Пептид YY

The gut hormone peptide YY regulates appetite.

Abstract
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.

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Peptide YY, appetite and food intake

Abstract
Obesity is taking on pandemic proportions. The laws of thermodynamics, however, remain unchanged, as energy will be stored if less energy is expended than consumed; the storage is usually in the form of adipose tissue. Several neural, humeral and psychological factors control the complex process known as appetite. Recently, a close evolutionary relationship between the gut and brain has become apparent. The gut hormones regulate important gastrointestinal functions such as motility, secretion, absorption, provide feedback to the central nervous system on availability of nutrients and may play a part in regulating food intake. Peptide YY (PYY) is a thirty-six amino acid peptide related to neuropeptide Y (NPY) and is co-secreted with glucagon-like peptide 1. Produced by the intestinal L-cells, the highest tissue concentrations of PYY are found in distal segments of the gastrointestinal tract, although it is present throughout the gut. Following food intake PYY is released into the circulation. PYY concentrations are proportional to meal energy content and peak plasma levels appear postprandially after 1 h. PYY3-36 is a major form of PYY in both the gut mucosal endocrine cells and the circulation. Peripheral administration of PYY3-36 inhibits food intake for several hours in both rodents and man. The binding of PYY3-36 to the Y2 receptor leads to an inhibition of the NPY neurones and a possible reciprocal stimulation of the pro-opiomelanocortin neurones. Thus, PYY3-36 appears to control food intake by providing a powerful feedback on the hypothalamic circuits. The effect on food intake has been demonstrated at physiological concentrations and, therefore, PYY3-36 may be important in the everyday regulation of food intake.

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Peptide YY(3–36) Inhibits Morning, but Not Evening, Food Intake and Decreases Body Weight in Rhesus Macaques

Abstract

Peptide YY(3–36) [PYY(3–36)] is a hormone that is released after meal ingestion that is currently being investigated for the treatment of obesity; however, there are conflicting reports of the effects of PYY(3–36) on energy balance in rodent models. To shed light on this controversy, we studied the effect of PYY(3–36) on food intake and body weight in a nonhuman primate. Intravenous PYY(3–36) infusions before a morning meal transiently suppressed the rate of food intake but did not suppress the evening meal or 24-h intake. Twice-daily or continuous intravenous PYY(3–36) infusions to supraphysiological levels (levels that exceeded normal physiological levels) again suppressed the rate of feeding for the morning but not the evening meal. Twice-daily intravenous PYY(3–36) infusions for 2 weeks significantly decreased body weight in all test animals (average weight loss 1.9%) without changing insulin response to glucose infusion. These results show that endogenous PYY(3–36) may alter morning but not evening meal intake, and supraphysiological doses are required for effective suppression of food intake.

ARH, arcuate nucleus of the hypothalamusIVGTT, intravenous glucose tolerance testNPY, neuropeptide YONPRC, Oregon National Primate Research CenterPYY(3–36), peptide YY(3–36)
The rising prevalence of obesity in the U.S. and other countries (1,2) is linked to increases in the incidence of obesity-related diseases (diabetes, cardiovascular disease, hypertension, and cancer), elevated health care costs, and reduced quality of life (3,4). The success of pharmacological intervention to reverse trends in obesity demographics depends on a better understanding of the physiology of appetite and body weight regulation. Because of their involvement in the regulation of energy homeostasis, hypothalamic and brainstem systems are major targets for pharmacological treatment of obesity (5,6).

The arcuate nucleus of the hypothalamus (ARH) contains two cell types that act antagonistically to regulate energy intake and expenditure: activation of cells that express proopiomelanocortin produces anorectic effects, whereas activation of cells that produce neuropeptide Y (NPY) elicits feeding and energy conservation (7). Ingestion of nutrients causes L-cells in the gastrointestinal tract to release PYY(1–36), which is an endogenous ligand for several NPY receptors (Y1, Y2, and Y5) (8). However, a cleavage product of PYY(1–36), PYY(3–36), is relatively selective for the NPY Y2 receptor (9). The NPY Y2 receptor is expressed in the ARH and other sites and is the dominant inhibitory autoreceptor on NPY neurons (10,11). Evidence of a nonsaturable transport mechanism for PYY(3–36) across the blood-brain barrier (12), coupled with recent data by Riediger et al. (13) that physiological doses of PYY(1–36) induced c-Fos in the ARH but not the area postrema (in the hindbrain), support the hypothesis that circulating PYY(3–36) is thought to suppress appetite through inhibition of ARH NPY neurons, but this does not exclude other possible sites of action.

