Proglumide fails to increase food intake after an ingested preload

Proglumide, a selective antagonist of exogenous cholecystokinin in vitro, also inhibits the reduction of food intake induced by the systemic administration of cholecystokinin octapeptide (CCK-8) in food deprived rats. On the basis of an increase in the size of a brief test meal which followed an oral preload and treatment with a single dose of proglumide, it was suggested that a role for endogenous cholecystokinin in satiety had been demonstrated. We attempted to replicate this finding and could not under very similar experimental conditions. Subsequently, we tested whether other proglumide doses would antagonize the satiating effect of a larger oral preload on test meal intake. When these results were also found to be negative, we confirmed that proglumide (at several doses) significantly antagonized the reduction in food intake induced by exogenous CCK-8 under our conditions. Since proglumide antagonized the satiating effect of exogenous CCK-8, but did not increase food intake after oral preloads that were presumed to release endogenous CCK, we conclude that a reliable satiating effect of endogenous CCK remains to be demonstrated.     

Peripheral administration of PYY(3-36) produces conditioned taste aversion in mice

Peptide YY (PYY) is a postprandially released gut hormone. Peripheral administration of one form of the peptide PYY3-36 produces a short-term reduction in food intake in rodents. Initial reports suggested that effects of PYY3-36 on food intake are mediated by increasing the anorexigenic drive from melanocortin neurons in the hypothalamic arcuate nucleus. However, more recent data have demonstrated that the anorexigenic activity of PYY3-36 is not dependent on melanocortin ligands or their receptors in the CNS. We demonstrate here that the anorexigenic actions of PYY3-36 are also not dependent on the vagus nerve, a common pathway of satiety signaling. Peripherally administered PYY3-36 activates neurons in the area postrema and nucleus tractus solitarius, brainstem areas known to mediate effects of certain aversive stimuli. Furthermore, peripheral administration of PYY3-36 causes conditioned taste aversion in mice. Thus, inhibition of food intake by PYY3-36 may result in part from induction of an aversive response.     

The role of PYY in feeding regulation

Peptide YY (PYY), a 36-amino-acid peptide, is secreted primarily from L-cells residing in the intestinal mucosa of the ileum and large intestine. PYY, which belongs to a family of peptides including neuropeptide Y (NPY) and pancreatic polypeptide, is released into the circulation as PYY(1-36) and PYY(3-36); the latter is the major form of PYY in gut mucosal endocrine cells and throughout the circulation. Plasma PYY levels begin to rise within 15 min after starting to eat and plateau within approximately 90 min, remaining elevated for up to 6 h. Exogenous administration of PYY(3-36) reduces energy intake and body weight in both humans and animals. Via Y2 receptors, the satiety signal mediated by PYY inhibits NPY neurons and activates pro-opiomelanocortin neurons within the hypothalamic arcuate nucleus. Peripheral PYY(3-36) binds Y2 receptors on vagal afferent terminals to transmit the satiety signal to the brain. PYY(3-36) may have therapeutic potential in human obesity.     

Acute effects of PYY3-36 on food intake and hypothalamic neuropeptide expression in the mouse

It has recently been suggested that gut-derived PYY(3-36) may be involved in the central mediation of post-prandial satiety signals. We have examined the acute effects of peripherally administered PYY(3-36) on food intake and hypothalamic gene expression of neuropeptides in mice. A single intraperitoneal injection of PYY(3-36) to mice that had been fasted for 24h resulted in a highly significant reduction in food intake at 6 and 24h post-injection but not at 48h. However, in freely fed mice, food intake was unaltered by PYY(3-36) administration. In the arcuate nucleus POMC mRNA expression was significantly elevated at 6h and remained elevated at 24h following PYY(3-36) injection. By contrast NPY mRNA expression in the arcuate nucleus was suppressed at 6h but not at 24h post-injection. In the lateral hypothalamus there were no differences in MCH mRNA expression at either time point. In conclusion, peripherally administered PYY(3-36) has a suppressive effect on food intake that is more prominent in recently fasted mice and lasts up to 24 h. This is associated with a short-lived suppression of NPY mRNA, a longer lasting increase in POMC mRNA but no change in MCH mRNA expression.     

