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. 2008 Dec 8;587(Pt 1):19–25. doi: 10.1113/jphysiol.2008.164269

The role of peptide YY in appetite regulation and obesity

Efthimia Karra 1, Keval Chandarana 1, Rachel L Batterham 1
PMCID: PMC2670018  PMID: 19064614

Abstract

The last decade has witnessed a marked increase in our understanding of the importance of gut hormones in the regulation of energy homeostasis. In particular, the discovery that the gut hormone peptide YY 3–36 (PYY3–36) reduced feeding in obese rodents and humans fuelled interest in the role of PYY3–36 in body weight regulation. Pharmacological and genetic approaches have revealed that the Y2-receptor mediates the anorectic effects of PYY3–36 whilst mechanistic studies in rodents identified the hypothalamus, vagus and brainstem regions as potential sites of action. More recently, using functional brain imaging techniques in humans, PYY3–36 was found to modulate neuronal activity within hypothalamic and brainstem, and brain regions involved in reward processing. Several lines of evidence suggest that low circulating PYY concentrations predispose towards the development and or maintenance of obesity. Subjects with reduced postprandial PYY release exhibit lower satiety and circulating PYY levels that correlate negatively with markers of adiposity. In addition, mice lacking PYY are hyperphagic and become obese. Conversely, chronic PYY3–36 administration to obese rodents reduces adiposity, and transgenic mice with increased circulating PYY are resistant to diet-induced obesity. Moreover, there is emerging evidence that PYY3–36 may partly mediate the reduced appetite and weight loss benefits observed post-gastric bypass surgery. Taken together these findings, coupled with the retained responsiveness of obese subjects to the effects of PYY3–36, suggest that targeting the PYY system may offer a therapeutic strategy to help treat obesity.

Obesity is one of the greatest public health challenges of the 21st century with 1.6 billion adults currently classified as being overweight and 400 million as obese. Overweight and obesity result in serious adverse health consequences including cardiovascular disease, type 2 diabetes, musculoskeletal disorders and some cancers. An increased understanding of the mechanisms that regulate body weight and how these are perturbed in obesity is essential for the development of effective treatments for this condition and strategies aimed at preventing the growing obesity pandemic.

The gastrointestinal (GI) tract is the body's largest endocrine organ producing hormones that have important sensing and signalling roles in the regulation of energy homeostasis (Cummings & Overduin, 2007). The last decade has seen a marked increase in our understanding of the role of gut hormones in regulating body weight and, as a consequence, strategies aimed at modulating gut hormone levels or targeting their receptors are being developed as potential therapies for obesity. Below we review studies examining the role of the gut hormone peptide YY in regulating body weight, the potential mechanisms by which PYY exerts its anorectic effects, the emerging evidence for a role of PYY in the weight loss benefits seen following gastric bypass surgery and the therapeutic potential of the PYY system for obesity.

Peptide YY

The gut hormone peptide YY (PYY) is a 36-amino acid peptide that is synthesized and released from specialized enteroendocrine cells called L-cells found predominantly within the distal GI tract. PYY was initially isolated from porcine intestinal extracts and named PYY due to the presence of tyrosine residues, the single letter amino acid code for tyrosine being Y, at the C- and N-termini of its 36-amino acids structure (Tatemoto & Mutt, 1980). Two main endogenous forms of PYY have been identified, PYY1–36 and PYY3–36, the latter being the predominant circulating form (Grandt et al. 1994; Batterham et al. 2006; Korner et al. 2006). The ubiquitously expressed enzyme di-peptidyl peptidase IV (DP-IV) is thought to mediate the conversion of PYY1–36 to PYY3–36 (Mentlein et al. 1993). Removing the NH2-terminal tyrosine–proline markedly changes the three-dimensional conformation of PYY, altering its receptor specificity and biological effects. PYY belongs to the family of peptides that include neuropeptide Y (NPY) and pancreatic polypeptide (PP). All three peptides share a common tertiary structure of an alpha-helix and polyproline helix connected by a beta-turn, resulting in a characteristic U-shaped peptide know as a PP-fold (Berglund et al. 2003). Members of the PP-fold family mediate their effects via Y-receptors that belong to the G-protein-coupled receptor superfamily. Five Y-receptors (Y1, Y2, Y4, Y5 and Y6) mediate the effects of PYY, NPY and PP. These receptors differ in distribution and function and are classified according to their affinity for PYY, NPY and PP (Cabrele & Beck-Sickinger, 2000). Whereas, PYY1–36 binds to all known Y-receptor subtypes, PYY3–36 shows high affinity for the Y2-receptor subtype and some affinity for the Y1-receptor and Y5-receptor subtypes.

