous measurements of EE, physical activity, and work efficiency during spontaneous activities and standardized exercises. Free-living physical activity and estimated free-living EE are measured using portable triaxial accelerometers individually calibrated in each subject during their stay in the AEMS. Representative data from two PWS patients and two matched control (CTR) subjects displayed EE during their inactive lifestyles. This combination of methods will allow the quantification of daily EE and its components, the amount and energy cost of physical activity, and the relationships between body composition and EE, in order to determine their roles in the development and maintenance of the morbid obesity in PWS.

Genetically determined obesity in Prader-Willi syndrome: the ethics and legality of treatment.

A central characteristic of people with Prader-Willi Syndrome (PWS) is an apparent insatiable appetite leading to severe overeating and the potential for marked obesity and associated serious health problems and...

Effect of Human Growth Hormone (hGH) Treatment on Growth Rate and Obesity in Prader-Willi Syndrome

Prader-Willi syndrome (PWS) is characterized by short stature, hypogonadism and marked obesity. Because of the effects of GH, it is anticipated to improve the short stature and obesity of PWS with human GH (hGH) treatment. Accordingly we treated two patients with PWS, aged 6 years 1 month and 6 years 4 months, with the dose of 0.5 U/kg/week of hGH. Height of both patients was below -2SD for normal Japanese standard. Peak GH values to provocation tests were over 10ng/mL in case 1, but below 5.1ng/mL in case 2. Growth rate significantly increased with GH treatment as follows: Case 1: Pretreatment growth rate 5.6cm/year, first year 10.6cm/year, second year 7.5cm/year, Case 2: pretreatment growth rate 5.3cm/year, first year 8.3cm/year, second year 6.5cm/year, third year 6.8cm/year, fourth year 7.4cm/year and fifth year 7.7cm/year. Obesity index and body-mass index (BMI) of both cases increased steadily even with GH treatment and these increments were similar to those of other untreated PWS children. From these results it is concluded that GH treatment is effective in accelerating the growth rate in short PWS children. However, this dose not necessarily reduce the obesity index and BMI in PWS. Therefore, it is indicated that another treatment regimen in addition to GH is necessary for improving the obesity and shortness.

Serum insulin-releasing activity and the Prader-Willi syndrome.

Pathogenesis and etiology of the various clinical features of the Prader-Willi syndrome (PWS) are not completely understood. There is evidence suggesting a hypothalamic abnormality leading to hypogonadism in this syndrome. To test the possible hypothalamic involvement in the pathogenesis of obesity in these patients we studied the sera of 5 patients with PWS for insulin-releasing activity of possible hypothalamic origin. In addition 4 patients with a PWS-like syndrome and 6 obese patients with signs of central nervous system damage were studied. All five patients with PWS showed significant insulin-releasing activity in their sera. Of the four patients with PWS-like symptoms three showed similar activity while three of the obese patients with central nervous system damage had this activity in their sera. Serum insulin-releasing activity has been shown earlier to be associated with childhood obesity and it could play a role in the pathogenesis of obesity in PWS.

ENERGY EXPENDITURE AND BODY COMPOSITION IN PRADER-WILLI SYNDROME

The assessment of energy expenditure (EE) in humans in a normal environment has recently become possible through measurement of the differential excretion of doubly labeled heavy water (2H218O) following oral ingestion. After 2H218O distribution, CO2 production and EE may be calculated from differential 2H and 18O enrichment in urine samples at 1 and 7 days. Further, isotope dilution at 4 hours may be used to calculate total body water and fat-free mass (FFM). We studied 10 individuals with Prader-Willi syndrome (PWS) (8-24 years) and 5 normal obese children (NO) (7-16 years). None had other chemical abnormalities, and both groups were similarly obese (PWS 157±9.7%, NO 152±11.7% ideal body weight). PWS were 47.9±2.3% fat comp. to NO 45.6±1.9% (N.S.). However, % fat linearly correlated with body mass index (kg/m2) only in PWS (r=0.93). Two normal-weight PWS had 40% and 37% body fat. EE in PWS was 2103±203 kcal vs. 3478±407 kcal, NO (p<.005). EE/kg FFM, 71.6±3.4 PWS vs. 76.3±6.4, NO, or EE/kg body weight, 37.6±2.6 PWS vs. 42.0±4.5, NO, was not significantly different, but the measured EE/calculated basal metabolic rate was less in the PWS, 1.34±.08 vs. 1.65±.12, NO, (p<.05). PWS have increased body fat even when of normal weight. EE in PWS normalized for FFM or weight is not significantly lower than in NO. These studies clarify the nature of obesity in PWS using a non-invasive technique with potential application to other disorders of EE and intake.

Behavioral treatment of obesity in prader-willi syndrome

The effectiveness of social isolation, aversion-relief treatment, one-to-one monitoring with point earning and point loss contingencies, and no-programmed contingencies were compared in treating a 22-year-old mildly retarded woman with Prader-Willi Syndrome for obesity. While the patient lost some weight during contingent social isolation and aversion therapy, her weight increased rapidly on discontinuing these procedures. The patient lost 44 lb. over 5 months of 1:1 monitoring with immediate point-gain and point-loss contingencies and dropped 8 more pounds over 3 succeeding months in a less rigorously controlled setting.