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Research Notes: Peptide YYCell Metab. 2006 Sep. Dietary protein enhances satiety and promotes weight loss, but the mechanisms by which appetite is affected remain unclear. We investigated the role of gut hormones, key regulators of ingestive behavior, in mediating the satiating effects of different macronutrients. In normal-weight and obese human subjects, high-protein intake induced the greatest release of the anorectic hormone peptide YY (PYY) and the most pronounced satiety. Long-term augmentation of dietary protein in mice increased plasma PYY levels, decreased food intake, and reduced adiposity. To directly determine the role of PYY in mediating the satiating effects of protein, we generated Pyy null mice, which were selectively resistant to the satiating and weight-reducing effects of protein and developed marked obesity that was reversed by exogenous PYY treatment. Our findings suggest that modulating the release of endogenous satiety factors, such as PYY, through alteration of specific diet constituents could provide a rational therapy for obesity. ~ ~ ~ ~ ~ (09/05/06 - WebMD) When released in the gut, the hormone known as PYY reduces hunger. And high-protein foods set off PYY better than other foods, according to a study by Rachel L. Batterham, MD, of University College London, and colleagues published in the journal Cell Metabolism. Recent studies suggest PYY is part of the solution to obesity. Compared with a normal-weight person, for example, an obese person has to eat twice as many calories to trigger PYY. "We've now found that increasing the protein content of the diet augments the body's own PYY, helping to reduce hunger and aid weight lossweight loss," said Batterham says. Batterham's team first looked at what kind of food best satisfies hunger. They studied nine obese men and 10 normal-weight men. After brief fasts, the men ate different meals. Each of the meals - a high-protein meal, a high-fat meal, and a high-carbohydrate meal - had the same number of calories. All the men said the high-protein meal best satisfied their hunger. Interestingly, the normal-weight men found the high-fat meal more satisfying than the high-carb meal, while the obese men did not. Measurements showed the high-protein meal triggered the most PYY in all of the men. In the normal-weight men - but not the obese men - the high-fat meal triggered more PYY than the high-carb meal. Batterham's team then genetically engineered a mouse strain that did not have the PYY gene. These mice ate huge amounts of food and quickly became obese. Normally, obese mice fed a high-protein diet will eat less and lose weight. But a high-protein diet didn't help the PYY-defective mice lose weight - unless they also got PYY treatments. Why does protein trigger PYY and satisfy hunger so well? It's not entirely clear, but Batterham and colleagues suggest evolution is the reason. The prehistoric humans whose genes we inherit had a different diet than we do. They got 19% to 35% of their energy from protein and 22% to 40% from carbs. Our modern diet gets 49% of its energy from carbs and only 16% from protein. "One potential weight loss strategy is therefore to increase the satiating power of the diet and promote weight loss through the addition of dietary protein - harnessing our own satiety system," Batterham says. "Such a diet is perhaps more typical to that of our hunter-gatherer ancestors." [article has been edited] Endocrinology. 2006 Jan. The responses of the gut hormone peptide YY (PYY) to food were investigated in 20 normal-weight and 20 obese humans in response to six test meals of varying calorie content. Human volunteers had a graded rise in plasma PYY (R2 = 0.96; P < 0.001) during increasing calorific meals, but the obese subjects had a lower endogenous PYY response at each meal size (P < 0.05 at all levels). The ratio of plasma PYY(1-36) to PYY(3-36) was similar in normal-weight and obese subjects. The effect on food intake and satiety of graded doses of exogenous PYY(3-36) was also evaluated in 12 human volunteers. Stepwise increasing doses of exogenous PYY(3-36) in humans caused a graded reduction in food intake (R2 = 0.38; P < 0.001). In high-fat-fed (HF) mice that became obese and low-fat-fed mice that remained normal weight, we measured plasma PYY, tissue PYY, and PYY mRNA levels and assessed the effect of exogenous administered PYY(3-36) on food intake in HF mice. HF mice remained sensitive to the anorectic effects of exogenous ip PYY(3-36). Compared with low-fat-fed fed mice, the HF mice had lower endogenous plasma PYY and higher tissue PYY but similar PYY mRNA levels, suggesting a possible reduction of PYY release. Thus, fasting and postprandial endogenous plasma PYY levels were attenuated in obese humans and rodents. The PYY(3-36) infusion study showed that the degree of plasma PYY reduction in obese subjects were likely associated with decreased satiety and relatively increased food intake. We conclude that obese subjects have a PYY deficiency that would reduce satiety and could thus reinforce their obesity. Am J Physiol Endocrinol Metab. 