Wheat gluten hydrolysate potently stimulates peptide-YY secretion and suppresses food intake in rats

ABSTRACT

The study was aimed to compare the satiating effect of various protein hydrolysates in rats and examine the underlying mechanism associated with the satiety hormones. Food intake and portal satiety hormone levels were measured in rats. Enteroendocrine cell-lines were employed to study the direct effect of protein hydrolysates on gut hormone secretions. The results showed that oral preload of wheat gluten hydrolysate (WGH) suppressed food intake greater and longer than other hydrolysates. The portal peptide-YY levels in WGH-treated rats at 2 h and 3 h were higher than those in control- and lactalbumin hydrolysate (LAH)-treated rats. In a distal enteroendocrine cell model, WGH more potently stimulated glucagon-like peptide-1 secretion than LAH, and the effect was largely enhanced by pepsin/pancreatin digestion of WGH. These results suggest WGH is potent in activating enteroendocrine cells to release satiety hormones leading to the prolonged suppression of food intake.     

PYY(3-36) reduces food intake and body weight and improves insulin sensitivity in rodent models of diet-induced obesity

The gut hormone peptide YY (PYY) was recently proposed to comprise an endogenous satiety factor. We have studied acute anorectic functions of PYY(3-36) in mice and rats, as well as metabolic effects of chronic PYY(3-36) administration to diet-induced obese (DIO) mice and rats. A single intraperitoneal injection of PYY(3-36) inhibited food intake in mice, but not in rats. We next investigated the effects of increasing doses (100, 300, and 1,000 microg.kg-1.day-1) of PYY(3-36) administered subcutaneously via osmotic minipumps on food intake and body weight in DIO C57BL/6J mice. Whereas only the highest dose (1,000 microg.kg-1.day-1) of PYY(3-36) significantly reduced food intake over the first 3 days, body weight gain was dose dependently reduced, and on day 28 the group treated with 1,000 microg.kg-1.day-1 PYY(3-36) weighed approximately 10% less than the vehicle-treated group. Mesenteric, epididymal, retroperitoneal, and inguinal fat pad weight was dose dependently reduced. Subcutaneous administration of PYY(3-36) (250 and 1,000 microg.kg-1.day-1) for 28 days reduced body weight and improved glycemic control in glucose-intolerant DIO rats. Neither 250 nor 1,000 microg/kg PYY(3-36) elicited a conditioned taste aversion in male rats.     

Peptide hormone isoforms: N‐terminally branched PYY3–36 isoforms give improved lipid and fat‐cell metabolism in diet‐induced obese mice

The prevalence of obesity is increasing with an alarming rate worldwide and there is a need for efficacious satiety drugs. PYY3–36 has been shown to play a role in hypothalamic appetite regulation and novel analogs targeting the Y2 receptor have potential as drugs for the treatment of obesity. We have designed a series of novel PYY3–36 isoforms, by first adding the dipeptide Ile–Lys N‐terminal to the N^α of Ser‐13 in PYY13–36 and then anchoring the N‐terminal segment, e.g. PYY3–12, to the new Lys N^ε‐amine. We hypothesized that such modifications would alter the folding of PYY, due to changes in the turn motif, which could change the binding mode to the Y receptor sub‐types and possibly also alter metabolic stability. In structure‐affinity/activity relationship experiments, one series of PYY isoforms displayed equipotency towards the Y receptors. However, an increased Y2 receptor potency for the second series of PYY isoforms resulted in enhanced Y receptor selectivity compared to PYY3–36. Additionally, acute as well as chronic mice studies showed body‐weight‐lowering effects for one of the PYY isoforms, which was also reflected in a reduction of circulating leptin levels. Interestingly, while the stability and pharmacokinetic profile of PYY3–36 and the N‐terminally modified PYY3–36 analogue were identical, only mice treated with the branched analogue showed marked increases in adiponectin levels as well as reductions in non‐esterified free fatty acids and triglycerides. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.     