Circulating PYY

PYY is released from the gut into the circulation in a nutrient-dependent manner. PYY levels are low in the fasting state, rapidly increase in response to food intake, reach a peak at 1–2 h after a meal and then remain elevated for several hours (Adrian et al. 1985). In response to food intake PYY levels increase within 15 min, before nutrients have reached the L-cells, implicating either a neural or hormonal mechanisms in this initial release. The temporal profile and peak PYY levels are influenced by caloric load, macronutrient composition and food consistency (Adrian et al. 1985; Batterham et al. 2006; Helou et al. 2008). However, to date there is little data on 24 h profiles of PYY. Preprandial decreases and postprandial increases in plasma PYY led to studies investigating the role of PYY as a satiety signal.

Effects of peripheral PYY administration on feeding

In 2002, Batterham et al. reported that intraperitoneal injection of PYY3–36 resulted in a dose-dependent reduction in food intake in rodents and that in normal-weight human subjects peripheral infusion of PYY3–36 reduced appetite and 24 h caloric intake (Batterham et al. 2002). Moreover, Batterham et al. went on to evaluate the effects of infusing PYY3–36 on caloric intake in lean and obese male and female subjects and found that obese subjects remained sensitive to the anorectic actions of PYY3–36 (Batterham et al. 2003). These findings ignited interest in PYY3–36 as a regulator of body weight and as a potential therapy for obesity. Despite initial claims that the feeding inhibitory effects of PYY3–36 could not be replicated in rodents, the acute anorectic actions of PYY3–36 have now been reproduced numerous times in rodents (Challis et al. 2003; Chelikani et al. 2004; Pittner et al. 2004; Abbott et al. 2005b; Koda et al. 2005; Scott et al. 2005; Talsania et al. 2005; Unniappan et al. 2006; Vrang et al. 2006; Unniappan & Kieffer, 2008), in non-human primates (Koegler et al. 2005) and humans (le Roux et al. 2006b; Batterham et al. 2007; Sloth et al. 2007). Peripheral infusion of PYY1–36 has also been shown to reduce food intake in rodents but is an order of magnitude less potent than PYY3–36 (Chelikani et al. 2004). These anorectic effects of PYY1–36 could result from the direct actions of PYY1–36 or result from in vivo conversion of PYY1–36 to PYY3–36 by DP-IV. Evidence to support the latter comes from studies undertaken by Unniappan and colleagues who found that whilst PYY1–36 reduced feeding in normal rats, the feeding inhibitory effects of PYY1–36 were abrogated in DP-IV-deficient rats (Unniappan et al. 2006). However, to date studies in humans examining the effects of PYY1–36 on food intake have not revealed any inhibitory effects on food intake (Sloth et al. 2007). In view of the fact that DP-IV inhibitors are now being used to treat patients with type 2 diabetes, further studies elucidating the role of DP-IV in regulating in vivo circulating levels of PYY3–36 are warranted.

Injection of PYY1–36 into the third, lateral or fourth cerebral ventricle (Clark et al. 1987), paraventricular nucleus (Stanley et al. 1985) or hippocampus stimulates food intake in rodents (Hagan et al. 1998). Similarly, intracerebroventricular injection of PYY3–36 increases food intake (Corp et al. 2001). However, this orexigenic action of PYY3–36 is reduced in Y1-receptor knockout mice and Y5-receptor knockout mice, suggesting that the Y1-receptor and Y5-receptor subtypes mediate the orexigenic effects of centrally administered PYY (Kanatani et al. 2000). In contrast, injection of PYY3–36 directly into the hypothalamic arcuate nucleus, where the Y2-receptor subtype is highly expressed, inhibits feeding (Batterham et al. 2002). Thus, the feeding effects of centrally administered PYY are dependent on which Y-receptor subtypes are activated.