2005 Dec. Stimulation of cholecystokinin and glucagon-like peptide-1 secretion by fat is mediated by the products of fat digestion. Ghrelin, peptide YY (PYY), and pancreatic polypeptide (PP) appear to play an important role in appetite regulation, and their release is modulated by food ingestion, including fat. It is unknown whether fat digestion is a prerequisite for their suppression (ghrelin) or release (PYY, PP). Moreover, it is not known whether small intestinal exposure to fat is sufficient to suppress ghrelin secretion. Our study aimed to resolve these issues. Sixteen healthy young males received, on two separate occasions, 120-min intraduodenal infusions of a long-chain triglyceride emulsion (2.8 kcal/min) 1) without (condition FAT) or 2) with (FAT-THL) 120 mg of tetrahydrolipstatin (THL, lipase inhibitor), followed by a standard buffet-style meal. Blood samples for ghrelin, PYY, and PP were taken throughout. FAT infusion was associated with a marked, and progressive, suppression of plasma ghrelin from t = 60 min (P < 0.001) and stimulation of PYY from t = 30 min (P < 0.01). FAT infusion also stimulated plasma PP (P < or = 0.01), and the release was immediate. FAT-THL completely abolished the FAT-induced changes in ghrelin, PYY, and PP. In response to the meal, plasma ghrelin was further suppressed, and PYY and PP stimulated, during both FAT and FAT-THL infusions. In conclusion, in healthy humans, 1) the presence of fat in the small intestine suppresses ghrelin secretion, and 2) fat-induced suppression of ghrelin and stimulation of PYY and PP is dependent on fat digestion. Excerpts from the full text article: A number of gastrointestinal peptides play a role in the regulation of energy intake in humans, including cholecystokinin (CCK) (19, 27), glucagon-like peptide-1 (GLP-1) (13, 17), peptide YY (PYY) (4), pancreatic polypeptide (PP) (5), and ghrelin (42). The secretion of CCK, GLP-1, and PYY from intestinal cells, and PP from the pancreas, is stimulated by meal ingestion or infusion of nutrients into the small intestine (10, 18, 21, 29). In contrast, ghrelin is secreted by the stomach, and plasma concentrations increase during fasting and are suppressed by a meal (7, 8). Plasma ghrelin concentrations decrease rapidly following food ingestion, and there is evidence that ghrelin plays a role in meal initiation (7, 8). Intravenously administered ghrelin has been shown to stimulate appetite and increase food intake in humans (42). Both carbohydrate and fat, when ingested orally, suppress ghrelin secretion (9, 15), whereas protein may stimulate ghrelin secretion (9) or have no effect (15). Although until recently it has been unclear whether the suppressive effect of carbohydrate and fat on ghrelin secretion is mediated by the presence of nutrients in the stomach, the small intestine, and/or the circulation, recent animal (41) and human (30) studies indicate that the interaction of nutrients with the small intestine is important in the glucose-induced modulation of ghrelin secretion. In rats, the prevention of gastric emptying with a pyloric cuff abolished the suppression of ghrelin secretion by intragastric glucose (41). Moreover, in healthy older humans, both intragastric and intraduodenal glucose infusions suppress ghrelin secretion with no difference between them (34). We (11) have recently established that the stimulation of both CCK and GLP-1 by a duodenal fat infusion is dependent on the interaction of the products of fat digestion with the gut. Inhibition of fat digestion by concomitant administration of the lipase inhibitor tetrahydrolipstatin (THL) completely abolished the increases in plasma CCK and GLP-1 concentrations induced by duodenal infusion of a long-chain triglyceride emulsion in healthy subjects (11). Intraduodenal infusion of the triglyceride emulsion was also associated with a reduction in perceptions of appetite as well as a decrease in energy intake at a buffet meal consumed immediately following the infusion compared with the condition in which fat digestion was inhibited (11). The