Neural mechanisms underlying hyperphagia in Prader-Willi syndrome

Objective: Prader‐Willi syndrome (PWS) is a genetic disorder associated with developmental delay, obesity, and obsessive behavior related to food consumption. The most striking symptom of PWS is hyperphagia; as such, PWS may provide important insights into factors leading to overeating and obesity in the general population. We used functional magnetic resonance imaging to study the neural mechanisms underlying responses to visual food stimuli, before and after eating, in individuals with PWS and a healthy weight control (HWC) group. Research Methods and Procedures: Participants were scanned once before (pre‐meal) and once after (post‐meal) eating a standardized meal. Pictures of food, animals, and blurred control images were presented in a block design format during acquisition of functional magnetic resonance imaging data. Results: Statistical contrasts in the HWC group showed greater activation to food pictures in the pre‐meal condition compared with the post‐meal condition in the amygdala, orbitofrontal cortex, medial prefrontal cortex (medial PFC), and frontal operculum. In comparison, the PWS group exhibited greater activation to food pictures in the post‐meal condition compared with the pre‐meal condition in the orbitofrontal cortex, medial PFC, insula, hippocampus, and parahippocampal gyrus. Between‐group contrasts in the pre‐ and post‐meal conditions confirmed group differences, with the PWS group showing greater activation than the HWC group after the meal in food motivation networks. Discussion: Results point to distinct neural mechanisms associated with hyperphagia in PWS. After eating a meal, the PWS group showed hyperfunction in limbic and paralimbic regions that drive eating behavior (e.g., the amygdala) and in regions that suppress food intake (e.g., the medial PFC).     

Sustained NPY Overexpression in the PVN Results in Obesity via Temporarily Increasing Food Intake

Increasing neuropeptide Y (NPY) signaling in the paraventricular nucleus (PVN) by recombinant adeno‐associated virus (rAAV)‐mediated overexpression of NPY in rats, results in hyperphagia and obesity in rats. To determine the importance of hyperphagia in the observed obesity phenotype, we pair‐fed a group of AAV‐NPY‐injected rats to AAV‐control‐injected rats and compared parameters of energy balance to ad libitum fed AAV‐NPY‐injected rats. For 3 weeks, AAV‐NPY‐injected rats, received the same amount of food as ad libitum‐fed rats injected with control rAAV They did not gain more body weight than these controls. When allowed access to food ad libitum, these AAV‐NPY‐injected rats increased food intake, which subsequently decreased when rats reached the same body weight as AAV‐NPY‐injected rats that were fed ad libitum for the entire study. These data indicate that overexpression of NPY in the PVN results in obesity by increasing food intake until a certain body weight is achieved.     

Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents

Objective: To characterize a model of atypical antipsychotic drug‐induced obesity and evaluate its mechanism. Research Methods and Procedures: Chronically, olanzapine or clozapine was self‐administered via cookie dough to rodents (Sprague‐Dawley or Wistar rats; C57Bl/6J or A/J mice). Chronic studies measured food intake, body weight, adiponectin, active ghrelin, leptin, insulin, tissue wet weights, glucose, clinical chemistry endpoints, and brain dopaminergic D2 receptor density. Acute studies examined food intake, ghrelin, leptin, and glucose tolerance. Results: Olanzapine (1 to 8 mg/kg), but not clozapine, increased body weight in female rats only. Weight changes were detectable within 2 to 3 days and were associated with hyperphagia starting ～24 hours after the first dose. Chronic administration (12 to 29 days) led to adiposity, hyperleptinemia, and mild insulin resistance; no lipid abnormalities or changes in D2 receptor density were observed. Topiramate, which has reversed weight gain from atypical antipsychotics in humans, attenuated weight gain in rats. Acutely, olanzapine, but not clozapine, lowered plasma glucose and leptin. Increases in glucose, insulin, and leptin following a glucose challenge were also blunted. Discussion: A model of olanzapine‐induced obesity was characterized which shares characteristics of patients with atypical antipsychotic drug‐induced obesity; these characteristics include hyperphagia, hyperleptinemia, insulin resistance, and weight gain attenuation by topiramate. This model may be a useful and inexpensive model of uncomplicated obesity amenable to rapid screening of weight loss drugs. Olanzapine‐induced weight gain may be secondary to hyperphagia associated with acute lowering of plasma glucose and leptin, as well as the inability to increase plasma glucose and leptin following a glucose challenge.     

