Physiological evidence for the involvement of peptide YY in the regulation of energy homeostasis in humans.

OBJECTIVE: To explore the potential role of the endogenous peptide YY (PYY) in the long-term regulation of body weight and energy homeostasis. RESEARCH METHODS AND PROCEDURES: Fasting and postprandial plasma PYY concentrations were measured after an overnight fast and 30 to 180 minutes after a standardized meal in 29 (21 men/8 women) non-diabetic subjects, 16 of whom had a follow-up visit 10.8 +/- 1.4 months later. Ratings of hunger and satiety were collected using visual analog scales. Resting metabolic rate (RMR) (15-hour RMR) and respiratory quotient (RQ) were assessed using a respiratory chamber. RESULTS: Fasting PYY concentrations were negatively correlated with various markers of adiposity and negatively associated with 15-hour RMR (r = -0.46, p = 0.01). Postprandial changes in PYY (area under the curve) were positively associated with postprandial changes in ratings of satiety (r = 0.47, p = 0.01). The maximal PYY concentrations achieved after the meal (peak PYY) were negatively associated with 24-hour RQ (r = -0.41, p = 0.03). Prospectively, the peak PYY concentrations were negatively associated with changes in body weight (r = -0.58, p = 0.01). DISCUSSION: Our data indicate that the endogenous PYY may be involved in the long-term regulation of body weight. It seems that this long-term effect was not exclusively driven by the modulation of food intake but also by the control of energy expenditure and lipid metabolism.

In pursuit of neural risk factors for weight gain in humans.

Obesity is a multifactorial disease associated with an increased risk of type 2 diabetes, coronary artery disease, cancer, and consequently, with a reduced length of life. Metabolic phenotypes of reduced energy expenditure have been associated with weight gain, but their contribution has been estimated to be relatively small. On the other hand, excessive food intake is likely to be the major determinant of positive energy balances and it is underlied by both non-conscious (homeostatic) and conscious (perceptual, emotional, and cognitive) phenomena processed in the brain. Functional neuroimaging is a promising tool to investigate these neural substrates in humans, because it provides a measurement of state-dependent brain regional activity, bridging the gap between neural events and behavioral responses. Using this technology, a few studies have provided the first evidence of functional differences between obese and lean individuals in the brain's response to energy intake and investigated the presence of neural risk factors of weight gain.

Sensory experience of food and obesity: a positron emission tomography study of the brain regions affected by tasting a liquid meal after a prolonged fast.

The sensory experience of food is a primary reinforcer of eating and overeating plays a major role in the development of human obesity. However, whether the sensory experience of a forthcoming meal and the associated physiological phenomena (cephalic phase response, expectation of reward), which prepare the organism for the ingestion of food play a role in the regulation of energy intake and contribute to the development of obesity remains largely unresolved. We used positron emission tomography (PET) and 15O-water to measure changes in regional cerebral blood flow (rCBF) and to assess the brain's response to the oral administration of 2 ml of a liquid meal (Ensure Plus, 1.5 kcal/ml) after a 36-h fast and shortly before consuming the same meal. Twenty-one obese (BMI > 35 kg/m2, 10M/11F, age 28 +/- 6 years, body fat 40 +/- 6%) and 20 lean individuals (BMI < 25 kg/m2, 10M/10F, age 33 +/- 9 years, body fat 21 +/- 7%) were studied. Compared to lean individuals, obese individuals had higher fasting plasma glucose (83.3 +/- 6.2 vs. 75.5 +/- 9.6 mg/dl; P = 0.0003) and insulin concentrations (6.1 +/- 3.5 vs. 2.5 +/- 1.7 microU/ml; P < 0.0001) and were characterized by a higher score of dietary disinhibition (i.e., the susceptibility of eating behavior to emotional factors and sensory cues, 5.7 +/- 3.6 vs. 3.5 +/- 2.7; P = 0.01) assessed by the Three Factor Eating Questionnaire. In response to the sensory experience of food, differences in rCBF were observed in several regions of the brain, including greater increases in the middle-dorsal insula and midbrain, and greater decreases in the posterior cingulate, temporal, and orbitofrontal cortices in obese compared to lean individuals (P < 0.05, after small volume correction). In a multiple regression model, percentage of body fat (P = 0.04), glycemia (P = 0.01), and disinhibition (P = 0.07) were independent correlates of the neural response to the sensory experience of the meal in the middle-dorsal insular cortex (R2 = 0.45). We conclude that obesity is associated with an abnormal brain response to the sensory aspects of a liquid meal after a prolonged fast especially in areas of the primary gustatory cortex. This is only partially explained by the elevated glycemia and high level of disinhibition which characterize individuals with increased adiposity. These results provide a new perspective on the understanding of the neuroanatomical correlates of abnormal eating behavior and their relationship with obesity in humans.