stimulation of phasic and tonic pyloric pressures by intraduodenal triglyceride was also attenuated by lipase inhibition (11). PYY and PP are both members of the pancreatic polypeptide family of peptides. PYY is secreted predominantly from endocrine cells in the ileum and colon and PP from endocrine cells in the pancreas, both in response to all three macronutrients, fat, carbohydrate, and protein, with fat being the most potent stimulus and carbohydrate the least potent or, possibly, impotent (2, 16, 29, 33). Enteral administration of free fatty acids, including dodecanoate (3) or oleate (22), are known to be potent stimuli of PYY secretion. Both PYY and PP, when infused intravenously, have been shown to reduce appetite and energy intake in healthy humans (4, 5), suggesting an important role for these peptides in the regulation of appetite. Because, as discussed, the appetite suppressant effect of duodenal lipid is dependent on fat digestion (11), it is possible that fat digestion is also a prerequisite for fat-induced suppression of ghrelin and stimulation of PYY and PP. The suppression of ghrelin by fat is not mediated by an increase in plasma concentrations of free fatty acids (30). Although the effects on CCK and GLP-1 secretion in our previous study were striking (11), it has so far been unclear whether these findings could also be extrapolated to ghrelin, PYY, and PP. This hypothesis has, hitherto, not been evaluated. We have now assayed the plasma samples from our previous study (11), in which we had evaluated the role of fat digestion on appetite and energy intake, antropyloroduodenal motility, and plasma CCK and GLP-1 concentrations. We hypothesized that, in response to duodenal fat infusion, 1) plasma ghrelin concentrations would be suppressed, and 2) the suppression of plasma ghrelin and stimulation of PYY and PP would be attenuated when triglyceride digestion is inhibited. Subjects and methods [...] Results Plasma Ghrelin Concentrations Effect of duodenal infusion. There was a significant treatment x time interaction (P < 0.001) for plasma ghrelin concentrations (Fig. 1A). Infusion of FAT was associated with a marked, and progressive, suppression of plasma ghrelin concentrations, which was significant from t = 60 min (P 0.001); in contrast, FAT-THL had no effect on plasma ghrelin. Plasma ghrelin concentrations were lower during infusion of FAT compared with infusion of FAT-THL from t = 45 min (P < 0.01). Effect of meal. During both conditions, plasma ghrelin concentrations decreased further following meal ingestion (time effects: P < 0.001) but remained significantly lower following infusion of FAT compared with FAT-THL (treatment effect: P = 0.001). Plasma PYY Concentrations Effect of duodenal infusion. There was a significant treatment x time interaction (P < 0.001) for plasma PYY concentrations (Fig. 1B). Infusion of FAT was associated with a marked, and progressive, rise in plasma PYY concentrations, which was significant from t = 30 min (P < 0.01); in contrast, infusion of FAT-THL did not affect plasma PYY concentrations. Plasma PYY concentrations were higher during infusion of FAT compared with FAT-THL from t = 15 min (P < 0.01). Effect of meal. Plasma PYY concentrations further rose during both conditions (time effects: P < 0.01) at t = 165 min, and were significantly higher following infusion of FAT compared with FAT-THL (treatment effect: P < 0.01). Plasma PP Concentrations Effect of duodenal infusion. There was a significant effect of treatment (P < 0.01) on plasma PP concentrations (Fig. 1C). During infusion of FAT, PP concentrations were higher from t = 15 min and then plateaued compared with infusion of FAT-THL; infusion of FAT-THL had no effect on plasma PP concentrations. Effect of meal. There was a significant treatment x time interaction (P = 0.01) for plasma PP concentrations. Plasma PP rose during both conditions (time effects: P < 0.001) but was higher following infusion of FAT-THL compared with infusion of FAT (P < 0.01). Discussion Our study establishes that, in healthy humans, 1) the presence of fat in the proximal small intestine is sufficient to suppress ghrelin secretion, and 2) the fat-induced suppression of ghrelin and stimulation of PYY and PP secretion are dependent on fat digestion. Although it is known that meal ingestion suppresses ghrelin (8) and that this effect is induced by both fat and carbohydrate, but not protein (9, 15), it has been unclear whether the stimulus was the presence of nutrients in the stomach, small intestine, and/or postabsorptive factors. There is evidence that gastric