Food Intake in Prader-Willi Syndrome and Controls with Obesity After Administration of a Benzodiazepine Receptor Agonist

Benzodiazepine receptor (BZR) agonists, used extensively for their anxiolytic effects, have been shown to increase food intake in many mammalian species. Little information, however, is available on the effects of BZR agonists on feeding behaviors of humans. Food intake was evaluated in a 60-minute free-feeding standardized test after the acute administration of the BZR agonist chlordiazepoxide (CDP, Librium; 5 mg or 20 mg) or placebo. Subjects were 12 individuals with the Prader Willi syndrome (PWS), a disorder characterized by extreme hyperphagia and morbid obesity, and 11 controls with obesity. PWS subjects showed the characteristic hyperphagia associated with the appetite disorder, consuming more than six times as many sandwiches as controls with obesity. Results revealed no significant effect of either dose of CDP on the food intake of either group. Serum assays revealed that dose-dependent, clinically effective levels of CDP and active metabolites were achieved. These results suggest that acute administration of the BZR agonist CDP, at the therapeutic levels used, may not increase food intake in populations with obesity. However, the chronic effects of CDP on appetite in human populations still need to be explored.     

Copy number variations at the Prader-Willi syndrome region on chromosome 15 and associations with obesity in whites

Obesity is a serious health problem with strong genetic determination. Copy number variation (CNV) is a common type of genomic variant associated with some complex human diseases. However, it is not clear how CNVs contribute to the etiology of obesity. In this study, we examined 1,000 unrelated US whites to search for CNVs that may predispose to obesity. We focused our analyses on the Prader‐Willi syndrome (PWS) critical region (chromosome 15q11–q13), because the PWS region is a hotspot for CNV generation and obesity is one of the major clinical manifestations for chromosome abnormalities at this region. We constructed a map containing 39 CNVs at the PWS critical region with CNV occurrence rates higher than 1%. Among them, three CNVs were significantly associated with body fat mass (P < 0.05), with a higher copy number (CN) associated with an increase of 5.08–9.77 kg in body fat mass. These three CNVs are close to two known PWS genes, NDN (necdin homolog) and C15orf2 (chromosome 15 open reading frame 2), and partially overlap with another obesity gene PWRN1 (Prader‐Willi region nonprotein‐coding RNA 1). Interestingly, our recently published whole genome association scan study using the same sample by examining single‐nucleotide polymorphisms (SNPs) did not find any significant associations at these CNV regions, suggesting the importance of examining both CNVs and SNPs for better understanding of genetic basis of obesity. Further studies are warranted to validate these CNVs and their importance to obesity.     

Body composition and fatness patterns in Prader-Willi syndrome: comparison with simple obesity

Objective: To characterize the body composition of Prader‐Willi syndrome (PWS) subjects and compare with simple obesity. Research Methods and Procedures: Seventy‐two individuals (27 PWS deletion, 21 PWS uniparental disomy, and 24 obese controls) 10 to 49 years old were studied with the use of DXA. Body composition measures were obtained, and regional fat and lean mass patterns were characterized. Significant differences were assessed with Student's t test and ANOVA adjusting for age, gender, and BMI. Results: Significant differences between the PWS and obese groups were found for lean measures of the arms, legs, and trunk. Total lean mass was significantly lower in PWS than in obese subjects for arms, trunk, and especially legs. Furthermore, two body regions (legs and trunk) showed significant differences for fat and lean measures between PWS and obese males. However, significant differences between PWS and obese females for these measures were found only for the legs. No significant differences were identified between PWS deletion and uniparental disomy subjects. Discussion: Our results demonstrate that PWS individuals do, in fact, have an unusual body composition and fatness patterns, characterized by reduced lean tissue and increased adiposity, with PWS males contributing most with fat patterns more similar to females.     