Effects of PYY on energy expenditure

Less attention has been paid to the effects of PYY3–36 on energy expenditure. However, there is increasing evidence that, in addition to regulating food intake, PYY3–36 has additional metabolic beneficial effects on energy expenditure and fuel partitioning. Firstly, chronic administration of PYY3–36 to rodents has been shown to alter substrate partitioning in favour of fat oxidation (van den Hoek et al. 2004, 2007; Adams et al. 2006). Secondly, in humans, peripheral infusion of PYY3–36 has been shown to increase energy expenditure and fat oxidation rates (Sloth et al. 2007). Thirdly, Guo and colleagues found a negative correlation between fasting PYY levels and 24 h resting energy rate (Guo et al. 2006). Fourthly, transgenic mice that over-express PYY exhibit increased basal temperature indicative of increased thermogenesis (Boey et al. 2008). Lastly, circulating postprandial PYY levels associate with postprandial energy expenditure and the thermic effect of food (Doucet et al. 2008). Taken together, these findings suggest that PYY regulates body weight by reducing food intake and by increasing energy expenditure. The mechanisms underlying the effects of PYY3–36 on energy expenditure remain to be determined.

Role of the Y2-receptor in mediating the effects of PYY3–36

A crucial role for the Y2-receptor in mediating the effects of PYY3–36 on feeding was first identified by Batterham and colleagues who found that mice with a targeted gene deletion of the Y2-receptor were resistant to the anorectic effects of PYY3–36 (Batterham et al. 2002). Subsequently, several groups have shown that the anorectic actions of PYY3–36 are abolished by co-administration of the Y2-receptor antagonist BIIE0246 (Abbott et al. 2005b; Scott et al. 2005; Talsania et al. 2005; Ghitza et al. 2007). Moreover, Y2-receptor agonists have been shown to reduce food intake and adiposity when administered peripherally (Ortiz et al. 2007).

Potential sites of action

Y2-receptors are present throughout the central nervous system, within the nodose ganglion and on vagal afferents thus raising the possibility that PYY3–36 exerts its feeding effects by acting centrally, via vagal activation or combinations of both. In addition, PYY3–36 has been shown to cross the blood–brain barrier by non-saturable mechanisms (Nonaka et al. 2003). Several lines of evidence suggest that PYY3–36 acts via the hypothalamus to exert its effects on feeding. Firstly, direct intra-arcuate PYY3–36 injection reduces feeding. Secondly, the anorectic effects of peripherally administered PYY3–36 are blocked by intra-arcuate injection of the Y2-receptor antagonist BIIE0246 (Abbott et al. 2005b). Thirdly, peripheral PYY3–36 administration increased c-fos expression, a marker of neuronal activation within the arcuate nucleus of the hypothalamus and altered hypothalamic neuropeptides (Batterham et al. 2002; Challis et al. 2003). Peripheral PYY3–36 administration also increases c-fos expression within brainstem regions (Halatchev & Cone, 2005; Koda et al. 2005; Blevins et al. 2008). Moreover, peripheral PYY3–36 has been shown to increase vagal afferent firing (Koda et al. 2005). However, the importance of the role of the vagus in mediating the effects of PYY3–36 on feeding is controversial. Two independent groups have shown that the anorectic effects of peripherally administered PYY3–36 are abolished in vagotomised rats (Abbott et al. 2005a; Koda et al. 2005) and that following vagotomy arcuate c-fos expression is also attenuated (Koda et al. 2005), whilst, in mice, neither vagotomy (Halatchev & Cone, 2005), nor systemic pre-treatment with capsaicin (Talsania et al. 2005), which causes selective degeneration of small-diameter unmyelinated sensory neurones including the nodose ganglion and the vagus nerve, failed to attenuate the anorectic effects of PYY3–36. Further insights into the central sites of action of PYY3–36 in humans have recently been gained from combining PYY3–36 infusion with functional magnetic resonance imaging in normal-weight humans. PYY3–36 infusion, which resulted in circulating PYY3–36 concentrations similar to those observed postprandially, modulated neuronal activity within the hypothalamus, brainstem regions, mid-brain areas and regions of the brain involved in reward processing (Batterham et al. 2007). These findings suggest that PYY3–36 exerts its effects on feeding by action on homeostatic and hedonic brain circuits.

