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Pancreatic Polypeptide Reduces Appetite and Food Intake in Humans
Abstract
Pancreatic polypeptide (PP) is a gut hormone released from the pancreas in response to ingestion of food. Plasma PP has been shown to be reduced in conditions associated with increased food intake and elevated in anorexia nervosa. In addition peripheral administration of PP has been shown to decrease food intake in rodents. These findings suggest that PP may act as a circulating factor that regulates food intake. Therefore we investigated the effect of intravenous infusion of PP (10 pmol/kg/min) on appetite and food intake in a randomised double-blind placebo-controlled crossover study in ten healthy volunteers. Infusion of PP reduced appetite and decreased the energy intake at a buffet lunch two hours post-infusion by 21.8 +/- 5.7% (P < 0.01). More importantly the inhibition of food intake was sustained, such that energy intake, as assessed by food diaries, was significantly reduced both the evening of the study and the following morning. Overall PP infusion reduced cumulative 24-hour energy intake by 25.3 +/- 5.8%. In conclusion our data demonstrates that PP causes a sustained decrease in both appetite and food intake.
... Accordingly, peripheral administration of PP results in reduced energy intake in rodents [61] and healthy humans [7]. Indeed, a blunted PP secretion was first observed in obese hyperphagic Prader-Willi patients [108] with exogenous PP application able to reduce food intake in these patients [9]. ...
... As suggested above, this could be related in part to the short biological half-life of native PP [25], as well as a more intense research focus on other satiety inducing peptide hormones such as GLP-1 and PYY [92]. In addition, whilst the mechanisms involved in PP-induced reductions of appetite have been investigated in rodents, related mechanistic pathways in humans remain to be fully elucidated, although inhibition of food intake is undoubtedly observed in both settings [7]. Moreover, recent evidence of pronounced appetite suppression and body weight lowering actions of combined regulatory peptide hormone receptor modulation, such as GLP-1 and Y2 [27], may see a rekindling of interest in Y4 receptor activating compounds as anti-obesity agents ( [13,27] ; Fig. 3). ...
... PP has established effects on appetite suppression providing potential promise as an anti-obesity agent [7]. Although PP was discovered some 45 years ago [47] and is known to be largely secreted from the endocrine pancreas, a putative role for the hormone in islet cell function has been largely overlooked. ...
Pancreatic polypeptide (PP), a member of the neuropeptide Y (NPY) family of peptides, is a hormone secreted from the endocrine pancreas with established actions on appetite regulation. Thus, through activation of hypothalamic neuropeptide Y4 (NPY4R or Y4) receptors PP induces satiety in animals and humans, suggesting potential anti-obesity actions. In addition, despite being actively secreted from pancreatic islets and evidence of local Y4 receptor expression, PP mediated effects on the endocrine pancreas have not been fully elucidated. To date, it appears that PP possesses an acute insulinostatic effect, similar to the impact of other peptides from the NPY family. However, it is interesting that prolonged activation of pancreatic Y1 receptors leads to established benefits on beta-cell turnover, preservation of beta-cell identity and improved insulin secretory responsiveness. This may hint towards possible similar anti-diabetic actions of sustained Y4 receptor modulation, since the Y1 and Y4 receptors trigger comparable cell signalling pathways. In terms of exploiting the prospective therapeutic promise of PP, this is severely restricted by a short circulating half-life as is the case for many regulatory peptide hormones. It follows that long-acting, enzyme resistant, forms of PP will be required to determine viability of the Y4 receptor as an anti-obesity and -diabetes drug target. The current review aims to refocus interest on the biology of PP and highlight opportunities for therapeutic development.
... Moreover, PP also seems to be involved in the modulation of food intake. It has been reported that the peripheral administration of PP exerts anorexigenic effects in humans, causing suppressed food intake (Batterham et al., 2003). On the other hand, studies in rodents and dogs have shown an increase of food intake after central administration of PP (Clark et al., 1984;Inui et al., 1991). ...
... Blunted postprandial PP release has also been observed in individuals with morbid obesity (Lieverse et al., 1994), whereas subjects with anorexia nervosa show an exaggerated postprandial PP secretion (Fujimoto et al., 1997). Exogenous administration of PP was followed by decreased food intake in both Prader-Willi syndrome and healthy individuals (Batterham et al., 2003;Berntson et al., 1993). These observations indicate possible involvement of PP in the regulation of food intake and potentially also in the etiology of disorders of food intake such as obesity and anorexia nervosa. ...
... For this study, we made an estimation for the n-value based on several earlier studies. Batterham and colleagues showed statistically significant suppressed energy intake by a PP10 dose in 10 individuals (Batterham et al., 2003). A 5 pmol*kg −1 *min −1 PP dose showed a significant reduction of energy intake, in a group of 14 volunteers (Jesudason et al., 2007). ...
Pancreatic polypeptide (PP) is known to affect food intake. In this exploratory study, we set out to investigate its supraphysiological effect on food tolerance, gastric accommodation, and emptying. In 12 healthy volunteers, 0, 3, or 10 pmol*kg⁻¹*min⁻¹ PP was administered intravenously (PP0, PP3 or PP10). Thirty minutes thereafter, nutrient drink infusion (60 ml*min⁻¹) through a nasogastric feeding tube was started until maximum satiation. Gastric accommodation was assessed by measuring the intragastric pressure (IGP; nasogastric manometry). In a separate test, the effect of PP0 or PP10 on gastric emptying was tested in 10 healthy volunteers and assessed using the ¹³C breath test. Results are presented as mean ± SEM, and p < 0.05 was considered significant. For the IGP test, PP increased ingested nutrient volume: 886 ± 93, 1059 ± 124, and 1025 ± 125 ml for PP0, PP3, and PP10, respectively (p = 0.048). In all groups, Nadir IGP values were reached upon food intake (transformed values: 1.5 ± 0.2, 1.7 ± 0.3, and 1.6 ± 0.3 mmHg for PP0, PP3, and PP10, respectively; NS) to return to baseline thereafter. For the gastric emptying study, volunteers ingested a similar nutrient volume: 802 ± 119 and 1089 ± 128 ml (p = 0.016), and gastric half‐emptying time was 281 ± 52 and 249 ± 37 min for PP0 and PP10, respectively (NS). No significant correlation between tolerated nutrient volume and IGP drop (R² < 0.01; p = 0.88 for PP0 vs. PP3 and R² =0.07; p = 0.40 for PP0 vs. PP10, respectively) or gastric half‐emptying time (R² = 0.12; p = 0.32) was found. A supraphysiological PP dose enhances food tolerance; however, this effect is not mediated through gastric motility.
Clinical Trial registry number
NCT03854708 is obtained from clinicaltrials.gov.
... Conversely, episodic signals play a role in the acute regulation of energy intake, for example, following food intake or exercise. The gastrointestinal peptides cholecystokinin (CCK) [15], glucagon-like peptide-1 (GLP-1) [16], pancreatic polypeptide (PP) [17], and peptide tyrosine tyrosine (PYY) [18] are notable anorexigenic hormones in this regard. These hormones are counteracted by the orexigenic peptide ghrelin [19]. ...
... In the postprandial exercise trial, PP levels were even reduced during exercise. A decrease in PP levels alongside a reduction in appetite seems contradictory, as a drop in PP levels would be expected to increase appetite [17]. This illustrates that hormones should not be considered in isolation when assessing the effects on subjective appetite perception. ...
This systematic review aims to analyze the effects of acute and chronic exercise on appetite and appetite regulation in patients with abnormal glycemic control. PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials were searched for eligible studies. The included studies had to report assessments of appetite (primary outcome). Levels of appetite-regulating hormones were analyzed as secondary outcomes (considered, if additionally reported). Seven studies with a total number of 211 patients with prediabetes or type 2 diabetes mellitus (T2DM) met the inclusion criteria. Ratings of hunger, satiety, fullness, prospective food consumption, nausea, and desire to eat, as well as levels of (des-)acylated ghrelin, glucagon-like peptide 1, glucose-dependent insulinotropic peptide, pancreatic polypeptide, peptide tyrosine tyrosine, leptin, and spexin were considered. Following acute exercise, the effects on appetite (measured up to one day post-exercise) varied, while there were either no changes or a decrease in appetite ratings following chronic exercise, both compared to control conditions (without exercise). These results were accompanied by inconsistent changes in appetite-regulating hormone levels. The overall risk of bias was low. The present results provide more evidence for an appetite-reducing rather than an appetite-increasing effect of (chronic) exercise on patients with prediabetes or T2DM. PROSPERO ID: CRD42023459322.
... 18,23,29 Peripheral administration (intraperitoneal and intravenous) of pancreatic peptide in mice and humans suppresses food intake, delays gastric emptying, and reduces weight. [98][99][100] Glucose-dependent insulinotropic peptide GIP is also an incretin, synthesized and secreted by the K-cells of the small intestine in the duodenum and proximal jejunum. 99 This hormone exerts its function by binding to the GIP receptor, found in the hypothalamus, NTS, pancreas, and adipocytes. ...