Capacity for growth compensation in juvenile three-spined sticklebacks experiencing cycles of food deprivation

The capacity of three‐spined sticklebacks Gasterosteus aculeatus (initial mean mass 0.280 g) to compensate for recurrent periods of food deprivation of 2, 4 or 6 days followed by 2 days of ad libitum feeding on enchytraeid worms over 56 days was assessed by measuring appetite and growth. Control fish were fed daily. The total number of days on which fish were fed ranged from 14 (6‐day cycle) to 56 (controls). Deprived sticklebacks were hyperphagic on the first day of re‐feeding in a cycle and this hyperphagia increased with successive cycles. Mean daily consumption on first day of refeeding was: controls, 62.9 mg; 2 days, 108 mg; 4 days, 98.8 mg; 6 days, 101 mg. The hyperphagia did not increase as the preceding period of deprivation within a cycle increased. Hyperphagia was not maintained on the second day of re‐feeding. The 4 day and 6 day groups initially showed hypophagia on the second day of re‐feeding. Mean daily consumption on second day of re‐feeding was: controls, 62.6 mg; 2 days, 62.2 mg; 4 days, 54.2 mg; 6 days, 50.0 mg. Over the experiment, consumption on the second day of the 4 day and 6‐day groups increased towards the control level, suggesting a developing compensatory response. The highest mean daily consumption per days fed was shown by the 2 day group. The relationship between number of days fed and total food consumption and specific growth rate suggested that the 2 day group almost compensated for the periods of deprivation. Performance declined for the 4 day and 6 day groups, although even at the highest level of deprivation, a positive growth was achieved. Mean specific growth rate in mass (% per day) was: controls, 2.33; 2 days, 1.89; 4 days, 1.21; 6 days, 0.86. Initial mass and total food consumption accounted for most of the variance in specific growth rate. Other indices of performance including lipid concentration, dry matter concentration and the RNA:DNA ratio in white muscle were positively related to quantity of food consumed by each group. Growth efficiency of sticklebacks in terms of wet mass gained and wet mass consumed over the experimental period was 19.4% and did not differ among control and treatment groups. The growth rates of the sticklebacks experiencing cyclical deprivation were comparable to growth rates previously recorded for sticklebacks fed daily, but consuming similar mean daily rations.     

Meal Pattern Analysis of Diet‐Induced Obesity in Susceptible and Resistant Rats

Objective: To characterize the meal patterns of free feeding Sprague‐Dawley rats that become obese or resist obesity when chronically fed a high‐fat diet. Research Methods and Procedures: Male Sprague‐Dawley rats (N = 120) were weaned onto a high‐fat diet, and body weight was monitored for 19 weeks. Rats from the upper [diet‐induced obese (DIO)] and lower [diet‐resistant (DR)] deciles for body‐weight gain were selected for study. A cohort of chow‐fed (CF) rats weight‐matched to the DR group was also studied. Food intake was continuously monitored for 7 consecutive days using a BioDAQ food intake monitoring system. Results: DIO rats were obese, hyperphagic, hyperleptinemic, hyperinsulinemic, hyperglycemic, and hypertriglyceridemic relative to the DR and CF rats. The hyperphagia of DIOs was caused by an increase in meal size, not number. CF rats ate more calories than DR rats; however, this was because of an increase in meal number, not size. When expressed as a function of lean mass, CF and DR rats consumed the same amount of calories. The intermeal intervals of DIO and DR rats were similar; both were longer than CF rats. The nocturnal satiety ratio of DIO rats was significantly lower than DR and CF rats. The proportion of calories eaten during the nocturnal period did not differ among groups. Discussion: The hyperphagia of a Sprague‐Dawley rat model of chronic diet‐induced obesity is caused by an increase in meal size, not number. These results are an important step toward understanding the mechanisms underlying differences in feeding behavior of DIO and DR rats.     