Ghrelin response to protein and carbohydrate meals in relation to food intake and glycerol levels in obese subjects

Obese subjects have lower basal and an attenuated decrease of postprandial plasma ghrelin following carbohydrate-rich meals, while the response to protein is unknown. Therefore, plasma ghrelin levels were examined after ingestion of satiating amounts of a protein- or carbohydrate-rich meal in relation to food and energy intake and hunger/satiety ratings in 30 obese subjects followed 240 min later by ad lib sandwiches. Food intake and hunger/satiety ratings were identical while energy intake was significantly greater after bread (861 +/- 62.7 vs. 441 +/- 50.4 kcal, p < 0.001). Second meal food and energy intake were not different. Ghrelin decreased after bread, but increased by 50 pg/ml (p < 0.001) after meat. The corresponding increase of insulin was 55 vs. 9 microU/ml (p < 0.001). Glycerol levels decreased significantly less after the protein meal compared to carbohydrates. After protein glycerol was significantly correlated to the rise of ghrelin but not insulin. These data demonstrate that, in obese subjects, protein has no different satiating effect than carbohydrate despite divergent ghrelin levels. Energy intake corresponds to energy density of the respective food items. Ghrelin response to both meals is qualitatively similar but quantitatively attenuated compared to normal weight subjects. The relationship between ghrelin and glycerol would support recent observations of a possible role of ghrelin in fat metabolism.     

Interactions between gut peptides and the central melanocortin system in the regulation of energy homeostasis

Genetic and pharmacological studies have shown that the central melanocortin system plays a critical role in the regulation of energy homeostasis. Animals and humans with defects in the central melanocortin system display a characteristic melanocortin obesity phenotype typified by increased adiposity, hyperphagia, metabolic defects and increased linear growth. In addition to interacting with long-term regulators of energy homeostasis such as leptin, more recent data suggest that the central melanocortin system also responds to gut-released peptides involved in mediating satiety. In this review, we discuss the interactions between these systems, with particular emphasis on cholecystokinin (CCK), ghrelin and PYY(3-36).     

Effect of total colectomy and PYY infusion on food intake and body weight in rats

PYY (3-36) is postulated to act as a satiety factor in the gut-hypothalamic pathway to inhibit food intake and body weight gain in humans and rodent models. We determined the effect of 14-day continuous intravenous infusion of PYY (3-36) (175 microg/kg/day) on food intake and body weight gain in colectomized male Wistar rats. Colectomy caused an increase in plasma PYY levels at 7 days which was reduced at 14 days but still significantly elevated compared to basal preoperative values. Animals treated with continuous PYY (3-36) infusion had significantly elevated PYY levels compared to the control group throughout the whole experiment, but showed a similar pattern of food intake and body weight gain. In conclusion, although continuous intravenous infusion is the most physiologically relevant method to mimic high postprandial PYY levels, we did not observe any significant effect on food intake and body weight gain in non-food deprived colectomized animals. This suggests that PYY has, if at all, only a minor role in food intake in rats.     

The pancreatic beta cell is a key site for mediating the effects of leptin on glucose homeostasis

The hormone leptin plays a crucial role in maintenance of body weight and glucose homeostasis. This occurs through central and peripheral pathways, including regulation of insulin secretion by pancreatic beta cells. To study this further in mice, we disrupted the signaling domain of the leptin receptor gene in beta cells and hypothalamus. These mice develop obesity, fasting hyperinsulinemia, impaired glucose-stimulated insulin release, and glucose intolerance, similar to leptin receptor null mice. However, whereas complete loss of leptin function causes increased food intake, this tissue-specific attenuation of leptin signaling does not alter food intake or satiety responses to leptin. Moreover, unlike other obese models, these mice have reduced fasting blood glucose. These results indicate that leptin regulation of glucose homeostasis extends beyond insulin sensitivity to influence beta cell function, independent of pathways controlling food intake. These data suggest that defects in this adipoinsular axis could contribute to diabetes associated with obesity.     