... [98][99][100] Glucose-dependent insulinotropic peptide GIP is also an incretin, synthesized and secreted by the K-cells of the small intestine in the duodenum and proximal jejunum. 99 This hormone exerts its function by binding to the GIP receptor, found in the hypothalamus, NTS, pancreas, and adipocytes. 101 GIP is secreted in response to glucose and fat-rich meals, 69 after which plasma levels increase over 10-15 minutes and return to baseline after 180 minutes. ...
Satiety is a complex state, influenced by numerous factors that go beyond food ingestion. Satiety influences food habits and behavior, thus affecting human health. This review provides an overview of physiological mechanisms involved in satiety and of methodologies to assess food intake and satiety in both animal models and humans. The following topics are highlighted: differences between satiety and satiation; how the central nervous system regulates food intake and satiety; the impact of different macronutrients on satiety; and how the manipulation of food composition might influence overall satiety. Bringing together knowledge on this myriad of satiety mechanisms and how we can study them is useful to better understand and control obesity and other eating disorders.
... L'insuline diminue le taux de glucose dans le sang, tandis que le glucagon vise à l'élever. La (Batterham et al., 2003;Katsuura et al., 2002). Les rôles de ces hormones endocrines seront abordés en détail dans le chapitre 1.2.5.2. ...
... Le peptide sécrété après un repas est régulé par le nerf vague et le système nerveux entérique (acétylcholine et l'adrénaline) (Field et al., 2010;Schwartz, 1983) et stimulé par les incrétines (comme le GIP) (Chia et al., 2014), les lipides et les acides aminés (Field et al., 2010;Weir et al., 1978). Chez les rongeurs et les humains, le PP agit comme une hormone anorexigène : il inhibe la motilité de l'estomac et de l'intestin, pour ralentir le processus digestif, régulant ainsi la satiété en réduisant l'appétit et la prise alimentaire (Batterham et al., 2003). ...
Les îlots pancréatiques sont des micro-organes multicellulaires impliqués dans l’homéostasie du glucose. Leur activité sécrétoire et leurs interactions sont modulées par des facteurs autocrine et paracrine potentialisant ou non le stockage ou la production de l’énergie pour maintenir une homéostasie glucidique. La cellule β est un capteur naturel du glucose qui intègre les signaux transmis par les autres nutriments et les hormones. L’activation des canaux ioniques présents à la surface de la membrane plasmique conduit à des flux ioniques responsables de l’activité électrique de la cellule β.La première étude de ma thèse concerne la régulation fine des îlots impliquant le neuromédiateur glutamate. L’objectif était d’étudier le rôle du récepteur au glutamate GluK2 présent dans les cellules α pancréatiques, dans l’homéostasie glucidique et dans la régulation de la sécrétion des îlots. La technique d’enregistrements extracellulaires sur matrices de microélectrodes (MEAs) a permis entre autres d’étudier l’activité électrique des îlots de souris transgéniques pour GluK2, de différents âges, de manière non-invasive sur le long-terme.Dans un second temps, j’ai consacré la majeure partie de ma thèse au développement de nouveaux biocapteurs, les transistors électrochimiques organiques (OECTs). Ces OECTs sont basés sur l’électronique organique améliorant davantage les enregistrements extracellulaires comme déjà montré avec les neurones et les cellules musculaires striées. Leur polymère semi-conducteur leur confère une conductivité électronique/ionique mixte permettant des enregistrements électriques plus riches et une amplification des signaux locaux avec un excellent rapport signal/bruit. Les OECTs sont accessibles aux modifications chimiques ; rendre le polymère spécifique à des ions inhérents à la fonction des cellules pancréatiques (K+, Na+, Ca2+, Zn2+) améliorerait davantage le pouvoir analytique. Le challenge fut de développer cette approche OECTs pour la première fois pour les îlots, en étudiant leur stabilité à long-terme, en contact de substrats biologiques, et en mettant en place des cartes électroniques pour le suivi de l’activité électrique.La première étude a montré que les souris mutées déficientes pour GluK2 présentaient une diminution de la sécrétion de glucagon et de l’insuline in-vivo et in-vitro, conduisant à une meilleure tolérance au glucose et une meilleure sensibilité à l’insuline, à l’âge adulte et lors du vieillissement. La suppression de ce récepteur améliore l’homéostasie glucidique et la préserve du vieillissement, suggérant que l’inactivation ou le blocage de GluK2 pourrait être bénéfique pour l’homéostasie glucidique et pourrait la préserver lors du vieillissement.La mise en place de la technologie OECTs a permis d’établir des paramètres électriques non-invasifs pour leur performance en termes d’amplification ce qui est primordial pour nos études biologiques quantitatives long-terme. La carte électronique développée est réglable par OECT permettant d’ajuster les paramètres électriques en fonction de leur niveau de performance. Nous l’avons validée grâce aux cellules cardiaques, déjà testées dans la littérature et montrant des signaux électriques de grande amplitude. Les cellules cardiaques ont permis de déterminer les conditions électriques non invasives pour lesquelles la détection des signaux est possible avec les meilleurs rapports signal/bruit. Nous avons ensuite enregistré l’activité électrique des îlots sur OECTs en mesurant les potentiels lents (PLs), signaux de couplages multicellulaires, et les potentiels d’action (PAs), signaux rapides unicellulaires. Ainsi, nous avons réalisé avec les OECTs des études quantitatives sur cellules cardiaques et îlots pour montrer la preuve du concept. À l’avenir, ces OECTs ouvrent la possibilité d'utiliser des polymères ions-spécifiques pour suivre l’activité de canaux ioniques précis lors d’expériences mimant la physiologie ou des conditions physiopathologiques.
... Accordingly, we selected the following five blood proteins that indicate the activities of biological processes: NEFL for neurodegeneration, 32 PARP1 for inflammation, 38,39 CD33 for innate immunity, 40,41 LIFR for vascular functions, 13,42,43 and PPY for metabolic activities. [44][45][46][47] By normalizing the changes of these five blood proteins into a unified scale from 0 to 100, we established a multiscale system that can simultaneously Spanish BIODEGMAR cohort, the dysregulation of vascular functions and innate immunity started at the early stage of AD ( Figure 5C,D). ...
INTRODUCTION
Existing blood‐based biomarkers for Alzheimer's disease (AD) mainly focus on its pathological features. However, studies on blood‐based biomarkers associated with other biological processes for a comprehensive evaluation of AD status are limited.
METHODS
We developed a blood‐based, multiplex biomarker assay for AD that measures the levels of 21 proteins involved in multiple biological pathways. We evaluated the assay's performance for classifying AD and indicating AD‐related endophenotypes in three independent cohorts from Chinese or European‐descent populations.
RESULTS
The 21‐protein assay accurately classified AD (area under the receiver operating characteristic curve [AUC] = 0.9407 to 0.9867) and mild cognitive impairment (MCI; AUC = 0.8434 to 0.8945) while also indicating brain amyloid pathology. Moreover, the assay simultaneously evaluated the changes of five biological processes in individuals and revealed the ethnic‐specific dysregulations of biological processes upon AD progression.
DISCUSSION
This study demonstrated the utility of a blood‐based, multi‐pathway biomarker assay for early screening and staging of AD, providing insights for patient stratification and precision medicine.
Highlights
The authors developed a blood‐based biomarker assay for Alzheimer's disease.
The 21‐protein assay classifies AD/MCI and indicates brain amyloid pathology.
The 21‐protein assay can simultaneously assess activities of five biological processes.
Ethnic‐specific dysregulations of biological processes in AD were revealed.
... Pancreatic polypeptides (PP) an anorectic hormone is secreted from PP cells in the pancreatic islets of Langerhans. In a study it was shown that, intravenous infusion of PP in healthy humans results in a 25% reduction in food intake (21). Furthermore, twice-daily infusion of PP in Prader willi Syndrome (PWS) patients caused a 12% reduction in food intake (22). ...
Obesity and its associated co-morbidities is pandemic and with scientific developments, many combating therapies are in prevalence. Bariatric Surgery (BS) is considered most effective treatment for morbid obesity. After the surgery however weight regain can occur in 20-30% cases. It has also been observed that some patients do not achieve successful outcomes of weight loss or even if they do so, they are unable to maintain it. Various factors like food choices, Basal metabolism, energy expenditure, lifestyle modifications and hormonal changes are seen to affect the weight status after surgery. This review study depicts factors as well as the mechanism of weight regain post bariatric surgery. It is imperative that weight gain occurs in patients, therefore, more studies are required towards the prevention and care in these subjects.
... PP has a high affinity for the hypothalamic Y4 receptor (also known as PPYR4) and mediates biological activity after binding with it (1). A number of studies have reported that PP plays an important role in increasing energy consumption and reducing body weight by regulating food intake, inhibiting gallbladder movement, and inhibiting gastric emptying (6)(7)(8)(9)(10). Therefore, PP may induce satiety by activating the PPYR4 receptor, suggesting its potential anti-obesity effects (11). ...
Objective
This study aims to compare the levels of serum pancreatic polypeptide (PP), insulin (INS), C-peptide (C-P), and glucagon (GCG) before and after glucose stimulation in type 2 diabetes mellitus (T2DM) patients with different body mass indexes (BMI), analyze the relevant factors associated with PP secretion, and further investigate the role of PP in the development of obesity and diabetes.