Hyperphagia and Obesity in Na,K‐ATPase α2 Subunit‐Defective Mice

Objective: The Na,K‐ATPase α2 subunit gene (Atp1a2) is expressed in the brain, skeletal muscles, heart, and adipocytes. Specific function of the α2 subunit, such as involvement in differentiation and function of adipocytes, has not been addressed. The aim of this study was to examine whether Atp1a2‐defective heterozygous mice show obesity and reveal the mechanisms underlying the obesity. Research Methods and Procedures: We measured the differentiation and glucose uptake function of in vitro‐differentiated adipocytes derived from embryonic fibroblasts of Atp1a2‐defective mice. Food intake, body temperature, metabolic rate, and spontaneous activity and mRNA levels of neuropeptide genes were compared between the heterozygous and wild‐type adult mice. Results: Atp1a2 heterozygous female mice developed obesity after middle age. The time course of in vitro adipocyte differentiation of embryonic fibroblasts isolated from wild type, heterozygous, and homozygous mice was not different, glucose and Rb uptake activities of the in vitro‐differentiated adipocytes were not altered, and the effects of insulin on glucose uptake and those of monensin and ouabain on Rb uptake were similar among the genotypes. However, food intake in the light phase was significantly greater in the heterozygous mice than the wild type in the 24‐hour dark‐light cycle, whereas it was similar under constant‐light condition. Body temperature, metabolic rate at rest, and spontaneous motor activity of the heterozygous mice were similar to those of the wild type. Orexin mRNA level was lower in heterozygous than wild‐type mice. Discussion: The Na,K‐ATPase α2 subunit is not involved in the differentiation or in glucose and Rb uptake function of in vitro‐differentiated adipocytes. Hyperphagia is the likely primary cause of obesity in Atp1a2 heterozygous mice.     

Prader-Willi Syndrome: Relationship of Adiposity to Plasma Leptin Levels

Objective : Prader-Willi syndrome (PWS) is an autosomal dominant disorder involving the proximal long arm of chromosome 15, in which obesity is common. However, there is limited information on the underlying physiological mechanisms promoting obesity in this population. We tested whether there was a significant positive association between leptin and total body fat (TBF) in subjects with PWS, and whether this association was stronger among subjects with than without PWS. Research Methods and Procedures : We studied 21 PWS patients and 64 non-PWS controls on whom we measured serum leptin, total body fat, glucose, insulin, and resting energy expenditure. We tested whether the slope of the regression line between leptin and TBF (in kg), measured by dual energy X-ray absorptiometry, was the same for PWS patients and aon-PWS controls. Results : Regression analyses indicated that the leptin-TBF association was significantly stronger among PWS patients. In contrast, the slope of the leptin-body mass index association did not significantly differ between PWS patients and non-PWS controls. None of the other outcome variables showed associations with leptin. Discussion : Results suggest that the role of leptin in promoting obesity may be greater among subjects with PWS than among non-PWS controls.     

The importance of catch-up growth after early malnutrition for the programming of obesity in male rat

Objective: To investigate whether catch‐up growth after maternal malnutrition would favor the development of obesity in adulthood. Research Methods and Procedures: Pregnant rats were submitted to protein or calorie restriction during the course of gestation. During lactation, pups were protein‐restricted, normally fed, or overfed [reduced litter size, control (C) diet]. At weaning, rats were transferred to chow or to a hypercaloric diet (HCD) known to induce obesity. Body weight, food intake, blood parameters, glucose tolerance, adipocyte cellularity, and adipose factors contributing to cardiovascular disease development were measured. Results: Protein and calorie restriction during gestation led to growth retardation at birth. If malnutrition was prolonged throughout lactation, adult body weight was permanently reduced. However, growth‐retarded offspring overfed during the suckling period underwent a rapid catch‐up growth and became heavier than the normally fed Cs. Offspring of calorie‐restricted rats gained more weight than those of dams fed protein‐restricted diet. Feeding an HCD postnatally amplified the effect of calorie restriction, and offspring that underwent catch‐up growth became more obese than Cs. The HCD was associated with hyperphagia, hyperglycemia, hyperinsulinemia, glucose intolerance, insulin resistance, and adipocyte hypertrophy. The magnitude of effects varied depending on the type and the timing of early malnutrition. The expression of genes encoding factors implicated in cardiovascular disease was also modulated differently by early malnutrition and adult obesity. Discussion: Catch‐up growth immediately after early malnutrition should be a key point for the programming of obesity.     