distension per se does not reduce ghrelin (34, 39, 41) in that, although an oral glucose load suppressed ghrelin secretion in healthy humans, a water load of identical volume had no effect (39). The effect of oral glucose on ghrelin secretion is probably accounted for by the action of glucose in the small intestine rather than a "gastric" effect. In rats, a gastric glucose load did not suppress ghrelin secretion when gastric emptying was prevented by a pyloric cuff (41). A recent study from our laboratory (34) indicates that gastric and duodenal glucose infusions suppress ghrelin to a similar degree in healthy older subjects. In considering the potential role of postabsorptive factors, intravenous infusion of glucose suppresses ghrelin in both rats (14) and humans (39), whereas intravenous infusion of a fat emulsion with subsequent elevation of free fatty acids had no effect in humans (30), but suppressed plasma ghrelin in rats (14). These latter observations argue against a role for postabsorptive factors in fat- but perhaps not glucose-induced suppression of ghrelin in humans. The current study is the first to demonstrate that duodenal infusion of a long-chain triglyceride emulsion potently suppresses ghrelin secretion in healthy young men, indicating that in humans ghrelin is sensitive to digested fats, an effect apparently not mediated by an increase in blood free fatty acids (30). The stimulation of PYY and PP by small intestinal fat is well documented (22, 26, 29). Our study also provides additional insights into the role of fat digestion products in the modulation of gastrointestinal peptide secretion. Inhibition of fat digestion abolished the suppression of ghrelin and the stimulation of PYY and PP secretion, indicating that fat digestion products, i.e., free fatty acids, play an important role. Although the current findings in relation to the regulation of ghrelin, PYY, and PP secretion are novel, they are consistent with previous observations that fat digestion is a prerequisite for the slowing of gastric emptying (6, 36, 38), proximal gastric relaxation (12), stimulation of pyloric and suppression of antral pressures (11), stimulation of CCK, GLP-1, and GIP (glucose-dependent insulinotropic polypeptide) secretion in healthy subjects and type 2 diabetes (11, 32, 36, 38), suppression of appetite perceptions (11), induction of upper gastrointestinal symptoms (12), and suppression of energy intake (11, 31). Although our study did not include a formal control condition (i.e., administration of THL alone), there is no evidence that THL per se has any effects on the gastrointestinal tract, including gastrointestinal hormone secretion; furthermore, systemic absorption of THL is known to be very low (personal communication, Dr. Jacques Bailly, Hoffmann-La Roche, Basel, Switzerland). Although lipase inhibition had substantial effects on the antropyloroduodenal motor responses to duodenal lipid (11), it is most unlikely that these would account for the observed hormonal responses. It is of interest that the pattern of suppression of ghrelin and stimulation of PYY and PP by the small intestinal triglyceride infusion differed markedly. The fall in ghrelin and rise in PYY appeared to be progressive between t = 0 and 120 min, whereas PP rose to a maximum within 15 min and did not change after that time. These discrepant responses provide insights into the potential small intestinal mechanisms that may modulate the secretion of these hormones. PYY-containing cells predominate in the distal small intestine and colon, and PYY secretion is initiated either by direct luminal contact of nutrients with the endocrine cells (3, 22, 25) and/or indirectly through neurohumoral signals (23, 25). The rise in PYY was relatively prompt and, hence, most unlikely due exclusively to direct exposure of the distal small intestine. In dogs, CCK, which is released from enteroendocrine cells located in the proximal small intestine, has been shown to modulate PYY release (23), and in our original report (11) we described that plasma CCK concentrations rose significantly within 15 min of commencing the duodenal triglyceride infusion but decreased after 30 min; this is consistent with the concept that the initial rise in PYY is due to a link between the proximal small intestine with PYY-releasing cells in the distal small intestine and that the continued rise of PYY throughout the infusion reflects the direct contact of lipid with the distal small intestine. The profile obtained for PYY plasma concentrations in our study closely resembles that observed after a meal (2). As the