Satiety: the roles of peptides from the stomach and the intestine

Rats were surgically prepared to allow perfusions of anatomically limited portions of the gastrointestinal (GI) surface during test meals. The results demonstrated that at least one potent satiety signal was generated when ingested food accumulated in the stomach and did not enter the small intestine. This gastric satiety signal did not require the vagus nerve for its operation. In addition, at least one other potent satiety signal was generated when food perfused the small intestine. This intestinal satiety signal did not require gastric distension for its operation. We tested a variety of GI peptides to determine whether any met the criteria imposed by this evidence for regionally specific satiety signals. Bombesin (BBS), a peptide present in high concentration in the stomach, was a potent and behaviorally specific inhibitor of food intake. Its satiating effect was not altered by subdiaphragmatic vagotomy. Cholecystokinin (CCK), a peptide hormone that is released from the small intestine by food, was also a potent and behaviorally specific inhibitor of food intake; its satiating effect did not require gastric distension for its expression, but its satiating effect was markedly reduced or abolished by subdiaphragmatic vagotomy. Thus, BBS and CCK may mediate at least part of the satiating effect of food acting in the stomach and in the small intestine, respectively.     

Effect of CCK-1 receptor blockade on ghrelin and PYY secretion in men

Cholecystokinin (CCK), peptide YY (PYY), and ghrelin have been proposed to act as satiety hormones. CCK and PYY are stimulated during meal intake by the presence of nutrients in the small intestine, especially fat, whereas ghrelin is inhibited by eating. The sequence of events (fat intake followed by fat hydrolysis and CCK release) suggests that this process is crucial for triggering the effects. The aim of this study was therefore to investigate whether CCK mediated the effect of intraduodenal (ID) fat on ghrelin secretion and PYY release via CCK-1 receptors. Thirty-six male volunteers were studied in three consecutive, randomized, double-blind, cross-over studies: 1) 12 subjects received an ID fat infusion with or without 120 mg orlistat, an irreversible inhibitor of gastrointestinal lipases, compared with vehicle; 2) 12 subjects received ID long-chain fatty acids (LCF), ID medium-chain fatty acids (MCF), or ID vehicle; and 3) 12 subjects received ID LCF with and without the CCK-1 receptor antagonist dexloxiglumide (Dexlox) or ID vehicle plus intravenous saline (placebo). ID infusions were given for 180 min. The effects of these treatments on ghrelin concentrations and PYY release were quantified. Plasma hormone concentrations were measured in regular intervals by specific RIA systems. We found the following results. 1) ID fat induced a significant inhibition in ghrelin levels (P < 0.01) and a significant increase in PYY concentrations (P < 0.004). Inhibition of fat hydrolysis by orlistat abolished both effects. 2) LCF significantly inhibited ghrelin levels (P < 0.02) and stimulated PYY release (P < 0.008), whereas MCF were ineffective compared with controls. 3) Dexlox administration abolished the effect of LCF on ghrelin and on PYY. ID fat or LCF significantly stimulated plasma CCK (P < 0.006 and P < 0.004) compared with saline. MCF did not stimulate plasma CCK release. In summary, fat hydrolysis is essential to induce effects on ghrelin and PYY through the generation of LCF, whereas MCF are ineffective. Furthermore, LCF stimulated plasma CCK release, suggesting that peripheral CCK is the mediator of these actions. The CCK-1 receptor antagonist Dexlox abolished the effect of ID LCF, on both ghrelin and PYY. Generation of LCF through hydrolysis of fat is a critical step for fat-induced inhibition of ghrelin and stimulation of PYY in humans; the signal is mediated via CCK release and CCK-1 receptors.     