Pancreatic polypeptide is involved in the regulation of body weight in pima Indian male subjects.

Pancreatic polypeptide (PP) is released from the pancreas in response to a meal. In humans, low-circulating PP levels have been observed in obesity, and administration of pharmacological doses of PP has been shown to decrease food intake. The aim of the present study was to investigate whether low circulating PP is associated with weight gain in Pima Indians. Plasma PP concentrations were measured after an overnight fast and 30 min after a standardized mixed meal in 33 nondiabetic male subjects who had a follow-up visit 4.9 +/- 2.5 years later. Cross-sectionally, fasting and postprandial PP levels were negatively associated with body size and adiposity. Prospectively, the change in PP response to the meal was negatively associated with the change in body weight (r = -0.53, P = 0.002). In contrast, a high fasting PP level was positively associated with change in body weight (r = 0.45, P = 0.009). In conclusion, our results provide evidence that, even within the physiological range, PP contributes to the regulation of energy balance in humans. However this contribution appears to be more complex than anticipated because of the opposite effect of fasting and postprandial PP on the risk of future weight gain.

Negative relationship between fasting plasma ghrelin concentrations and ad libitum food intake.

Ghrelin is a novel GH secretagogue with orexigenic effects. We hypothesized that high fasting plasma ghrelin concentrations (FxGhr) might predict high ad libitum food intake. FxGhr were measured in 30 normoglycemic subjects: 15 Pima Indians (8 male/7 female; age, 32 +/- 7 yr; body weight, 87 +/- 21 kg; mean +/-sd) and 15 Caucasians (12 male/3 female, 36 +/- 8 yr, 94 +/- 26 kg) in energy balance for 3 d before testing. Subjects then self-selected their food ad libitum for the following 3 d. Mean daily energy intake (DEI) was calculated from the weight of foods consumed and expressed as a percent of weight maintenance energy needs. FxGhr were twice as high in Caucasians as in Pima Indians (103 +/- 53 vs. 52 +/- 18 fmol/ml, P < 0.001) and remained higher after adjustment for age, gender, and body weight (P < 0.0001). Neither DEI, nor percent of weight maintenance energy needs, nor percent of calories from fat differed between the races. In both groups, FxGhr were negatively correlated with DEI (r = -0.61, P = 0.01; r = -0.54, P = 0.04, respectively). These negative relationships were not explained by interindividual differences in age, gender, or body weight. This unexpected finding that low FxGhr predict ad libitum food intake suggests that the role of endogenous ghrelin in the regulation of energy homeostasis remains uncertain.

Taste preferences and body weight changes in an obesity-prone population.

BACKGROUND: Taste preferences for highly palatable foods rich in sugar and fat may underlie the current epidemic of obesity. OBJECTIVE: This study aimed to determine whether the hedonic response to sweet and creamy solutions differs between whites and Pima Indians and whether a preference for these tastes predicts weight gain. DESIGN: One hundred twenty-three Pima Indian and 64 white volunteers taste tested solutions of nonfat milk (0.1% fat), whole milk (3.5% fat), half and half (11.3% fat), and cream (37.5% fat) containing 0%, 5%, 10%, or 20% sugar by weight. Solutions were rated for perceived sweetness, creaminess, and pleasantness (hedonic response) on a 100-mm visual analogue scale. Follow-up body weight was measured in 75 Pima Indians 5.5 +/- 3.0 y ( +/- SD) after baseline taste testing. RESULTS: The Pima Indians had a significantly (P = 0.006) lower hedonic response than did the whites (repeated-measures analysis of variance). Neither body size (P = 0.56) nor adiposity (P = 0.86) was a significant predictor of the hedonic response. There was a positive correlation (r = 0.28, P = 0.01) between the maximal hedonic response at baseline and subsequent weight gain in the Pima Indians. CONCLUSION: 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.