emulsion containing THL resulted in only 75%, the observed total abolition of PYY secretion and ghrelin suppression suggests that a critical threshold concentration or load for luminal fatty acids is required for these effects. Conversely, there was a progressive suppression of ghrelin secretion over the infusion period. Hence, for both PYY and ghrelin, our data suggest that a critical nutrient load and/or exposure of a specific length or region of intestine to nutrient is required for their stimulation. This is not surprising, as studies in experimental animals have provided convincing evidence for a role of nutrient load, as well as the length of intestine exposed to nutrient, in the regulation of both gastric emptying and food intake (24, 28). In terms of the regulation of ghrelin secretion from the small intestine, it remains to be determined what factors and pathways may be involved in feeding back luminal signals to the ghrelin-secreting cells in the stomach. It has recently been demonstrated that intravenous PYY suppresses ghrelin secretion (4), suggesting that PYY and ghrelin may operate in a negative feedback relationship. In contrast to PYY and ghrelin secretion, there was a prompt rise in PP in response to the duodenal triglyceride infusion with no further increase over the course of the infusion. This pattern is consistent with that observed in response to meal ingestion (1) and suggests that regulation of PP secretion is confined to the proximal small intestine and that the critical nutrient load required for secretion had been exceeded. Alternatively, it is possible that a further increase in PP throughout the infusion was suppressed by negative feedback mechanisms induced by other peptides released from the distal small intestine. In this study, THL was administered with the duodenal lipid infusion, which was ceased immediately before the meal. Because THL is known to only inhibit fat digestion from the meal it is ingested with (or in the case of this study, the duodenal lipid infusion), it was to be expected that meal ingestion would have an additional effect on hormone secretion. Although both PYY and ghrelin secretions were modified markedly by the duodenal lipid infusion, meal ingestion had only a moderate additional effect. PP secretion was, in contrast, stimulated markedly by the meal. This may suggest that, in contrast to PYY and ghrelin, gastric distension, enhanced by the greater amount of food eaten during the FAT-THL condition, may be a more important stimulus for PP. Indeed, moderate gastric distension with a balloon (volume: 600 ml) has been shown to cause a substantial (71%) increase in PP secretion in healthy volunteers (20). Alternatively, it is possible that the other macronutrients, carbohydrate and protein, are more important stimuli for PP secretion than fat. It remains perplexing that protein, the most satiating of the three macronutrients, does not decrease ghrelin (9). However, it needs to be recognized that interpretation of the meal-induced changes in plasma hormone concentrations in our study is limited by the fact that energy intake was variable between subjects and 15% greater following lipase inhibition [as reported previously (11), energy intake after infusion of FAT-THL (5,999 ± 1,433 kJ) was greater than after infusion of FAT (5,177 ± 1,740 kJ, P < 0.05)] and that the changes in hormones are likely to be dependent on the premeal values, which were markedly different for ghrelin and PYY but not PP. There is persuasive evidence that ghrelin, PYY, and PP play a role in the regulation of food intake, ghrelin as a stimulant (8, 42), and PYY and PP as suppressants (4, 5). Given that, as our data demonstrate, the secretion of all three hormones is modulated by fat and the inhibition of fat digestion abolishes this modulation, ghrelin, PYY, and PP may contribute to the suppression of energy intake by fat (11). Such a relationship has been established for CCK, in that the CCK-A receptor antagonist loxiglumide attenuated the inhibitory effects of an intraduodenally administered long-chain fatty acid, oleic acid, on energy intake (27). In summary, our study demonstrates that, in healthy adults, 1) proximal small intestinal exposure to nutrients, in this case long-chain triglycerides, is sufficient to suppress ghrelin secretion; 2) fat digestion is required for the suppression of ghrelin and stimulation of PYY and PP secretion; and 3) the effects of small intestinal fat on ghrelin and PYY secretion occur progressively, indicative of modulation by mechanisms that depend on the nutrient load and length of intestine exposed to nutrient. J Clin Endocrinol Metab. 