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.

Cortical areas involved in controlling inappropriate behavioral responses, such as the DPFC, are particularly activated in successful dieters in response to meal consumption. The association between the degree of dietary restraint and the coordinated neural changes in the DPFC and OFC raises the possibility that cognitive control of food intake is achieved by modulating neural circuits controlling food reward.

OBJECTIVE:To determine whether abnormal obese-like neural responses to a meal persist in postobese individuals, who achieved and maintained a normal body weight despite a past history of severe obesity. DESIGN AND SUBJECTS: Cross-sectional study of the brain's response to tasting and consuming a satiating meal in 11 postobese (age: 4076 y, body mass index (BMI): 23.671.9 kg/m 2 ), 23 obese (age: 2976 y, BMI: 39.673.8 kg/m 2 ) and 21 lean (age: 3379 y, BMI: 22.872.1 kg/m 2 ) subjects. MEASUREMENTS: Regional cerebral blood flow (rCBF, a marker of neural activity) at baseline (after a 36-h fast), after tasting and after consuming a satiating liquid meal was assessed using positron emission tomography and state-dependent changes (taste-baseline; satiation-baseline), and compared across groups. Subjective ratings of hunger and fullness were measured by a visual analogue scale and body fatness by dual-energy X-ray absorptiometry. RESULTS: In response to tasting the liquid meal, changes in rCBF were different in the obese as compared to the lean individuals (Po0.05, corrected for multiple comparisons) in the middle insula (peak voxel, x ¼ À41, y ¼ 1, z ¼ 8; Montreal Neurological Institute coordinates) and posterior cingulate cortex (peak voxel, x ¼ 17, y ¼ À47, z ¼ 40). The middle insular cortex exhibited a similar increase of neural activity in the obese and postobese subjects, whereas in the lean subjects the regional activity did not change. In the posterior cingulate cortex, the changes in rCBF in the postobese subjects were not different from those in the other groups. In response to a satiating amount of the same liquid meal, changes in rCBF were different in the obese as compared to the lean individuals (Po0.05, corrected for multiple comparisons) in the posterior hippocampus (peak voxel, x ¼ 21, y ¼ À45, x ¼ 4), posterior cingulate cortex (peak voxel, x ¼ 17, y ¼ À47, z ¼ 40), and amygdala (peak voxel, x ¼ 27, y ¼ 1, z ¼ À24). The posterior hippocampus exhibited a similar decrease of neural activity in the obese and postobese subjects, whereas in the lean subjects the regional activity increased. In the posterior cingulate cortex and amygdala, the changes in rCBF were not different between the postobese and lean individuals. None of the changes in neural activity were correlated with the age of the individuals, the subjective ratings of hunger and fullness, or the meal induced-changes in plasma glucose, insulin, or serum free fatty acids. CONCLUSION: Persistence of abnormal neural responses to a meal in the postobese individuals, a group at high risk for relapse, indicates that a predisposition to obesity may involve areas of the brain that control complex aspects of eating behavior including anticipation and reward, chemosensory perception, and autonomic control of digestion (insular cortex), as well as enteroception and learning/memory (hippocampus).

Although the Pima Indians liked sweet and creamy solutions less than the whites did, a heightened hedonic response for these solutions among the Pima Indians was associated with weight gain.

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