Methods
Data were collected from 83 patients from the hospital. The subjects were divided into normal-weight group, overweight group, and obese group according to their BMI. All subjects were tested with the standard bread meal test (SBMT). PP and relevant parameters were measured, and the area under the curve (AUC) was calculated after 120 min of SBMT. AUC pp (AUC of PP) was used as the dependent variable, and the potential influencing factors were used as independent variables for multiple linear regression analysis.
Results
The obese and overweight groups had significantly lower PP secretion than the normal-weight group (485.95 pg·h/ml, 95% CI 76.16–895.74, p = 0.021; 664.61 pg·h/ml, 95% CI 285.46–1043.77, p = 0.001) at 60 min postprandial. PP secretion in the obese and overweight groups was also significantly lower than that in the normal-weight group (520.07 pg·h/ml, 95% CI 186.58–853.56, p = 0.003; 467.62 pg·h/ml, 95% CI 159.06–776.18, p = 0.003) at 120 min postprandial. AUC pp was negatively associated with BMI (r = -0.260, p = 0.017) and positively associated with AUC GCG (r = 0.501, p< 0.001). Multiple linear regression analysis showed that there was a linear correlation between AUC GCG , BMI, and AUC pp ( p< 0.001, p = 0.008). The regression equation was calculated as follows: AUC pp = 1772.255–39.65 × BMI + 0.957 × AUC GCG (R 2 = 54.1%, p< 0.001).
Conclusion
Compared with normal-weight subjects, overweight and obese subjects had impaired PP secretion after glucose stimulation. In T2DM patients, PP secretion was mainly affected by BMI and GCG.
Clinical trial registry
The Ethics Committee of the Affiliated Hospital of Qingdao University.
Clinical trial registration
http://www.chictr.org.cn , identifier ChiCTR2100047486.
... Peripheral administration of PP was reported to reduce food intake in obese humans, suggesting its potential as an obesity treatment (Batterham et al., 2003). The application of PP as an anti-obesity treatment is limited by its short circulating half-life. ...
... PP is secreted by PP cells in response to nutrient ingestion and acts by inhibiting pancreatic exocrine and biliary secretion, gallbladder contraction, gastric motility and acid secretion after a meal [65]. PP also acts by reducing food intake and appetite [66]. PP has also been shown to play a role in glucose homeostasis by mediating hepatic sensitivity to insulin through its regulation of hepatic insulin receptor (IR) gene expression and hepatocyte IR availability [20,67,68]. ...
Introduction
: Diabetes of the exocrine pancreas (DEP; a.k.a. pancreatic diabetes or pancreatogenic diabetes or type 3c diabetes mellitus or T3cDM) refers to different diabetes types resulting from disorders of the exocrine pancreas and is characterized by the structural and functional loss of glucose-normalizing insulin secretion in the context of exocrine pancreatic dysfunction. Among these forms, new-onset diabetes mellitus secondary to total pancreatectomy (TP) has unique pathophysiological and clinical features, for which we propose a new nomenclature such as post-total pancreatectomy diabetes mellitus (PTPDM).
Areas covered
TP results in the complete loss of pancreatic parenchyma, with subsequent absolute insulinopenia and lifelong need for exogenous insulin therapy. Patients with PTPDM also exhibit deficiency of glucagon, amylin and pancreatic polypeptide. These endocrine abnormalities, coupled with increased peripheral insulin sensitivity, deficiency of pancreatic enzymes and TP-related modifications of gastrointestinal anatomy, can lead to marked glucose variability and increased risk of iatrogenic (insulin-induced) severe hypoglycemic episodes (“brittle diabetes”).
Expert opinion
: We believe that diabetes mellitus secondary to TP should not be included in the DEP spectrum in light of its peculiar pathophysiological and clinical features. Therefore, we propose a new classification for this entity, that would likely provide more accurate prognosis and treatment strategies.
... Pancreatic polypeptide is produced by PP cells of the pancreas and is a hormone that reduces appetite 96 . In healthy adults, the 24-h pattern of circulating levels of pancreatic polypeptide shows higher levels during the daytime with food intake and lower levels at night [97][98][99] . ...
Traditional risk factors for obesity and the metabolic syndrome, such as excess energy intake and lack of physical activity, cannot fully explain the high prevalence of these conditions. Insufficient sleep and circadian misalignment predispose individuals to poor metabolic health and promote weight gain and have received increased research attention in the past 10 years. Insufficient sleep is defined as sleeping less than recommended for health benefits, whereas circadian misalignment is defined as wakefulness and food intake occurring when the internal circadian system is promoting sleep. This Review discusses the impact of insufficient sleep and circadian misalignment in humans on appetite hormones (focusing on ghrelin, leptin and peptide-YY), energy expenditure, food intake and choice, and risk of obesity. Some potential strategies to reduce the adverse effects of sleep disruption on metabolic health are provided and future research priorities are highlighted. Millions of individuals worldwide do not obtain sufficient sleep for healthy metabolic functions. Furthermore, modern working patterns, lifestyles and technologies are often not conducive to adequate sleep at times when the internal physiological clock is promoting it (for example, late-night screen time, shift work and nocturnal social activities). Efforts are needed to highlight the importance of optimal sleep and circadian health in the maintenance of metabolic health and body weight regulation.
... Langerhans (Aragón et al., 2015;Asakawa et al., 2003;Batterham et al., 2003). ...
L’adénocarcinome canalaire pancréatique (ADKP) est l’une des tumeurs solides les plus agressives en raison de son diagnostic tardif, de son potentiel métastatique élevé et de sa résistance aux traitements conventionnels. La voie du TGF-β (Transforming Growth Factor beta) est l’une des seules cascades de signalisation altérées dans la quasi-totalité de ces tumeurs pancréatiques. L’une des mutations les plus fréquentes touche le gène SMAD4, qui code un facteur de transcription impliqué dans la transduction de la voie du TGF-β. Sa mutation est un facteur de mauvais pronostic. L’induction de la voie du TGF-β induit l’association de SMAD4 aux deux autres effecteurs de la voie, SMAD2 et/ou SMAD3, qui subissent ensemble, une translocation nucléaire afin d’exercer leurs fonctions de facteurs de transcription. L’impact oncogénique de la mutation de SMAD4 est donc largement supposé résulter de la perte de fonction de cette protéine. Cependant, le rôle de SMAD2 et SMAD3 en l’absence de SMAD4 reste peu étudié. Au cours de ma thèse, j’ai montré qu’en l’absence de SMAD4, les protéines SMAD2 et SMAD3 agissent de manière indépendante et déclenchent l’expression de gènes impliqués dans des processus oncogéniques tels que la migration et l’invasion des cellules cancéreuses pancréatiques. J’ai pu caractériser l’impact phénotypique de l’activité oncogénique de SMAD2/3 en l’absence de SMAD4 à l’aide de modèles cellulaires originaux. Enfin, la pertinence de ces observations réalisées in vitro a été confirmée par l’étude d’une cohorte d’adénocarcinomes pancréatiques. Nous avons en effet établi que les tumeurs associant l’absence de SMAD4 et un haut niveau d’activation de SMAD2 étaient plus agressives et de moins bon pronostic. L’impact phénotypique des altérations de la voie du TGF-β est complexe, compte-tenu de la dualité fonctionnelle de cette cytokine au cours de la tumorigenèse. Dans son ensemble, ma thèse a permis de révéler un niveau additionnel de complexité, en montrant l’impact oncogénique du complexe SMAD2/3 sur l’échappement tumoral en l’absence de SMAD4.
... Pancreatic polypeptide (PP) is secreted by PP cells of the pancreas, and its level is reduced under conditions associated with increased food intake but elevated in anorexia nervosa. On fasting, the plasma PP concentration is 80 pg/mL, and after the meal, it rises by 8 to 10 times (40). The plasma PP levels were significantly reduced in the HFD-C. ...
Candida albicans survives as a commensal fungus in the gastrointestinal tract, and that its excessive growth causes infections in immunosuppressed individuals is widely accepted. However, any mutualistic relationship that may exist between C. albicans and the host remains undetermined. Here, we showed that a long-term feeding of C. albicans does not cause any noticeable infections in the mouse model. Our 16S and 18S ribosomal DNA (rDNA) sequence analyses suggested that C. albicans colonizes in the gut and modulates microbiome dynamics, which in turn mitigates high-fat-diet-induced uncontrolled body weight gain and metabolic hormonal imbalances. Interestingly, adding C. albicans to a nonobesogenic diet stimulated the appetite-regulated hormones and helped the mice maintain a healthy body weight. In concert, our results suggest a mutualism between C. albicans and the host, contrary to the notion that C. albicans is always an adversary and indicating it can instead be a bona fide admirable companion of the host. Finally, we discuss its potential translational implication as a probiotic, especially in obese people or people dependent on high-fat calorie intakes to manage obesity associated complications.