Parasympathetic blockade attenuates augmented pancreatic polypeptide but not insulin secretion in Pima Indians.

There is evidence from animal models of obesity and type 2 diabetes that increased parasympathetic vagal input to the pancreas contributes to hyperinsulinemia. Compared with Caucasians, Pima Indians have a high risk of type 2 diabetes and exhibit marked hyperinsulinemia and elevated plasma levels of pancreatic polypeptide (PP), an islet hormone considered a surrogate marker of parasympathetic nervous system (PNS) drive to the pancreas. To test if hyperinsulinemia in Pima Indians is due to increased vagal input to the beta-cell, we examined the effect of PNS blockade in 17 Caucasian (aged 35 +/- 8 years, body fat 23 +/- 7% [mean +/- SD]) and 17 Pima Indian males (aged 28 +/- 8 years, body fat 29 +/- 5%) with normal glucose tolerance. Each participant underwent four consecutive standardized liquid meal tests (64% carbohydrate, 22% fat, and 14% protein) during which a primed infusion of atropine was administered for 120 min at the following doses: 0, 2.5, 5, and 10 micro g. kg fat-free mass (FFM)(-1). h(-1). Areas under the curve for early (AUC(0-30 min)) and total (AUC(0-120 min)) postprandial insulin and PP secretory responses were calculated. Early postprandial insulin and PP secretory responses were higher in Pima Indians compared with those of Caucasians (both P = 0.01). Secretion of insulin and PP was inhibited by atropine (both P < 0.001). Increasing doses of atropine attenuated the ethnic difference in PP (P = 0.01) but not in early insulin secretory responses (P = 0.6), an effect that was not due to differences in gastric emptying rate (acetaminophen test) and/or circulating glucose. Similar results were observed for total secretory responses. These results confirm that compared with Caucasians, Pima Indians have an exaggerated PNS drive to pancreatic F-cells that secrete PP. However, the hyperinsulinemia of this population does not appear to be due to increased vagal input to pancreatic beta-cells.

Cross-sectional and prospective relationships of fasting plasma ghrelin concentrations with anthropometric measures in pima Indian children.

Ghrelin, a recently discovered GH secretagogue with orexigenic effects, is proposed to be a regulator of energy balance. To test whether fasting plasma ghrelin concentrations predict future gain in body weight or adiposity, we measured weight, height, body mass index (BMI), percentage of body fat (by dual energy x-ray absorptiometry), and fasting plasma concentrations of ghrelin, insulin, and glucose in 10-yr-old Pima Indians (n = 40; 13 males and 27 females) and subsequent weight, height, and BMI 1.7 +/- 0.6 yr later. At baseline, the fasting plasma ghrelin concentration was negatively associated with height (r = -0.52; P = 0.0006), weight, (r = -0.37; P = 0.02), percentage of body fat (r = -0.33, P = 0.04), and fasting plasma insulin concentration (r = -0.41; P = 0.01). In multiple regression models adjusting for gender and fasting plasma insulin, the fasting plasma ghrelin concentration was an independent determinant of height (beta = -13.9; P = 0.02), but not weight or BMI. Prospectively, the baseline fasting plasma ghrelin concentration was not an independent determinant of the relative rate of increase in weight, height, or adiposity. In conclusion, the fasting plasma ghrelin concentration was lower in taller and fatter Pima Indian children, but did not independently predict baseline weight, adiposity, or future growth rates. These data do not support a direct relationship between the fasting plasma ghrelin concentration and subsequent relative changes in height or weight in growing children.

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.