Obese Adolescents Show Impaired Meal Responses of the Appetite‐Regulating Hormones Ghrelin and PYY

Ghrelin and peptide YY (PYY) stimulate hunger and satiety, respectively. The physiology of these hormones during normal meal intake remains unclear. This study was designed to compare the responses of these two hormones to meal intake between lean and obese Hispanic adolescents. A total of 10 obese and 7 lean Hispanic youth, aged 11–14 years, consumed two mixed meals, one small and one large, during which plasma measurements of active and total ghrelin and total PYY were obtained. Obese subjects tended to consume more calories during the small meal than lean subjects, although this did not reach statistical significance. Intake of the small meal significantly suppressed active ghrelin and stimulated PYY levels in the lean subjects, and these changes were further accentuated by the large meals. In obese subjects, the suppression of active ghrelin and stimulation of PYY by caloric intake were blunted. Interestingly, a paradoxical stimulation of active ghrelin levels was noted during the small meals in both lean and obese subjects. This stimulation was not seen during the larger meals in lean subjects, but remained present in the obese subjects. Thus, meal‐related changes in active ghrelin and PYY are blunted in obese as compared to lean Hispanic subjects. This blunting could contribute to the development or worsening of obesity.     

Cholecystokinin and bombesin act independently to decrease food intake in the rat

The satiating effects of cholecystokinin-octapeptide (CCK-8) and bombesin (BBS) when injected alone and in combination were compared in intact rats. When injected alone, both CCK-8 and BBS elicited a dose-related decrease of 30-minute food intake. Injections of BBS were less potent than the equivalent doses of CCK-8 in producing satiety. BBS reached an asymptotic level of suppression of approximately 40 percent at a dose of 2 micrograms/kg, whereas injections of 4 micrograms/kg of CCK-8 resulted in a 72 percent suppression of food intake. When the two peptides were administered in a single injection, the resulting suppression of food intake was equivalent to that which would be predicted if their effects were completely additive. These results support the hypothesis that CCK-8 and BBS act via independent mechanisms to induce satiety. A preliminary model of peptidergic satiety, based on this hypothesis, is proposed.     

The role of peptide YY in regulating glucose homeostasis

The gut-derived hormone peptide YY (PYY) is most commonly known for its effect on satiety, decreasing food intake and body weight in animals and humans. However, PYY is also involved in a wide range of digestive functions including regulating insulin secretion and glucose homeostasis. Over the last few years, there have been several interesting clinical and animal studies investigating the role of PYY in glucose homeostasis. This review aims to present an updated summary of findings over the last few decades highlighting the role of PYY in regulating insulin output and insulin sensitivity, and the potential mechanisms involved.     

Peptides that regulate food intake: norepinephrine is not required for reduction of feeding induced by cholecystokinin

CCK octapeptide (CCK-8) is released by the gut in response to a meal and acts via CCK(A) receptors on vagal afferents to induce satiety. However, the central neural pathways by which peripheral CCK-8 affects feeding are poorly understood. In the present study, we tested the hypothesis that norepinephrine (NE) is necessary for satiety induced by peripheral CCK-8 by using mice lacking dopamine beta-hydroxylase (Dbh(-/-)), the enzyme responsible for synthesizing NE and epinephrine from dopamine. We found that Dbh(-/-) mice are as responsive to the satiating effects of CCK-8 as their normal littermates.     

Peptide YY regulates bone remodeling in mice: a link between gut and skeletal biology

Background & Aims

Gastrointestinal peptides are increasingly being linked to processes controlling the maintenance of bone mass. Peptide YY (PYY), a gut-derived satiety peptide of the neuropeptide Y family, is upregulated in some states that also display low bone mass. Importantly, PYY has high affinity for Y-receptors, particularly Y1R and Y2R, which are known to regulate bone mass. Anorexic conditions and bariatric surgery for obesity influence circulating levels of PYY and have a negative impact on bone mass, but the precise mechanism behind this is unclear. We thus examined whether alterations in PYY expression affect bone mass.

Methods

Bone microstructure and cellular activity were analyzed in germline PYY knockout and conditional adult-onset PYY over-expressing mice at lumbar and femoral sites using histomorphometry and micro-computed tomography.