IMPORTANCE Candida albicans is mostly considered an opportunistic pathogen that causes fetal systemic infections. However, this study demonstrates that in its commensal state, it maintains a long-term mutualistic relationship with the host and regulates microbial dynamics in the gut and host physiology. Thus, we concluded that C. albicans is not always an adversary but rather can be a bona fide admirable companion of the host. More importantly, as several genomic knockout strains of C. albicans were shown to be avirulent, such candidate strains may be explored further as preferable probiotic isolates to control obesity.
... In conclusion, as the endogenous Y4R agonist PP was shown to reduce appetite and food intake in humans 255,256 , Y4R agonists might be useful as antiobesity drugs, and such new selective and potent Y4R ...
In this work, computational chemistry methods including homology modeling, molecular docking and molecular dynamics simulations have been applied to elucidate the dynamical behavior of GPCRs and GPCR-ligand complexes. By these modeling studies, detailed atomistic insights have been obtained regarding GPCR dynamics and GPCR-ligand interactions. These findings improve the knowledge about GPCR activation and guide the structure-based design of novel molecular tool compounds and novel ligand scaffolds with improved affinity, selectivity and signaling profiles.
... Langerhans (Aragón et al., 2015;Asakawa et al., 2003;Batterham et al., 2003). ...
L’adénocarcinome canalaire pancréatique (ADKP) est l’une des tumeurs solides les plus agressives en raison de son diagnostic tardif, de son potentiel métastatique élevé et de sa résistance aux traitements conventionnels. La voie du TGF-β (Transforming Growth Factor beta) est l’une des seules cascades de signalisation altérées dans la quasi-totalité de ces tumeurs pancréatiques. L’une des mutations les plus fréquentes touche le gène SMAD4, qui code un facteur de transcription impliqué dans la transduction de la voie du TGF-β. Sa mutation est un facteur de mauvais pronostic. L’induction de la voie du TGF-β induit l’association de SMAD4 aux deux autres effecteurs de la voie, SMAD2 et/ou SMAD3, qui subissent ensemble, une translocation nucléaire afin d’exercer leurs fonctions de facteurs de transcription. L’impact oncogénique de la mutation de SMAD4 est donc largement supposé résulter de la perte de fonction de cette protéine. Cependant, le rôle de SMAD2 et SMAD3 en l’absence de SMAD4 reste peu étudié. Au cours de ma thèse, j’ai montré qu’en l’absence de SMAD4, les protéines SMAD2 et SMAD3 agissent de manière indépendante et déclenchent l’expression de gènes impliqués dans des processus oncogéniques tels que la migration et l’invasion des cellules cancéreuses pancréatiques. J’ai pu caractériser l’impact phénotypique de l’activité oncogénique de SMAD2/3 en l’absence de SMAD4 à l’aide de modèles cellulaires originaux. Enfin, la pertinence de ces observations réalisées in vitro a été confirmée par l’étude d’une cohorte d’adénocarcinomes pancréatiques. Nous avons en effet établi que les tumeurs associant l’absence de SMAD4 et un haut niveau d’activation de SMAD2 étaient plus agressives et de moins bon pronostic. L’impact phénotypique des altérations de la voie du TGF-β est complexe, compte-tenu de la dualité fonctionnelle de cette cytokine au cours de la tumorigenèse. Dans son ensemble, ma thèse a permis de révéler un niveau additionnel de complexité, en montrant l’impact oncogénique du complexe SMAD2/3 sur l’échappement tumoral en l’absence de SMAD4.
... The peptide secreted after a meal is regulated by the vagus nerve and enteric nervous system (acetylcholine and adrenaline (Field, Chaudhri, et Bloom 2010;Schwartz et al. 2000) and stimulated by incretins (such as GIP) (Chia et al. 2014) lipids and amino acids (Field, Chaudhri, et Bloom 2010). In rodents and humans, PP acts as an anorectic hormone: it inhibits stomach and intestinal motility to slow down the digestive process, thus regulating satiety by reducing appetite and food intake (Batterham et al. 2003). ...
In diabetes mellitus (DM), continuous glucose monitoring (CGM) linked to insulindelivery presents a major advance but is still limited by current algorithms and thenature of glucose sensors. DIABLO is a multidisciplinary project from diabetology, isletbiology, and microelectronics to automation control, with the objective to establish anew model of CGM (i) by high-resolution techniques to decipher and model islet'sendogenous algorithms, (ii) by design of novel control algorithms inspired byaeronautics and (iii) by the proof of concept of maintaining glucose homeostasis bythis hybrid biosensor. DIABLO will impact research by multi-physics system modellingand healthcare technology as well as life quality in DM by novel algorithms and aninnovative module for the artificial pancreas. The project will also advance for DM andother chronic diseases monitoring of stem-cell derived therapeutic means and thedevelopment of Organs-on-Chip.
... [8][9][10][11] As a gastrointestinal hormone, PP can increase satiety, delay gastric emptying, inhibit gallbladder movement, and play an important role in weight loss and energy consumption. [12][13][14] Evidence shows that PP can maintain sensitivity of the liver to insulin by regulating the expression of insulin receptor gene on the liver surface. 15,16 In addition, some scholars believe that PP may have an important paracrine interaction with insulin (INS) and glucagons (GCs). ...
Background:
The purpose of this study is to compare serum pancreatic polypeptide (PP), insulin, C-peptide, and glucagon in different glucose tolerance stages; analyze the influencing factors of PP secretion; and further explore the role of PP in the pathogenesis of diabetes mellitus.
Methods:
Data were collected from 100 subjects from hospital. According to the results of oral glucose tolerance test (OGTT), the subjects were divided into a normal glucose tolerance (NGT) group, an impaired glucose regulation (IGR) group, and a newly diagnosed type 2 diabetes mellitus (T2DM) group. PP and the related parameters were measured, and the area under the curve (AUC) 120 min after OGTT was calculated. AUCpp (AUC of PP) was used as the dependent variable and the potentially influencing factors were used as the independent variable for multiple linear regression analysis.
Results:
Postprandial 60 min PP in the IGR group was higher than those in the NGT group (2973.80 [±547.49] pg·h/mL vs 2663.55 [±594.89] pg·h/mL, p < 0.05). AUCpp was significantly higher in the IGR group (428.76 pg·h/mL, 95% confidence interval [CI] [41.06 -816.46], p = 0.031) and newly diagnosed T2DM group (404.35 pg·h/mL, 95% CI [5.37-803.33], p = 0.047) than in the NGT group. AUCpp was negatively correlated with body mass index (BMI) (r = -0.235, p = 0.038) and positively correlated with postprandial 60 min blood glucose (r = 0.370, p = 0.001) and AUCbg (AUC of blood glucose) (r = 0.323, p = 0.007). Multiple linear regression analysis indicated that there was a linear correlation between BMI, AUCbg , and AUCpp (p = 0.004, p = 0.001), and the regression equation was calculated as: AUCpp = 6592.272 + 86.275 × AUCbg -95.291 × BMI (R2 = 12.7%, p < 0.05).
Conclusions:
Compared with NGT subjects, IGR and T2DM patients have an enhanced postprandial PP secretion. In T2DMs, the secretion of PP is mainly affected by BMI and blood glucose.
... Livoletide, an unacylated ghrelin analogue, showed initially a significant reduction in hyperphagia, waist circumference and fat mass in PWS subjects, without changes in ghrelin concentrations [27], but these effects were not sustained after three months of treatment [28]. PP is a peptide that induces satiety [29]. The finding of low concentrations in patients with PWS suggests that it may be involved in their lack of satiety. ...
Hyperphagia is one of the main problems of patients with Prader-Willi syndrome (PWS) to cope with everyday life. The underlying mechanisms are not yet well understood. Gut-brain hormones are an interrelated network that may be at least partially involved. We aimed to study the hormonal profile of PWS patients in comparison with obese and healthy controls. Thirty adult PWS patients (15 men; age 27.5 ± 8.02 years; BMI 32.4 ± 8.14 kg/m2), 30 obese and 30 healthy controls were studied before and after eating a hypercaloric liquid diet. Plasma brain-derived neurotrophic factor (BDNF), leptin, total and active ghrelin, peptide YY (PYY), pancreatic polypeptide (PP), Glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and amylin were determined at times 0′, 30′, 60′ and 120′. Cluster analysis was used. When considering all peptides together, two clusters were established according to fasting hormonal standardized concentrations. Cluster 1 encompassed most of obese (25/30) and healthy controls (28/30). By contrast, the majority of patients with PWS were located in Cluster 2 (23/27) and presented a similar fasting profile with hyperghrelinemia, high levels of leptin, PYY, GIP and GLP-1, compared to Cluster 1; that may reflect a dysfunction of these hunger/satiety hormones. When peptide behavior over the time was considered, PP concentrations were not sustained postprandially from 60 min onwards in Cluster 2. BDNF and amylin did not help to differentiate the two clusters. Thus, cluster analysis could be a good tool to distinguish and characterize the differences in hormone responses between PWS and obese or healthy controls.
... 38 Hormones from peripheral tissues such as leptin, ghrelin, cholecystokinin, pancreatic polypeptide, PYY (PYY3-36), GLP-1, and oxyntomodulin have been shown to regulate appetite. [39][40][41][42][43][44][45][46][47] Resistance to the actions of some of these hormones appears to be associated with common obesity. For example, leptin is secreted by adipose tissue and is thought to be a key peptide in reducing food intake based on the extreme obesity that develops in the absence of leptin signaling. ...