2005 May. The cause of the unique elevation in fasting plasma levels of the orexigenic gastric hormone ghrelin in many patients with Prader-Willi syndrome (PWS) is unclear. We measured fasting and postprandial plasma ghrelin in nonobese (n = 16 fasting and n = 8 postprandial) and obese non-PWS adults (n = 16 and 9), adults with genetically confirmed PWS (n = 26 and 10), and patients with hypothalamic obesity from craniopharyngioma tumors (n = 9 and 6). We show that 1) plasma ghrelin levels decline normally after food consumption in PWS, but there is still fasting and postprandial hyperghrelinemia relative to the patient's obesity (2.0-fold higher fasting ghrelin, 1.8-fold higher postprandial ghrelin, adjusting for percentage of body fat); 2) the fasting and postprandial hyperghrelinemia in PWS appears to be at least partially, but possibly not solely, explained by the concurrent relative hypoinsulinemia and preserved insulin sensitivity for the patient's obesity (residual 1.3- to 1.6-fold higher fasting ghrelin, 1.2- to 1.5-fold higher postprandial ghrelin in PWS, adjusting for insulin levels or homeostasis model assessment of insulin resistance); 3) hyperghrelinemia and hypoinsulinemia are not found in craniopharyngioma patients with hypothalamic obesity, and indeed, these patients have relative hyperinsulinemia for their obesity; and 4) there is no deficiency of the anorexigenic intestinal hormone peptide YY(3-36) in PWS contributing to their hyperghrelinemia. Int J Mol Med. 2005 Apr. Ghrelin and peptide YY (PYY) are peptides generally produced by the gastrointestinal organs which are involved in appetite regulation via highly specialized centers in the brain. Abnormal plasma ghrelin and PYY levels compared with controls have been reported for subjects with Prader-Willi syndrome (PWS) which is characterized by infantile hypotonia, poor suck reflex and failure to thrive followed by hyperphagia and marked obesity in early childhood. We studied gene expression of ghrelin, peptide YY, and their receptors (i.e., GHS-R1a, GHS-R1b, and NPY2R) in six different brain regions (frontal cortex, temporal cortex, visual cortex, pons, medulla, and hypothalamus) obtained from three subjects with PWS, two individuals with Angelman syndrome, and six controls to determine if expression of these genes is detectable in different regions of the brain in subjects with and without PWS. In general, expression of these genes using RT-PCR was detected in all subjects and no obvious differences were seen in their pattern of expression between subjects with or without PWS. Additional studies including quantitative gene expression measurements will be required to further evaluate the role of these genes in the eating disorder seen in PWS. J Pediatr Endocrinol Metab. 2004 Sep. An insatiable appetite is a cardinal feature of Prader-Willi syndrome (PWS) with stomach rupturing as a reported consequence. Peptide YY, secreted by the intestine and released post-prandially, inhibits appetite, while ghrelin, secreted by the stomach during mealtime hunger, stimulates appetite. Both peptide YY and ghrelin act at the brain level, particularly the hypothalamus. Recently, plasma ghrelin levels were reported to be elevated in children and adults with PWS but peptide YY levels have not been studied in this syndrome or ghrelin in infants with PWS. To further address the abnormal eating behavior in PWS, we obtained fasting plasma peptide YY and ghrelin levels in 12 infants and children with PWS ranging in age from 2.5 months to 13.3 years and compared them with values from normal populations reported in the literature. Plasma ghrelin levels in our patients with PWS were similar to those of other children with PWS and were significantly higher than those reported in obese children without PWS. Our infants with PWS had similar plasma ghrelin levels compared with our children with PWS but peptide YY levels in our children and infants with PWS were lower than reported in similarly aged individuals without PWS. In addition, we performed preliminary gene expression analysis of ghrelin and peptide YY and their receptors in patients with PWS using established lymphoblastoid cell lines but gene expression did not correlate with plasma ghrelin or peptide YY levels. N Engl J Med. 2003 Sep 4. Background: The gut hormone fragment peptide YY3-36 (PYY) reduces appetite and food intake when infused into subjects of normal weight. In common with the adipocyte hormone leptin, PYY reduces food intake by modulating appetite circuits in the hypothalamus. However, in