Peripheral PYY(3–36) administration reduces food intake in humans and rodents (14–16). Although the effects of PYY(3–36) on gastric emptying are reproducible (17–19), the effectiveness of PYY(3–36) at inhibiting feeding in rodents is inconsistent. Recently published results demonstrate that intramuscular PYY(3–36) injection effectively delays gastric emptying and modestly reduces food intake in rhesus monkeys (20), yet plasma PYY(3–36) levels that produced this effect were not reported, and the effect of continuous PYY(3–36) treatment on body weight remains to be determined. Therefore, we addressed the efficacy of physiological and pharmacological doses of PYY(3–36) at reducing food intake and body weight in the rhesus monkey.

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A role for PYY3-36 in GLP1-induced insulin secretion

The increasing worldwide prevalence of obesity and its commonly associated disease type 2 diabetes has a dramatic influence on morbidity and mortality in the human population [1]. Among currently available obesity treatments, bariatric surgery achieves the best substantial and permanent weight loss [1]. Interestingly, surgeries inducing a rapid reduction in appetite and a normalization of glycemic index (e.g. Roux-en-Y gastric bypass) are notably associated with an increase in the anorexigenic gut peptides PYY and GLP-1 [1]. These two hormones act as peripheral sensory inputs integrated by the central nervous system (CNS) to modulate appetite and energy expenditure. The pharmacological mimicry of the hormonal milieu after bariatric surgery has thus been proposed as a potential strategy for the treatment of obesity [1]. However, such therapies will require a complete understanding of the mechanisms by which gut hormonal signals interact and integrate with other peripheral and central informations to modulate appetite.

PYY is an amidated peptide of 36-amino acids composed of tyrosine residues (Y) at each end. PYY is highly homologous to another gut hormone (pancreatic polypeptide) and to the central neurotransmitter NPY. Whereas PYY1-36 is an agonist of three mammalian NPY receptors (Y1, 2 and 5), PYY3-36, resulting from the digestion of PYY1-36 by the enzyme dipeptidyl peptidase 4 (DPP-4) is a selective Y2 receptor (Y2R) agonist. PYY is synthesized after the meal by the L endocrine cells of the small intestine in proportion to energy intake. The anorectic effect of PYY is specifically mediated by Y2R via interactions with both the vagus nerve and the arcuate nucleus of the hypothalamus [2]. In animals and humans, intravenous infusion of PYY3-36 reduces food intake in both lean and obese individuals [3]. Whereas the role of PYY3-36 in appetite control has been well characterized, its role in glucose homeostasis remains controversial.

[+] Открыть спойлер: In this issue, Chandarana and colleagues address the role of peripheral PYY on glucose homeostasis, including the context of bariatric surgery in mice [4]. The administration of PYY3-36 during an intraperitoneal glucose tolerance test (IPGTT) had a lowering effect on glycemia, which depended on Y2R. On the contrary, PYY1-36 administration had no effect. Moreover, the lowering effect of peripheral PYY3-36 on glycemia was not inhibited by the central administration of an Y2R antagonist, but only by the peripheral (IP) injection of such an antagonist. The lowering effect of PYY3-36 on glycemia occurred in parallel to an increase in blood insulin levels. However, whilst PYY1-36 had an inhibitory effect on insulin secretion as already described, PYY3-36 had no direct effect on insulin secretion. Interestingly, exogenous PYY3-36 decreased blood glucose levels only in a postprandial context. This is in line with the fact that endogenous PYY is secreted in response to lipids or glucose by intestinal L-cells [1]. The authors thus hypothesized that the postprandial increase in PYY levels measured in the portal vein after a meal could have a role in regulating postprandial insulin secretion via an incretin effect. Enterogastric anastomosis (EGA) performed in obese mice is an operation that mimics RYGBP surgery in humans [5]. The authors used this model to decipher the effect of PYY3-36 on glucose homeostasis. In wild-type EGA mice, the increase in PYY3-36 paralleled an increase in GLP-1. This was abrogated in PYY null mice. This suggested that PYY3-36 might regulate GLP-1 secretion. Accordingly, the authors showed that PYY3-36 enhanced glucose-stimulated and meal-stimulated GLP-1 secretion in the portal vein of control mice. Moreover, this effect was dependent on peripheral Y2R receptors. The use of exendin 9-39, an antagonist of GLP-1 receptor, confirmed that the positive effect of PYY3-36 on glucose homeostasis was, at least in part, due to GLP-1 action.