Obesity is a chronic, multifactorial, relapsing disease. Despite multicomponent lifestyle interventions, including pharmacotherapy, maintaining bodyweight loss is challenging for many people. The pathophysiology of obesity is complex, and currently approved pharmacotherapies only target a few of the many pathways involved; thus, single-targeting agents have limited efficacy. Proglucagon-derived peptides, glucagon, and the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), represent attractive targets for managing obesity and metabolic disorders because they may have direct roles in multiple mechanisms including satiety, energy homeostasis, and lipolytic activity. Unimolecular dual and triple agonists targeting glucagon and incretin hormone receptors have been shown to promote bodyweight loss, lower glucose levels, and reduce food intake in animal models of obesity. Multiple dual receptor agonists are in clinical development for the treatment of obesity, including GLP-1/GIP and GLP-1/glucagon receptor agonists. The extent to which glucagon contributes to treatment effects remains to be understood, but it may promote bodyweight loss by reducing food intake, while concomitant GLP-1 receptor agonism ensures normal glucose control. Further research is required to fully understand the molecular mechanisms of action and metabolic effects of both dual and triple receptor agonists.
... In obese patients intravenous infusion of physiological levels of PYY reduces the caloric intake [104]. Similarly, PP reduces appetite and food intake in healthy human volunteers [105]. However, chronic peripheral administration of PP in lean and obese mice reduces caloric intake, but central administration leads to increases caloric intake [106]. ...
Obesity represents a major public health problem with a prevalence increasing at an alarming rate worldwide. Continuous intensive efforts to elucidate the complex pathophysiology and improve clinical management have led to a better understanding of biomolecules like gut hormones, antagonists of orexigenic signals, stimulants of fat utilization, and/or inhibitors of fat absorption. In this article, we will review the pathophysiology and pharmacotherapy of obesity including intersection points to the new generation of antidiabetic drugs. We provide insight into the effectiveness of currently approved anti-obesity drugs and other therapeutic avenues that can be explored.
... PYY3-36 may act centrally by completive inhibition of NPY Y2 receptor (Y2R) on NPY neurons suppressing food intake. Decreased endogenous levels of PYY in obese subjects when compared to lean subjects (44) . Obese people have lowered PYY3-36 levels while fasting PYY3-36 levels have been elevated since gastric bypass operation and other conditions associated with reduced appetite (43) . ...
In recent decades, global obesity has increased significantly, causing a major health problem with associated complications and major socioeconomic issues. The central nervous system (CNS), particularly the hypothalamus, regulates food intake through sensing the metabolic signals of peripheral organs and modulating feeding behaviors. The hypothalamus interacts with other brain regions such as the brain stem to perform these vital functions. The gut plays a crucial role in controlling food consumption and energy homeostasis. The gut releases orexigenic and anorexigenic hormones that interact directly with the CNS or indirectly through vagal afferent neurons. Gastrointestinal peptides (GIP) including cholecystokinin, peptide YY, Nesfatin-1, glucagon-like peptide 1, and oxyntomodulin send satiety signals to the brain and ghrelin transmit hunger signals to the brain. The GIP is essential for the control of food consumption; thus, explain the link between the gastrointestinal tract (GIT) and the brain is important for managing obesity and its associated diseases. This review aimed to explain the role of gut peptides in satiety and hunger control. * العراق ، بغداد ، بغداد جامعة ، الصيدلة كلية ، السريرية المختبرية العلوم فرع. الخالصة ، األخيرة العقود في العالمية السمنة زادت بشكل كبير االجتماعية والمشاكل بها المرتبطة المضاعفات مع كبيرة صحية مشكلة في تسبب مما ، اشار استشعار طريق عن الطعام تناول تنظيم في حاسما دورا ، المهاد تحت والسيما ، المركزي العصبي الجهاز يلعب الرئيسية. واالقتصادية ات الت سلوكيات وتعديل الطرفية لألعضاء الغذائي التمثيل الحيوية. الوظائف هذه ألداء الدماغ جذع مثل الدماغ في أخرى مناطق مع المهاد يتفاعل غذية. و الغذاء استهالك في التحكم في ً حاسما ً دورا الهضمية القناة تلعب توازن مع مباشرة تتفاعل التي هرمونات الهضمية القناة تطلق الطاقة. العصبي الجهز خال من مباشر غير بشكل او المركزي. العصبية الخاليا ل البيبتيد ، البيبتيد ، كوليسيستوكينين ذلك في بما المعوية المعدية البيبتيدات 1 و الدماغ الى الشبع اشارات ترسل أوكسيتومودولين و الجلوكاجون الجوع اشارات يرسل جريلين الدماغ الى فإن ، وبالتالي الطعام. استهالك على للسيطرة ضروري األمعاء من المشتق الببتيد هرمون. شرح العالقة والدماغ الهضمي الجهاز بين مهم ت إلى المراجعة هذه تهدف بها. المرتبطة واألمراض السمنة إلدارة وضيح والسيطرة الشبع في المعوية الببتيدات دور الجوع على. المفتا الكلمات أوكسينتومودولين ، جريلين ، المعوية المعدية الببتيدات ، السمنة حية:
In healthy humans, the complex biochemical interplay between organs maintains metabolic homeostasis and pathological alterations in this process result in impaired metabolic homeostasis, causing metabolic diseases such as diabetes and obesity, which are major global healthcare burdens. The great advancements made during the last century in understanding both metabolic disease phenotypes and the regulation of metabolic homeostasis in healthy individuals have yielded new therapeutic options for diseases like type 2 diabetes (T2D). However, it is unlikely that highly desirable more efficacious treatments will be developed for metabolic disorders until the complex systemic regulation of metabolic homeostasis becomes more intricately understood. Hormones produced by pancreatic islet beta-cells (insulin) and alpha-cells (glucagon) are pivotal for maintaining metabolic homeostasis; the activity of insulin and glucagon are reciprocally correlated to achieve strict control of glucose levels (normoglycaemia). Metabolic hormones produced by other pancreatic islet cells and incretins produced by the gut are also crucial for maintaining metabolic homeostasis. Recent studies highlighted the incomplete understanding of metabolic hormonal synergism and, therefore, further elucidation of this will likely lead to more efficacious treatments for diseases such as T2D. The objective of this review is to summarise the systemic actions of the incretins and the metabolic hormones produced by the pancreatic islets and their interactions with their respective receptors.
Pancreatic polypeptide (PP) is a postprandial hormone secreted from pancreatic islets that activates neuropeptide Y4 receptors (NPY4Rs). PP is known to induce satiety but effects at the level of the endocrine pancreas are less well characterized. In addition, rapid metabolism of PP by dipeptidyl peptidase‐4 (DPP‐4) limits the investigation of the effects of the native peptide. Therefore, in the present study, five novel amino acid substituted and/or fatty acid derivatized PP analogs were synthesized, namely [P ³ ]PP, [K ¹³ Pal]PP, [P ³ ,K ¹³ Pal]PP, [N‐Pal]PP, and [N‐Pal,P ³ ]PP, and their impact on pancreatic beta‐cell function, as well as appetite regulation and glucose homeostasis investigated. All PP analogs displayed increased resistance to DPP‐4 degradation. In addition, all peptides inhibited alanine‐induced insulin secretion from BRIN‐BD11 beta cells. Native PP and related analogs (10 ⁻⁸ and 10 ⁻⁶ M), and especially [P ³ ]PP and [K ¹³ Pal]PP, significantly protected against cytokine‐induced beta‐cell apoptosis and promoted cellular proliferation, with effects dependent on the NPY4R for all peptides barring [N‐Pal,P ³ ]PP. In mice, all peptides, except [N‐Pal]PP and [N‐Pal,P ³ ]PP, evoked a dose‐dependent (25, 75, and 200 nmol/kg) suppression of appetite, with native PP and [P ³ ]PP further augmenting glucagon‐like peptide‐1 (GLP‐1) and cholecystokinin (CCK) induced reductions of food intake. The PP peptides had no obvious detrimental effect on glucose tolerance and they did not noticeably impair the glucose‐regulatory actions of GLP‐1 or CCK. In conclusion, Pro ³ amino acid substitution of PP, either alone or together with mid‐chain acylation, creates PP analogs with benefits on beta‐cell rest, islet cell turnover, and energy regulation that may be applicable to the treatment of diabetes and obesity.