obesity there is a marked resistance to the action of leptin, which greatly limits its therapeutic effectiveness. We investigated whether obese subjects were also resistant to the anorectic effects of PYY. Methods: We compared the effects of PYY infusion on appetite and food intake in 12 obese and 12 lean subjects in a double-blind, placebo-controlled, crossover study. The plasma levels of PYY, ghrelin, leptin, and insulin were also determined. Results: Caloric intake during a buffet lunch offered two hours after the infusion of PYY was decreased by 30 percent in the obese subjects (P<0.001) and 31 percent in the lean subjects (P<0.001). PYY infusion also caused a significant decrease in the cumulative 24-hour caloric intake in both obese and lean subjects. PYY infusion reduced plasma levels of the appetite-stimulatory hormone ghrelin. Endogenous fasting and postprandial levels of PYY were significantly lower in obese subjects (the mean [+/-SE] fasting PYY levels were 10.2+/-0.7 pmol per liter in the obese group and 16.9+/-0.8 pmol per liter in the lean group, P<0.001). Furthermore, the fasting PYY levels correlated negatively with the body-mass index (r = -0.84, P<0.001). Conclusions: We found that obese subjects were not resistant to the anorectic effects of PYY. Endogenous PYY levels were low in the obese subjects, suggesting that PYY deficiency may contribute to the pathogenesis of obesity. Ann N Y Acad Sci. 2003 Jun. The gut hormone peptide YY (PYY) belongs to the pancreatic polypeptide (PP) family along with PP and neuropeptide Y (NPY). These peptides mediate their effects through the NPY receptors of which there are several subtypes (Y1, Y2, Y4, and Y5). The L cells of the gastrointestinal tract are the major source of PYY, which exists in two endogenous forms: PYY(1-36) and PYY(3-36). The latter is produced by the action of the enzyme dipeptidyl peptidase-IV (DPP-IV). PYY(1-36) binds to and activates at least three Y receptor subtypes (Y1, Y2, and Y5), whereas PYY(3-36) is more selective for Y2 receptor (Y2R). The hypothalamic arcuate nucleus, a key brain area regulating appetite, has access to nutrients and hormones within the peripheral circulation. NPY neurons within the arcuate nucleus express the Y2R. In response to food ingestion plasma PYY(3-36) concentrations rise within 15 min and plateau by approximately 90 min. The peak PYY(3-36) level achieved is proportional to the calories ingested, suggesting that PYY(3-36) may signal food ingestion from the gut to appetite-regulating circuits within the brain. We found that peripheral administration of PYY(3-36) inhibited food intake in rodents and increased C-Fos immunoreactivity in the arcuate nucleus. Moreover, direct intra-arcuate administration of PYY(3-36) inhibited food intake. We have shown that Y2R null mice are resistant to the anorectic effects of peripherally administered PYY(3-36), suggesting that PYY(3-36) inhibits food intake through the Y2R. In humans, peripheral infusion of PYY(3-36), at a dose which produced normal postprandial concentrations, significantly decreased appetite and reduced food intake by 33% over 24 h. These findings suggest that PYY(3-36) released in response to a meal acts via the Y2R in the arcuate nucleus to physiologically regulate food intake. Nature. 2002 Aug 8. Food intake is regulated by the hypothalamus, including the melanocortin and neuropeptide Y (NPY) systems in the arcuate nucleus. The NPY Y2 receptor (Y2R), a putative inhibitory presynaptic receptor, is highly expressed on NPY neurons in the arcuate nucleus, which is accessible to peripheral hormones. Peptide YY(3-36) (PYY(3-36)), a Y2R agonist, is released from the gastrointestinal tract postprandially in proportion to the calorie content of a meal. Here we show that peripheral injection of PYY(3-36) in rats inhibits food intake and reduces weight gain. PYY(3-36) also inhibits food intake in mice but not in Y2r-null mice, which suggests that the anorectic effect requires the Y2R. Peripheral administration of PYY(3-36) increases c-Fos immunoreactivity in the arcuate nucleus and decreases hypothalamic Npy messenger RNA. Intra-arcuate injection of PYY(3-36) inhibits food intake. PYY(3-36) also inhibits electrical activity of NPY nerve terminals, thus activating adjacent pro-opiomelanocortin (POMC) neurons. In humans, infusion of normal postprandial concentrations of PYY(3-36) significantly decreases appetite and reduces food intake by 33% over 24 h. Thus, postprandial elevation of PYY(3-36) may act through the arcuate nucleus Y2R to inhibit feeding in a gut-hypothalamic pathway. |