Associations between the home food environment and obesity-promoting eating behaviors in adolescence

Objective: This study examines relationships between multiple aspects of the home food environment and obesity‐promoting characteristics of 12‐ to 13‐year‐old adolescents' diets, specifically frequency of consumption of high‐energy fluids, sweet snacks, savory snacks, and take‐out foods. Research Methods: This was a cross‐sectional study including 347 adolescents 12 to 13 years of age and their parents. Data were collected via self‐completed surveys. The adolescents' diets were assessed using a Food Frequency Questionnaire derived from existing age‐appropriate National Nutrition Survey data. An extensive range of domains within the home food environment were assessed. Bivariate linear regression analyses were run split by gender. Forced entry multiple linear regression analyses (adjusting for all variables significant in bivariate analyses as well as for maternal education) were also performed, stratified by the sex of the child. Results: The influence of mothers, either as models for eating behaviors or as the providers of food, was pervasive. Mothers' intake of high‐energy fluids (p = 0.003), sweet snacks (p = 0.010), savory snacks (p = 0.008), and take‐out food (p = 0.007) was positively associated with boys' intake of all these foods. In addition, mothers' intake of high‐energy fluids was positively associated with daughters' consumption of these drinks (p = 0.025). Furthermore, availability of unhealthy foods at home was positively associated with girls' sweet snack (p = 0.001), girls' savory snack (p < 0.001), boys' savory snack (p = 0.002), and, in the bivariate analyses, girls' high‐energy fluid consumption (p = 0.002). Discussion: This study of home food environment influences on adolescent diet highlights the pervasive influence of mothers in determining adolescents' obesity‐promoting eating, providing direction for obesity prevention strategies and future research.     

Loss of Necdin impairs myosin activation and delays cell polarization

NDN is one of several genes inactivated in Prader–Willi syndrome (PWS), a developmental disorder characterized by obesity, hypotonia, and developmental delay. We demonstrate that loss of Necdin in murine and human fibroblasts impairs polarity initiation through a Cdc42‐myosin‐dependent pathway, thereby reducing cell migration. We identified defective polarization in both primary neuron cultures and in the developing limb in Ndn‐null mice. Ndn‐null neurons fail to activate myosin light chain and display defective polarization with respect to a brain‐derived neurotrophic factor gradient. Pax3+ muscle progenitors in Ndn‐null developing forelimbs display defective polarization, do not adequately migrate into the dorsal limb bud, and extensor muscles are consequently smaller. These results provide strong evidence that Necdin is a key protein regulating polarization of the cytoskeleton during development. Furthermore, this is the first demonstration of a cellular defect in PWS and suggests a novel molecular mechanism to explain neurological and muscular pathophysiologies in PWS. genesis 48:540–553, 2010. © 2010 Wiley‐Liss, Inc.     

Obesity in Insulin Receptor Substrate‐2–Deficient Mice: Disrupted Control of Arcuate Nucleus Neuropeptides

Objectives : Disturbances in insulin signaling have been shown to induce obesity and/or hyperphagia in brain insulin receptor or insulin receptor substrate‐2 (IRS‐2) knockout (KO) mice. This study aimed to examine the central and peripheral mechanisms underlying the phenotype in IRS‐2 KO mice. Research Methods and Procedures : We measured the histological characterization of adipose tissues, mRNA levels of pro‐opiomelanocortin, agouti‐related protein, and neuropeptide Y in the hypothalamus and uncoupling proteins (UCPs) in peripheral tissues of IRS‐2 KO mice. Results : Female IRS‐2 KO mice showed increased daily food intake. Body weight and adiposity were increased in both sexes, although these differences were more pronounced in female than in male IRS‐2 KO mice. Both male and female IRS‐2 KO mice showed decreased UCP1 mRNA expression in brown adipose tissue with defective thermoregulation, and UCP2 mRNA expression was increased in the white adipose tissue of female knockout mice. Furthermore, arcuate nucleus mRNA expression of pro‐opiomelanocortin, was decreased in both male and female IRS‐2 KO mice, whereas expression of agouti‐related protein and neuropeptide Y were increased in female IRS‐2 KO mice. Discussion : In IRS‐2 KO mice, disrupted control of hypothalamic neuropeptide levels and UCP mRNA expression may contribute to the development of obesity.     