Citation: Clemente-Suárez, V.J.; Peris-Ramos, H.C.; Redondo-Flórez, L.; Beltrán-Velasco, A.I.; Martín-Rodríguez, A.; David-Fernandez, S.; Yáñez-Sepúlveda, R.; Tornero-Aguilera, J.F. Personalizing Abstract: In recent years, although life expectancy has increased significantly, non-communicable diseases (NCDs) continue to pose a significant threat to the health of the global population. Therefore, eating habits have been recognized as key modifiable factors that influence people's health and well-being. For this reason, it is interesting to study dietary patterns, since the human diet is a complex mixture of macronutrients, micronutrients, and bioactive compounds, and can modulate multiple physiological processes, including immune function, the metabolism, and inflammation. To ensure that the data we acquired were current and relevant, we searched primary and secondary sources, including scientific journals, bibliographic indexes, and databases in the last 15 years with the most relevant articles. After this search, we observed that all the recent research on NCDs suggests that diet is a critical factor in shaping an individual's health outcomes. Thus, cardiovascular, metabolic, mental, dental, and visual health depends largely on the intake, habits and patterns, and nutritional behaviors. A diet high in processed and refined foods, added sugars, and saturated fats can increase the risk of developing chronic diseases. On the other hand, a diet rich in whole, nutrient-dense foods, such as vegetables, fruits, nuts, legumes, and a high adherence to Mediterranean diet can improve health's people.
Since hypothalamic obesity (HyOb) was first described over 120 years ago by Joseph Babinski and Alfred Fröhlich, advances in molecular genetic laboratory techniques have allowed us to elucidate various components of the intricate neurocircuitry governing appetite and weight regulation connecting the hypothalamus, pituitary gland, brainstem, adipose tissue, pancreas, and gastrointestinal tract. On a background of an increasing prevalence of population-level common obesity, the number of survivors of congenital (eg, septo-optic dysplasia, Prader–Willi syndrome) and acquired (eg, central nervous system tumors) hypothalamic disorders is increasing, thanks to earlier diagnosis and management as well as better oncological therapies. Although to date the discovery of several appetite-regulating peptides has led to the development of a range of targeted molecular therapies for monogenic obesity syndromes, outside of these disorders these discoveries have not translated into the development of efficacious treatments for other forms of HyOb. This review aims to summarize our current understanding of the neuroendocrine physiology of appetite and weight regulation, and explore our current understanding of the pathophysiology of HyOb.
Positive allosteric modulators targeting the Y4 receptor (Y4R), a G protein-coupled receptor (GPCR) involved in the regulation of satiety, offer great potential in anti-obesity research. In this study, we selected 603 compounds by using quantitative structure-activity relationship (QSAR) models and tested them in high-throughput screening (HTS). Here, the novel positive allosteric modulator (PAM) VU0506013 was identified, which exhibits nanomolar affinity and pronounced selectivity toward the Y4R in engineered cell lines and mouse descending colon mucosa natively expressing the Y4R. Based on this lead structure, we conducted a systematic SAR study in two regions of the scaffold and presented a series of 27 analogues with modifications in the N- and C-terminal heterocycles of the molecule to obtain insight into functionally relevant positions. By mutagenesis and computational docking, we present a potential binding mode of VU0506013 in the transmembrane core of the Y4R. VU0506013 presents a promising scaffold for developing in vivo tools to move toward anti-obesity drug research focused on the Y4R.
Traditionally, adipose tissue was perceived as a storage depot for excess energy. However, recently, it has been recognized to act as a highly dynamic endocrine organ that is involved in the regulation of insulin sensitivity, glucose and lipid metabolism, as well as cardiovascular homeostasis. Adiponectin is the most abundant circulating adipocytokine, principally secreted from adipose tissue. This adipocytokine plays a crucial role in the endocrine functions of adipose tissue and in obesity-associated disorders. Additionally, it exerts pleiotropic beneficial effects such as insulin-sensitizing, anti-inflammatory, anti-atherosclerotic, and cardioprotective properties. Herein are discussed adiponectin’s relationship with cardiovascular risk factors (including insulin resistance and type 2 diabetes mellitus, hypertension, dyslipidemia, and cigarette smoking), as well as its role in atherosclerotic and cardiac-related disorders. Therapeutic strategies to modulate adiponectin and its receptor pathway are also explored. Gut-proglucagon-derived peptides are also briefly introduced as essential molecules in the regulation of glucose and energy metabolism.KeywordsAdiponectinAdipose tissueGut-proglucagon-derived peptidesCardiovascularAtherosclerosisAdipocytokine
Glucose homeostasis is the maintenance and regulation of blood glucose concentration within a tight physiological range, essential for the functioning of most
tissues and organs. This is primarily achieved by pancreatic secretion of insulin
and glucagon. Deficient pancreatic endocrine function, coupled with or without
peripheral insulin resistance leads to prolonged hyperglycemia with chronic impairment of glucose homeostasis, most commonly seen in diabetes mellitus. High
protein diets (HPDs) are thought to modulate glucose homeostasis through various metabolic pathways. Insulin secretion can be directly modulated by the amino
acid products of protein digestion, which activate nutrient receptors and nutrient
transporters expressed by the endocrine pancreas. Insulin secretion can also be
modulated indirectly, through incretin release from enteroendocrine cells, and
via vagal neuronal pathways. Additionally, glucose homeostasis can be promoted
by the satiating effects of anorectic hormones released following HPD consumption. This review summarizes the insulinotropic mechanisms by which amino
acids and HPDs may influence glucose homeostasis, with a particular focus on
their applicability in the management of Type 2 diabetes mellitus.
This book, edited by two innovative leaders in the field, focuses on the new discipline of translational medicine as it pertains to drug development within the pharmaceutical and biotechnology industry. Translational medicine seeks to translate biological and molecular knowledge of disease and how drugs work into innovative development strategies that reduce the cost and increase the speed of delivering new medicines for patients. This book outlines general strategies, biomarker development, imaging tools, translational human models and examples of their application to real drug development. The latest thinking is presented by researchers from many of the world's leading drug development companies, including Pfizer, Merck, Eli Lilly, Abbott and Novartis, as well as academic institutions and public-private partnerships that support translational research. This book is essential for anyone interested in translational medicine from a variety of backgrounds: university institutes, medical schools, pharmaceutical companies and drug development researchers and decision-makers.
This book, edited by two innovative leaders in the field, focuses on the new discipline of translational medicine as it pertains to drug development within the pharmaceutical and biotechnology industry. Translational medicine seeks to translate biological and molecular knowledge of disease and how drugs work into innovative development strategies that reduce the cost and increase the speed of delivering new medicines for patients. This book outlines general strategies, biomarker development, imaging tools, translational human models and examples of their application to real drug development. The latest thinking is presented by researchers from many of the world's leading drug development companies, including Pfizer, Merck, Eli Lilly, Abbott and Novartis, as well as academic institutions and public-private partnerships that support translational research. This book is essential for anyone interested in translational medicine from a variety of backgrounds: university institutes, medical schools, pharmaceutical companies and drug development researchers and decision-makers.
Metabolic syndrome is a cluster of risk factors for cardiovascular disease afflicting more than 1 billion people worldwide and is increasingly being identified in younger age groups and in socioeconomically disadvantaged settings in the global south. Enteropathogen exposure and environmental enteropathy in infancy may contribute to metabolic syndrome by disrupting the metabolic profile in a way that is detectable in cardiometabolic markers later in childhood. A total of 217 subjects previously enrolled in a birth cohort in Amazonian Peru were monitored annually from ages 2 to 5 years. A total of 197 blood samples collected in later childhood were analyzed for 37 cardiometabolic biomarkers, including adipokines, apolipoproteins, cytokines, which were matched to extant early-life markers of enteropathy ascertained between birth and 2 years. Multivariate and multivariable regression models were fitted to test for associations, adjusting for confounders. Fecal and urinary markers of intestinal permeability and inflammation (myeloperoxidase, lactulose, and mannitol) measured in infancy were associated with later serum concentrations of soluble CD40-ligand, a proinflammatory cytokine correlated with adverse metabolic outcomes. Fecal myeloperoxidase was also associated with later levels of omentin-1. Enteric protozoa exposure showed stronger associations with later cardiometabolic markers than viruses, bacteria, and overall diarrheal episodes. Early-life enteropathy markers were associated with altered adipokine, apolipoprotein, and cytokine profiles later in childhood consistent with an adverse cardiometabolic disease risk profile in this cohort. Markers of intestinal permeability and inflammation measured in urine (lactulose, mannitol) and stool (myeloperoxidase, protozoal infections) during infancy may predict metabolic syndrome in adulthood.
Hunger und Sättigung werden vorrangig über peptiderge Transmitter vermittelt, die im Gastrointestinaltrakt gebildet werden und über die Darm-Gehirn-Achse ihre Wirkung entfalten. Während eine Vielzahl von anorexigenen (die Nahrungsaufnahme hemmenden) Botenstoffe bekannt ist, gibt es derzeit nur einen bekannten peripher produzierten und zentral wirksamen orexigenen (die Nahrungsaufnahme stimulierenden) Botenstoff. Interessanterweise wird mittlerweile auch das Darm-Mikrobiom als wichtiger Regulator von Hunger und Sättigung gesehen. Das peptiderge Signalmuster ist unter den Bedingungen der Adipositas deutlich verändert. Bariatrische Chirurgie kann einige dieser Veränderungen beeinflussen, dies wird maßgeblich mit dem Erfolg der Methode in Zusammenhang gebracht. Das Kapitel gibt einen Überblick über entsprechende Kompensations- und Adaptationsmechanismen, zeigt aber auch bestehende Lücken in unserem Verständnis zu diesen Regelkreisen auf.