Evidence for a role of endogenous PYY in regulating energy homeostasis

Fasting circulating levels of total PYY are reported to be low in mice subjected to high-fat feeding (Yang et al. 2005; Batterham et al. 2006; le Roux et al. 2006b; Rahardjo et al. 2007). Moreover, Rahardjo and colleagues found that mice that developed obesity when exposed to a high-fat diet had significantly lower circulating PYY levels than mice that were obesity resistant (Rahardjo et al. 2007). Similarly, in humans, a negative association between circulating PYY and markers of adiposity has been reported in adults (Alvarez Bartolome et al. 2002; Batterham et al. 2003; Guo et al. 2006; le Roux et al. 2006b; Essah et al. 2007; Sodowski et al. 2007), children (Roth et al. 2005) and infants (Siahanidou et al. 2005). However, not all studies have found low levels of PYY in obese subjects (Korner et al. 2006; Pfluger et al. 2007).

Several studies suggest a role for endogenous PYY in satiety regulation in humans. Firstly, Le Roux et al. reported that attenuated postprandial PYY release observed in obese subjects was associated with impaired satiety (le Roux et al. 2006b). Secondly, Guo et al. reported a positive correlation between postprandial PYY release and postprandial changes in ratings of satiety (Guo et al. 2006). More recently, Stoeckel et al. examined the effects of a 417 kcal meal on PYY release and satiety scores in 12 normal-weight subjects (Stoeckel et al. 2008). These authors divided their study subjects into low- and high-PYY responders and found that there was a temporal association between circulating PYY and satiety scores. Moreover, they found that the high-PYY responders had the greatest reduction in hunger (Stoeckel et al. 2008). Currently we do not know why some subjects were low-PYY responders and others high-PYY responders. However, it is becoming clear that many factors impinge upon the regulation of fasting and postprandial release of PYY.

Guo et al. undertook a prospective analysis to establish whether circulating PYY levels were associated with body weight changes. They found that fasting PYY concentrations correlated negatively with BMI and waist circumference and negatively with 15 h resting metabolic rate, which accounts for the greatest proportion of daily energy expenditure (Guo et al. 2006). Moreover, postprandial peak PYY concentrations were found to associate negatively with 24 h respiratory quotient. In addition, they found postprandial peak PYY concentrations negatively associated with changes in body weight over a 6 month period and were a significant determinant of changes in waist circumference over time (Guo et al. 2006). Based on these findings Guo et al. suggested that endogenous PYY might be involved in the long-term regulation of body weight and that this might not be exclusively driven by modulation of food intake but also by the control of energy expenditure and lipid metabolism (Guo et al. 2006).

To investigate the physiological role of PYY in regulating body weight Batterham et al. generated transgenic mice which globally lacked Pyy. These PyyKO mice were hyperphagic when freely feeding and ate significantly more than their wild type litter mates when exposed to a fast re-feed protocol (Batterham et al. 2006). Moreover, these mice were significantly heavier with markedly increased subcutaneous and visceral adiposity. Both the hyperphagia and adiposity were abrogated by exogenous replacement of PYY3–36 (Batterham et al. 2006). These findings confirm that PYY deficiency results in obesity and that PYY3–36 replacement ameliorates the obese phenotype resulting from this.

Role of PYY in mediating the weight loss benefits of gastric bypass surgery

Bariatric surgery is the most effective weight-loss treatment for morbidly obese patients ameliorating obesity co-morbidities and decreasing mortality (Sjostrom et al. 2007). Historically, the surgical strategies for weight loss relied on stomach volume restriction (e.g. gastroplasty), malabsorption (e.g. jejunoileal bypass), or both. Currently the gold standard is the Roux-en-Y gastric bypass (RYGBP), which results in the generation of a small stomach pouch to which the mid-jejunum is connected. Thus, meal contents bypass the lower stomach and upper small bowel. The duodenum and upper jejunal segment is anastomosed at a distal site in the jejunum so that the biliary and exocrine pancreatic drainage contacts luminal nutrients only in the latter half of their passage through the gut. RYGBP has a restrictive component but does not result in substantial malabsorption. However, RYGBP does result in more accelerated delivery of partially digested nutrients to the L-cells in the distal GI tract. The mechanisms promoting effective and sustained weight loss post-surgery are incompletely understood but there is increasing evidence that alterations in gut hormones play a role. In 1997 Naslund and colleagues measured fasted and meal-stimulated PYY levels in control subjects and patients who had undergone jejunoileal bypass 20 years previously (Naslund et al. 1997). They found that both fasting and meal-stimulated PYY levels were markedly elevated. However, at this stage the role of peripheral PYY in reducing appetite was unknown. In 2003 Strader et al. were the first to suggest that increased circulating PYY might play a role in mediating the weight changes seen following bariatric surgery. They undertook studies in rats in which the total length of the gut remained unaltered but where a 10 cm ileal segment was transposed to the proximal jejunum. Rats who had undergone ileal transposition ate less, had reduced body weight, increased PYY expression within the transposed segment and increased circulating PYY levels (Strader et al. 2005). Subsequently, Korner and colleagues reported that patients who had undergone RYGBP had significantly higher meal-stimulated PYY levels compared with weight-matched controls or lean control subjects (Korner et al. 2006). This finding of increased nutrient-stimulated PYY levels following RYGBP has been confirmed by several independent investigators (Chan et al. 2006; le Roux et al. 2006a; Morinigo et al. 2006). A role for PYY in mediating the observed reduction in food intake post-bariatric surgery is supported by the finding that blockade of endogenous PYY by administration of PYY antiserum resulted in increased food intake in rats that had undergone jejuno-intestinal bypass (le Roux et al. 2006a).