Results

PYY displayed a negative relationship with osteoblast activity. Male and female PYY knockout mice showed enhanced osteoblast activity, with greater cancellous bone mass. Conversely, PYY over-expression lowered osteoblast activity in vivo, via a direct Y1 receptor mediated mechanism involving MAPK stimulation evident in vitro. In contrast to PYY knockout mice, PYY over expression also altered bone resorption, as indicated by greater osteoclast surface, despite the lack of Y-receptor expression in osteoclastic cells. While evident in both sexes, cellular changes were generally more pronounced in females.

Conclusions

These data demonstrate that the gut peptide PYY is critical for the control of bone remodeling. This regulatory axis from the intestine to bone has the potential to contribute to the marked bone loss observed in situations of extreme weight loss and higher circulating PYY levels, such as anorexia and bariatric obesity surgery, and may be important in the maintenance of bone mass in the general population.     

The intestinal peptide transporter PEPT1 is involved in food intake regulation in mice fed a high-protein diet

High-protein diets are effective in achieving weight loss which is mainly explained by increased satiety and thermogenic effects. Recent studies suggest that the effects of protein-rich diets on satiety could be mediated by amino acids like leucine or arginine. Although high-protein diets require increased intestinal amino acid absorption, amino acid and peptide absorption has not yet been considered to contribute to satiety effects. We here demonstrate a novel finding that links intestinal peptide transport processes to food intake, but only when a protein-rich diet is provided. When mice lacking the intestinal peptide transporter PEPT1 were fed diets containing 8 or 21 energy% of protein, no differences in food intake and weight gain were observed. However, upon feeding a high-protein (45 energy%) diet, Pept1(-/-) mice reduced food intake much more pronounced than control animals. Although there was a regain in food consumption after a few days, no weight gain was observed which was associated with a reduced intestinal energy assimilation and increased fecal energy losses. Pept1(-/-) mice on high-protein diet displayed markedly reduced plasma leptin levels during the period of very low food intake, suggesting a failure of leptin signaling to increase energy intake. This together with an almost two-fold elevated plasma arginine level in Pept1(-/-) but not wildtype mice, suggests that a cross-talk of arginine with leptin signaling in brain, as described previously, could cause these striking effects on food intake.     

The Influence of Higher Protein Intake and Greater Eating Frequency on Appetite Control in Overweight and Obese Men

The purpose of this study was to determine the effects of dietary protein intake and eating frequency on perceived appetite, satiety, and hormonal responses in overweight/obese men. Thirteen men (age 51 ± 4 years; BMI 31.3 ± 0.8 kg/m²) consumed eucaloric diets containing normal protein (79 ± 2 g protein/day; 14% of energy intake as protein) or higher protein (138 ± 3 g protein/day; 25% of energy intake as protein) equally divided among three eating occasions (3‐EO; every 4 h) or six eating occasions (6‐EO; every 2 h) on four separate days in randomized order. Hunger, fullness, plasma glucose, and hormonal responses were assessed throughout 11 h. No protein × eating frequency interactions were observed for any of the outcomes. Independent of eating frequency, higher protein led to greater daily fullness (P < 0.05) and peptide YY (PYY) concentrations (P < 0.05). In contrast, higher protein led to greater daily ghrelin concentrations (P < 0.05) vs. normal protein. Protein quantity did not influence daily hunger, glucose, or insulin concentrations. Independent of dietary protein, 6‐EO led to lower daily fullness (P < 0.05) and PYY concentrations (P < 0.05). The 6‐EO also led to lower glucose (P < 0.05) and insulin concentrations (P < 0.05) vs. 3‐EO. Although the hunger‐related perceived sensations and hormonal responses were conflicting, the fullness‐related responses were consistently greater with higher protein intake but lower with increased eating frequency. Collectively, these data suggest that higher protein intake promotes satiety and challenge the concept that increasing the number of eating occasions enhances satiety in overweight and obese men.