Sacubitril/valsartan is a first-in-class Angiotensin Receptor-Neprilysin inhibitor (ARNi) to be approved for the treatment of heart failure with reduced ejection fraction (HFrEF). The combination tablet has become a mainstay of treatment in the management of heart failure (HF) due to its composite inhibition of the neurohumoral system. There is growing support to show that sacubitril/valsartan may enhance glycaemic control through the augmentation of neprilysin substrates – in particular, glucagon-like peptide 1 (GLP-1). Given that HF and Diabetes Mellitus (DM) frequently coexist, with 44% of patients hospitalised with heart failure also having diabetes as a co-morbidity, it is plausible that sacubitril/valsartan may represent a novel way to address glucose intolerance in HF. However, the role of neprilysin in the degradation of GLP-1 raises important clinical considerations such as the risk of hypoglycaemia and potential drug-drug interactions in patients with and without concurrent DM. We review the current body of research addressing the effect of neprilysin inhibition on GLP-1 receptor signalling and discuss the implications for treatment of HF and DM.
Neuropeptide Y (NPY) is a vastly studied biological peptide with numerous physiological functions that activate the NPY receptor family (Y1, Y2, Y4 and Y5). Moreover, these receptors are correlated with the pathophysiology of several diseases such as feeding disorders, anxiety, metabolic diseases, neurodegenerative diseases, some types of cancers and others. In order to deepen the knowledge of NPY receptors’ functions and molecular mechanisms, neuroimaging techniques such as positron emission tomography (PET) have been used. The development of new radiotracers for the different NPY receptors and their subsequent PET studies have led to significant insights into molecular mechanisms involving NPY receptors. This article provides a systematic review of the imaging biomarkers that have been developed as PET tracers in order to study the NPY receptor family.
Polycystic ovary syndrome (PCOS) is one of the most common reproductive health problems of women, causing irregular periods and potential infertility amongst other challenging symptoms. Effective treatment remains a significant challenge and is largely achieved through hormonal medication and lifestyle changes. This third edition covers the aetiology, pathology, impact on fertility and effective medical and surgical management. The content has been thoroughly revised in line with updated guidelines and research developments in the field. A new chapter on the patient's perspective has been included, bringing valuable insight into the lived experience of the condition. Mood disorders and the psychological aspects of PCOS are also covered for the first time. This is a key reference for all clinicians involved in the care of patients with PCOS, including gynaecologists, IVF specialists and reproductive endocrinologists.
Objective:
The aim of this study was to determine whether the hormone changes following weight loss are proportional to the degree of weight loss and to starting BMI.
Methods:
A very low-energy diet was used to achieve 15% weight loss. Fasting and postprandial gut hormones and leptin were measured during a meal test at baseline and at 5% (1%), 10% (2%), and 15% (2.5%) weight loss. Linear mixed-effects models were used to analyze hormone changes.
Results:
From baseline to 5% weight loss, decreases were seen in fasting concentrations of leptin (-8.25 ng/mL; p < 0.001), amylin (-21.3 pg/mL; p < 0.001), and glucagon-like peptide 1 (-59.55 pg/mL; p < 0.001). There was a small further reduction in leptin between 5% and 15% weight loss (-1.88 ng/mL; p = 0.019) but not in glucagon-like peptide 1 and amylin. Fasting ghrelin showed a significant increase at 10% weight loss (41.64 pg/mL; p = 0.002), with a nonsignificant increase from 10% to 15% loss (26.03 pg/mL; p = 0.065). Postprandial changes in hormone levels were variable. There was no correlation between baseline weight and the degree of hormone changes.
Conclusions:
The majority of changes in fasting gut hormones and leptin occurred in early weight loss, with minor further changes up to 15% weight loss. Starting weight did not affect the degree of hormone change.
En 2019, la Fédération Internationale du Diabète a révélé que près de 500 millions de personnes étaient atteintes de diabète dans le monde. On estime que cette incidence atteindra les 700 millions de personnes en 2045. Outre, l’aspect financier de la prise en charge, le diabète est un véritable enjeu de santé publique. En effet, l’environnement hyperglycémique délétère associé au diabète est à l’origine de graves complications pouvant altérer le fonctionnement de nombreux organes tels que le cœur, le cerveau ou encore le rein. La résistance à l’insuline associée à la détérioration de la sécrétion d’insuline et à la perte de la masse cellulaire bêta pancréatique constituent les principales caractéristiques du diabète de type 2. Ainsi, afin d’améliorer la prise en charge des patients diabétiques, l’identification d’une approche thérapeutique maîtrisée permettant de protéger la masse cellulaire bêta et de favoriser la sécrétion d’insuline uniquement en réponse au glucose et ce, sans effets secondaires, apparaît idéale.Les précédents travaux du laboratoire ont identifié le PE endogène et ses dérivés synthétiques la Spadine et la Mini-Spadine comme des inhibiteurs sélectifs des canaux potassiques TREK-1 au fort potentiel antidépresseur et impliqués dans la sécrétion de sérotonine, la prolifération et la survie neuronale. Au niveau périphérique, la Spadine a été décrite in vitro et in vivo comme un peptide à l’effet incrétine comparable à celui de l’exendine-4, un antidiabétique couramment utilisé en clinique. Ainsi, à la suite de cette étude et par analogie aux effets protecteurs observés sur le neurone, nous avons émis l’hypothèse que le PE et ses dérivés pouvaient avoir un rôle bénéfique dans les mécanismes de survie de la cellule bêta pancréatique.Dans ce manuscrit, nous démontrons que le PE endogène et ses dérivés protègent les cellules bêta de l’apoptose induite par la présence chronique de l’interleukine pro-inflammatoire et diabétogène IL-1β, ainsi que d’un choc toxique aigu induit par la staurosporine. De plus, l’analyse des mécanismes intracellulaires révèle que ces peptides provoquent une augmentation de la concentration en calcium intracellulaire, activent les voies prolifératives et de survie ERK et Akt, et maintiennent l’activité du facteur transcriptionnel CREB dans un environnement délétère via un mécanisme dépendant des calmodulines kinases.Ainsi, ces travaux de thèse montrent que le PE et ses dérivés synthétiques protègent la cellule bêta pancréatique et initient des processus cellulaires vertueux par une voie de signalisation originale indépendante de la PKA, où le potentiel de membrane et le calcium occupent un rôle crucial. Ces données suggèrent le PE endogène et ses dérivés synthétiques comme une nouvelle classe de peptides protecteurs des cellules bêta pancréatiques.
The family of neuropeptide Y (NPY) receptors comprises four subtypes (Y1R, Y2R, Y4R, Y5R), which are addressed by at least three endogenous peptides, i.e., NPY, peptide YY, and pancreatic polypeptide (PP), the latter showing a preference for Y4R. A series of cyclic oligopeptidic Y4R ligands were prepared by applying a novel approach, i.e., N-terminus to arginine side-chain cyclization. Most peptides acted as Y4R partial agonists, showing up to 60-fold higher Y4R affinity compared to the linear precursor peptides. Two cyclic hexapeptides (18, 24) showed higher Y4R potency (Ca2+ aequorin assay) and, with pKi values >10, also higher Y4R affinity compared to human pancreatic polypeptide (hPP). Compounds such as 18 and 24, exhibiting considerably lower molecular weight and considerably more pronounced Y4R selectivity than PP and previously described dimeric peptidic ligands with high Y4R affinity, represent promising leads for the preparation of labeled tool compounds and might support the development of drug-like Y4R ligands.
Glucose homeostasis is maintained by the glucoregulatory hormones, glucagon, insulin and somatostatin, secreted from the islets of Langerhans. Glucagon is the body’s most important anti-hypoglycemic hormone, mobilizing glucose from glycogen stores in the liver in response to fasting, thus maintaining plasma glucose levels within healthy limits. Glucagon secretion is regulated by both circulating nutrients, hormones and neuronal inputs. Hormones that may regulate glucagon secretion include locally produced insulin and somatostatin, but also urocortin-3, amylin and pancreatic polypeptide, and from outside the pancreas glucagon-like peptide-1 and 2, peptide tyrosine tyrosine and oxyntomodulin, glucose-dependent insulinotropic polypeptide, neurotensin and ghrelin, as well as the hypothalamic hormones arginine-vasopressin and oxytocin, and calcitonin from the thyroid. Each of these hormones have distinct effects, ranging from regulating blood glucose, to regulating appetite, stomach emptying rate and intestinal motility, which makes them interesting targets for treating metabolic diseases. Awareness regarding the potential effects of the hormones on glucagon secretion is important since secretory abnormalities could manifest as hyperglycemia or even lethal hypoglycemia. Here, we review the effects of each individual hormone on glucagon secretion, their interplay, and how treatments aimed at modulating the plasma levels of these hormones may also influence glucagon secretion and glycemic control.