PYY as a potential therapy for obesity

Continuous administration of PYY3–36 via osmotic mini-pump or intermittent intravenous/intraperitoneal infusions has been shown to reduce body weight and adiposity in normal-weight rodents, obese rodents fed a high-fat diet and monkeys (Pittner et al. 2004; Koegler et al. 2005; Adams et al. 2006; Vrang et al. 2006; Chelikani et al. 2007). Further evidence that PYY3–36 may offer a viable therapeutic target comes from the recent findings by Boey et al. who generated mice that over-express PYY resulting in moderate increases in circulating PYY concentrations. These PYY transgenic mice were shown to be protected against diet-induced obesity (Boey et al. 2008). Moreover, crossing PYY transgenic mice with genetically obese ob/ob mice resulted in decreased weight gain and adiposity, reduced triglycerides and improved glucose homeostasis (Boey et al. 2008).

In addition to affecting food intake and energy expenditure, systemic administration of PYY3–36 has been shown to reduce the motivation to seek high-fat food after exposure to pellet priming or pellet cues, suggesting that PYY3–36 may help prevent relapse to high-fat diets (Ghitza et al. 2007). Furthermore, peripheral administration of PYY3–36 and Y2 agonist compounds has been shown to improve insulin sensitivity at doses which do not affect body weight (Vrang et al. 2006; van den Hoek et al. 2007). Taken together these finding suggests that long-term administration of PYY3–36 or Y2-agonists or stimulation of PYY3–36 release in vivo can reduce excess adiposity and improve glucose tolerance. However, from a physiological perspective, energy balance is regulated by several hormones that act in concert. Moreover, in response to a reduction in food intake and adiposity the body mounts a counter-regulatory response to prevent further weight loss thus limiting the effectiveness of single-agent weight-loss therapies. Consequently, several groups have examined the effects of combining PYY3–36/Y2 agonists with other anorectic agents that act on different receptor systems. Synergistic anorectic effects have been observed in rodents with combined administration of PYY-36 and exendin-4 (Talsania et al. 2005); additive effects on feeding inhibition in rodents and humans have been seen by combined administration of GLP-1 with PYY3–36 (Neary et al. 2005). PYY3–36 combined with the cannabanoid receptor-1 antagonist SR141716 decreases food intake greater than either compound alone (White et al. 2008). Combined administration of PYY3–36 with amylin resulted in a greater feeding inhibition and weight-reducing effect in diet-induced obesity-prone rats (Roth et al. 2007). Similarly, combined PYY3–36 and leptin administration results in greater feeding inhibition (Unniappan & Kieffer, 2008).

Conclusions

Our knowledge of the role of PYY3–36 in regulating energy balance has markedly increased over the last decade. However, the factors that regulate PYY3–36 synthesis and release and more importantly the mechanisms that underpin obesity-induced reductions in circulating PYY3–36 remain to be elucidated. Moreover, an increased understanding of how gastric bypass surgery augments endogenous PYY3–36 circulating levels could result in the generation of novel PYY3–36 secretagogues.

Taken together, the retained responsiveness of obese subjects to the anorectic effects of PYY3–36, the adiposity-reducing effects of chronic PYY3–36 administration, the insulin-sensitizing action of PYY3–36 coupled with the findings that PYY3–36 modulates both homeostatic and hedonic brain circuitry support on-going endeavours to develop obesity treatments that target the PYY system.

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