The main interest of these findings is that they complement previous studies on the importance of intestinal signals in glucose homeostasis by providing a new link dealing with the regulation of insulin secretion by PYY. The authors first showed that PYY3-36 controlled glucose homeostasis though a regulation of insulin secretion and secondly that this regulation is independent of central Y2R. On the contrary, the anorectic action of peripheral administration of PYY3-36 has been shown to be dependent on brain Y2R [6]. The highly interesting point of this study concerns the link between the two gut hormones PYY3-36 and GLP-1. Data from Chandarana and colleagues suggest that PYY3-36 improves insulin secretion after a meal in a GLP-1 dependent manner (Figure 1). However, a perceived weakness is the lack of a comprehensive cellular mechanism linking the secretions of both hormones. Future studies will have to decipher this mechanism. Important questions remain unresolved. For example, does PYY3-36 act directly on Y2R present in intestinal L-cells to induce and/or improve GLP-1 secretion? Does PYY3-36 act on Y2R via the autonomous nervous system, which is very dense within the walls of the portal vein [7], to stimulate GLP-1 secretion? Is there a role in this chain of the central nervous system via a reflex arc? It is noteworthy that a neural mechanism has been suggested to account at least in part for the anorectic effect of PYY3-36[2] or for the benefits of GLP-1 on glucose control [8] and [9]. Moreover, it is concerning that the interplay between PYY, GLP-1 and Y2R may be complicated by the possible involvement of DPP-4. Indeed, PYY3-36 is produced from the digestion of PYY1-36 by DPP-4. The data reported in this study suggested that PYY3-36 improves glucose homeostasis, whilst PYY1-36 does not. Thus, DPP-4 inhibitors, which are currently used as a treatment to prolong the GLP-1 incretin effect in type-2-diabetes patients, might oppose rather than contribute to the PYY3-36 positive effect. If the mechanism suggested here were of primary importance, it would be hardly reconcilable with the benefits of DDP-4 inhibitors on GLP-1 incretin effects in pathophysiological situations [10].

Figure 1.
PYY3-36 improves insulin secretion after a meal in a GLP-1 dependent manner. The results obtained by Chandarana et al. are illustrated in orange (arrows): meal/glucose increase the levels of PYY3-36 in blood. PYY3-36, via the activation of peripheral Y2R, enhances GLP-1 secretion. As a result, GLP-1 levels increase in the portal vein leading to an increase in insulin secretion. Some questions that have to be solved to specify the cellular mechanisms linking the secretions of both hormones are illustrated in dotted lines. Full-size image (11 K): Does PYY3-36 act directly on Y2R expressed by intestinal L-cells to improve GLP-1 secretion? Full-size image (11 K): Does PYY3-36 act on Y2R expressed by neurons of the autonomic nervous system to improve GLP-1 secretion? Full-size image (11 K): Is the brain involved in the enhanced GLP-1 secretion promoted by PYY3-36?

In the obesity and diabetes field, it is obvious that implementing the knowledge on the peripheral effects of PYY3-36 could represent an important step in the understanding of the complex interplay between gut hormones, their maturation processes and their roles in regulating glucose and energy homeostasis. Further research in this field is warranted, since it may provide novel paradigms that could be useful in the elaboration of future approaches of prevention and/or treatment of metabolic diseases.

https://www.youtube.com/watch?v=mdNNVzUDyBA

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Конечно, информация и гормонах-пептидах и пр. - это хорошо.

Но не возникает разве вопрос: а чЁ делать-то с этим?

Вот-с:

The interaction between the gut microbiota and intestinal L cells can be modulated by the use of prebiotics (fermentable carbohydrates). Prebiotic supplementation in humans increases the plasma concentrations of GLP-1 and PYY, which is associated with satiety and a decrease of postprandial glucose levels [50]. Experiments in obese mice show that prebiotic treatment causes a change in the composition of the gut microbiota alongside with a decrease of inflammatory tone and an enforcement of mucosal barrier function [51]. The complex interactions between gut microbiota, mucosal function and metabolic homeostasis also involve the endocannabinoid system [52] and GLP-2 which improves intestinal function [51]. These interrelationships suggest that prebiotic supplementation has therapeutic potential as “pharmaco-nutritional” approach to reversing host metabolic alterations linked to intestinal dysbiosis in obesity and diabetes [53].

Given that nutritional status, dietary factors, physical activity and age have an important influence on the composition of the gut microbial community [54,55] it is not surprising that appetite-regulating hormones other than PYY, GLP-1 and GLP-2 will also interact with the gut microbiota in shaping appetite and metabolic status. Emerging evidence indicates that this applies to ghrelin [55,56], cholecystokinin [56] as well as leptin [56]. In addition, germ-free mice have a smaller number of enteroendocrine cells than conventionally colonized animals [56].

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