Early obesity and age-related mimicry of metabolic syndrome in female mice with sex hormonal imbalances

Objective: To investigate the relationship of early obesity to metabolic syndrome during sex hormonal imbalances in mutant female mice at different ages. Research Methods and Procedures: Hormonal imbalances, accumulation and nature of adipose tissue, food intake, glucose tolerance, and expression of candidate genes and markers of inflammation were studied by comparing wild‐type, null, and haploinsufficient follitropin receptor knockout female mice at different ages. Results: Follitropin receptor deletion in mice produced null females that are infertile and haploinsufficient mice that undergo accelerated biological aging. Both types of mutants with sex hormonal imbalances have central obesity without hyperphagia, but circulating leptin is elevated. Adipocyte hyperplasia and hypertrophy is attributed to elevated peroxisome proliferator‐activated receptor γ expression. Adiponectin protein levels increase in fat tissue and plasma. Only mutants but not controls acquire age‐dependent decline in glucose tolerance with high insulin and altered pancreatic β cells. Changes in inflammation markers, decreased muscle insulin receptor phosphorylation, and increase of the enzyme protein tyrosine phosphatase 1B indicate insulin resistance. Discussion: In this animal model, the chronological appearance of early obesity induced by hormonal imbalances culminates in characteristics that are attributable to metabolic syndrome, including cardiovascular abnormalities. Dissection of the depot‐specific alterations and defining molecular interrelationships could help in developing targeted remedies and resolving complications and controversies related to health benefits and adversities of current hormone replacement therapy.     

The effect of obesity management on body image in patients seeking treatment at medical centers

Objective: Body image dissatisfaction is common in treatment‐seeking patients with obesity. We aimed to investigate the effects of obesity management on body image in patients with obesity attending Italian medical centers for weight loss programs. Research Methods and Procedures: A total of 473 obese patients seeking treatment in 13 Italian medical centers (80% females; age, 45.9 ± standard deviation 11.0 years; BMI, 36.8 ± 5.7 kg/m²) were evaluated at baseline and after a 6‐month weight loss treatment. Body uneasiness, psychiatric distress, and binge eating were tested by Body Uneasiness Test (BUT, Part A), Symptom CheckList‐90 (SCL‐90), and Binge Eating Scale (BES), respectively. Results: At 6‐month follow‐up, the percentage weight loss was significantly higher in men (9.0 ± 6.3%) than in women (6.8 ± 7.3%; p = 0.010). Both men and women had a significant improvement in BUT Global Severity Index and in all of the BUT subscales with the exception of the Compulsive Self‐Monitoring subscale. Linear regression analysis selected baseline psychological and behavioral measures (global score of BUT and SCL‐90) and improved psychiatric distress and binge eating as independent predictors of changes in basal body dissatisfaction in females, whereas in males, changes were associated only with baseline BUT‐Global Severity Index score, binge eating, and its treatment‐associated improvement. Pre‐treatment BMI and BMI changes did not enter the regression. Discussion: Obesity treatment, even with a modest degree of weight loss, is associated with a significant improvement of body image, in both females and males. This effect depends mainly on psychological factors, not on the amount of weight loss.     

A mechanism underlying mature-onset obesity: evidence from the hyperphagic phenotype of brain-derived neurotrophic factor mutants

Mice deficient in brain-derived neurotrophic factor (BDNF) develop mature-onset obesity, primarily due to overeating. To gain insight into the mechanism of this hyperphagia, we characterized food intake, body weight, meal pattern, and meal microstructure in young and mature mice fed balanced or high-fat diets. Hyperphagia and obesity occurred in mature but not young BDNF mutants fed a balanced diet. This hyperphagia was mediated by increased meal number, which was associated with normal meal size, meal duration, and satiety ratio. In contrast, the high-fat diet induced premature development of hyperphagia and obesity in young BDNF mutants and a similar magnitude hyperphagia in mature mutants. This hyperphagia was supported by increased meal size and was accompanied by a reduced satiety ratio. Thus the mechanism underlying hyperphagia was present before significant weight gain, but whether it occurred, and whether meal frequency or meal size was altered to support it, was modulated by a process associated with aging and by diet properties. Meal pattern changes associated with the balanced diet suggested meal initiation, and the oropharyngeal positive feedback that drives feeding, were enhanced and might have contributed to overeating in BDNF mutants, whereas negative feedback was normal. Consistent with this hypothesis, meal microstructure revealed that all hyperphagic mutant groups exhibited increased intake rates at meal onset. Therefore, the central nervous system targets of BDNF actions may include orosensory brain stem neurons that process and transmit positive feedback or forebrain neurons that modulate its strength.     

Development and Validation of a Measurement System for Assessment of Energy Expenditure and Physical Activity in Prader-Willi Syndrome

CHEN, KONG Y., MING SUN, MERLIN G. BUTLER, TRAVIS THOMPSON, AND MICHAEL G. CARLSON. Development and validation of a measurement system for assessment of energy expenditure and physical activity in Prader—Willi syndrome. Obes Res. Objective: 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. Research Methods and Procedures: 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. Results: Representative data from two PWS patients and two matched control (CTR) subjects displayed EE during their inactive lifestyles. Discussion: 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.     

Effects of neuropeptide Y antagonists on food intake in rats: differences with cold-adaptation

Hyperphagia followed both central neuropeptide Y (NPY) administration and the presumed increase of endogenous NPY activity after food deprivation. NPY induced greater hyperphagia in cold-adapted than non-adapted rats; fasting of comparable severity caused similar hyperphagia in the two groups. NPY-receptor-antagonist D-Tyr(27,36), D-Thr32-NPY(27,36) or functional NPY-antagonist D-myo-inositol-1,2,6-trisphosphate attenuated the hyperphagic effect of both NPY and fasting in non-adapted rats. However, while completely preventing the NPY-hyperphagia, they did not influence the fasting-induced hyperphagia in cold-adapted rats. With cold-adaptation the sensitivity to NPY and to its antagonists increases, but the hypothalamic NPY loses from its fundamental role in the regulation of food intake, and the hyperphagia seen in cold-adaptation may need some other explanation.     

Maintenance of a normal meal-induced decrease in plasma ghrelin levels in children with Prader-Willi syndrome.

Ghrelin is a 28-amino acid peptide recently identified in the stomach as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R1a). Ghrelin is a potent stimulator of GH secretion. It was recently shown that circulating ghrelin levels in humans rise shortly before and fall shortly after every meal, and that ghrelin administration increases voluntary food intake. The hypothesis that ghrelin hypersecretion might contribute to genetic obesity has never been investigated. In this context, Prader-Willi syndrome is the most common form of human syndromic obesity. As ghrelin affects appetite as well as GH secretion and both are abnormal in PWS, it has been surmised that these alterations might be due to ghrelin dysregulation. The aim of the study was to investigate whether ghrelin is suppressed by the meals differently in PWS children than in PWS adults. Overnight circulating fasting ghrelin levels and ghrelin levels 120 min after breakfast were assayed in 7 PWS children (10.2 +/- 1.7 yr), 7 subjects with morbid obesity (10.3 +/- 1.3 yr), and 5 normal controls (8.4 +/- 1.4 yr). Because of the data spread, no statistical difference was observed in fasting ghrelin levels between PWS and control children (p = NS); anyway, fasting ghrelin levels were significantly lower in obese children than in the other groups (p < 0.05 vs. control and PWS children). Ghrelin levels were slightly suppressed by the meal in control subjects (mean fasting ghrelin: 160.2 +/- 82 pg/ml; after the meal, 141.2 +/- 57 pg/ml, p = NS); the meal failed to suppress ghrelin levels in obese children (mean fasting ghrelin: 126.4 +/- 8.5 pg/ml; after the meal, 119.1 +/- 8.3 pg/ml, p = NS). Interestingly, the meal markedly suppressed ghrelin levels in PWS children (mean fasting ghrelin: 229.5 +/- 70.4 pg/ml; after the meal, 155.8 +/- 34.2 pg/ml, p < 0.01). In conclusion, since a lack of decrease in circulating ghrelin induced by the meal was previously reported in PWS adults, the finding of a meal-induced decrease in ghrelin levels in our population of young PWS would imply that the regulation of the ghrelin system involved in the orexigenic effects of the peptide is operative during childhood, although it progressively deteriorates and is absent in adulthood when hyperphagia and obesity progressively worsen.