Type 2 diabetes and obesity are factors that may cause elevation in the insulin level in the body, possibly leading to insulin resistance. Recent studies have shown the association between insulin resistance and obesity leading to various cancer types including breast, colon, liver, kidney, pancreatic, gastric, and leukemia. The increase in bioavailable insulin-like growth factor 1 (IGF-1) and hyperinsulinemia are instrumental in the formation of tumors in insulin-resistant patients. Overproduction of reactive oxygen species is another cause of developing cancer in insulin-resistant patients as it damages the DNA that contributes to mutagenesis and carcinogenesis. The adipose tissue in diabetic and obese individuals produces high levels of inflammation in cells which promotes tumorigenesis. Hence, weight loss and preventive diabetic therapies offer protective interventions in the development of cancers. In this chapter, we examined the interrelationship between obesity, diabetes, and the mechanism linking to cancer development and also the potential treatment recommendations that may help in controlling cancer.
A simple and reliable radioimmunoassay has been developed for a new gut hormone, HPP. In the primate 93% of the total PP was found in the pancreas with a small amount throughout the remaining gastrointestinal tract. HPP has been shown to be produced by a number of pancreatic apudomas and their metastases. The immunoreactive PP from these tumours and from normal pancreas was chromatographically indistinguishable from the pure peptide. The plasma PP concentration rose rapidly after a meal in normal subjects and was still raised six hours later. Fasting plasma PP levels in patients with PP cell containing pancreatic endocrine tumours were higher than even the postprandial level in normal subjects. PP measurements is thus useful in diagnosis of pancreatic endocrine tumours.
Although subjective appetite scores are widely used, studies on the reproducibility of this method are scarce. In the present study nine healthy, normal weight, young men recorded their subjective appetite sensations before and during 5 h after two different test meals A and B. The subjects tested each meal twice and in randomized order. Visual analogue scale (VAS) scores, 10 cm in length, were used to assess hunger, satiety, fullness, prospective food consumption and palatability of the meals. Plasma glucose and lactate concentrations were determined concomitantly. The repeatability was investigated for fasting values, delta-mean 5 h and mean 5 h values, delta-peak/nadir and peak/nadir values. Although the profiles of the postprandial responses were similar, the coefficients of repeatability (CR = 2SD) on the mean differences were large, ranging from 2.86 to 5.24 cm for fasting scores, 1.36 to 1.88 cm for mean scores, 2.98 to 5.42 cm for delta-mean scores, and 3.16 to 6.44 cm for peak and delta-peak scores. For palatability ratings the CR values varied more, ranging from 2.38 (taste) to 8.70 cm (aftertaste). Part of the difference in satiety ratings could be explained by the differences in palatability ratings. However, the low reproducibility may also be caused by a conditioned satiation or hunger due to the subjects' prior experience of the meals and therefore not just be a reflection of random noise. It is likely, however, that the variation in appetite ratings is due both to methodological day-to-day variation and to biological day-to-day variation in subjective appetite sensations.
This study was designed to investigate the effects of synthetic mouse pancreatic polypeptide (mPP) on feeding and anxiety in mice. The intracerebroventricular (ICV) injection of mPP (0.003–3 nmol) dose-dependently increased food intake. A significant increase was observed 20 min after ICV injection and continued for 4 h. The intraperitoneal (IP) injection of mPP (0.03–30 nmol) dose-dependently decreased food intake. A significant decrease was observed 20 min after IP injection and continued for 4 h. In the elevated plus maze test, the ICV injection of mPP (0.003–3 nmol) did not affect anxiety behavior. These results suggest that mPP modulates food intake and the Y4 receptor in the brain may contribute to the regulation of feeding, whereas appearing not to influence anxiety in mice.
Pancreatic polypeptide (PP) may function as a regulator of satiety. Its secretion is impaired in certain animal models of obesity and the administration of PP may improve the hyperphagia and hyperinsulinism seen in these animals. In obese humans, decreased, normal or increased, basal and stimulated concentrations of PP in plasma have been reported. However the advent of diabetes confounds the picture since PP levels in diabetes are generally raised. We have therefore examined the PP responses to intravenous secretin, a known PP secretagogue, in 23 obese subjects, 12 with normal and 11 with abnormal glucose tolerance, and compared the results with those in 23 age and sex-matched healthy controls. The mean maximum PP level in obese subjects with normal glucose tolerance (98 +/- 13 pg/ml) was significantly less than that in normal subjects (218 +/- 23 pg/ml) but in obese subjects with abnormal glucose tolerance, it was significantly greater (578 +/- 115 pg/ml). Within each of the 3 study groups taken separately, PP response to secretin was not correlated with glucose or insulin levels, or with the degree of obesity. Thus, obesity per se appears to be associated with impaired PP responses, which may be masked by abnormalities in glucose tolerance.
Bovine pancreatic polypeptide (PP) was infused intravenously in 5 healthy subjects on two separate occasions with mean doses of 1 and 2 pmol kg-1 min-1, respectively, which achieved plasma levels equal to and twice those observed after a normal mixed breakfast. The gastric emptying rate of a carbohydrate-rich breakfast 20 min after the start of each PP infusion was not significantly different from a control infusion of 0.15 M saline. PP is unlikely to be an important physiological modulator of gastric emptying rate in man.
The present study examined the effect of pancreatic polypeptide (PP) on gastric acid secretion. A 45-min infusion of PP was delivered into the jugular vein of urethan-anesthetized rats. Rat PP (100 pmol) significantly increased acid secretion over baseline; bilateral cervical vagotomy or peripheral atropine both eliminated this acid response. Neither intraperitoneal infusion nor close intra-arterial infusion of 100 pmol PP into the gastric circulation altered acid secretion. These results suggest that although PP requires intact vagal reflexes to stimulate acid output, it does not act on afferent or presynaptic efferent terminals of the vagus or directly within the stomach. Given that vagal reflexes consist of an afferent limb, an efferent limb, and a central relay, it may be that the target of circulating PP lies within the central nervous system. Indeed, previous studies from our laboratory have shown that microinjection of PP into the dorsal vagal complex results in long-lasting vagal-dependent elevation of gastric acid secretion.
Neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) are structurally related but functionally diverse peptides, encoded by separate genes and expressed in different tissues. Although the human NPY gene has been mapped to chromosome 7, we demonstrate here that the genes for human PYY and PP (PPY) are localized only 10 kb apart from each other on chromosome 17q21.1. The high degree of homology between the members of this gene family, both in primary sequence and exon/intron structure, suggests that the NPY and the PYY genes arose from an initial gene duplication event, with a subsequent tandem duplication of the PYY gene being responsible for duplication of the PYY gene being responsible for the creation of the PPY gene. A second weaker hybridization signal also found on chromosome 17q11 and results obtained by Southern blot analysis suggest that the entire PYY-PPY region has undergone a further duplication event.
Prader-Willi syndrome is characterized by dramatic hyperphagia and morbid obesity, and is associated with a deficiency in basal and meal-stimulated serum pancreatic polypeptide (PP) levels. Intravenous infusions of pancreatic polypeptide (90 min, 50 pmol/kg/h) restored normal serum PP levels, and a regimen of morning and afternoon PP infusions was found to significantly reduce food intake in Prader-Willi subjects. Food intake was evaluated in a 60-min free-feeding test that shows high reliability and validity. Basal food intake during saline infusions was striking (approximately 60 chicken sandwich quarters), and this intake was reduced overall by approximately 12% during PP infusions. This reduction was apparent only for female subjects, and may have reflected enhanced satiation rather than an overall suppression of food intake. No differences were apparent across subjects, in either basal food intake or the PP-related decrease in food intake, in the presence or absence of the widely recognized chromosomal marker for this syndrome [deletion of 15(q11-q13)]. More specific gene defects as recently reported in these subjects, however, suggest that the Prader-Willi syndrome may represent an important model for the study of food intake regulation.
Molecular cloning techniques have recently led to the identification of a growing number of neuropeptide Y-receptor subtypes, suggesting possible subtype-specific involvement in different physiological processes. Here we report the first study which determines and compares the mRNA expression of all four cloned functional Y-receptor subtypes (Y1, Y2, Y4 and Y5) in consecutive sections of the rat brain on a cellular level, using a uniform in situ hybridization technique. Our results demonstrate that Y-receptor subtype mRNA expression is widely distributed throughout the rat brain. Interestingly, coexpression of all four Y-receptors, at different levels, is particularly evident within the limbic system, including the hypothalamus, hippocampus, amygdala, piriform and cingulate cortices and tegmental areas, all of which are heavily involved in behaviour, emotion and homeostatic regulation. Particularly interesting is the demonstration that Y5-receptor mRNA expression always coincides with the presence of Y1-receptor mRNA (although not vice versa), possibly due to the overlapping organization and transcriptional control of their genes. However, it is also clear that several brain nuclei display preferential expression of one or a selective combination of Y-receptor subtype mRNAs. Furthermore, it is evident that there is regionalization of expression within certain loci which express all four receptor subtype mRNAs, particularly within the paraventricular and arcuate hypothalamic nuclei. Our results suggest that some of neuropeptide Y's (NPY) effects may be mediated through one particular subtype, whereas other physiological processes might require the coordinated action of different subtypes within the same or discrete areas.
Pancreatic polypeptide (PP) is produced in pancreatic islets of Langerhans and released into the circulation after ingestion of a meal. Peripherally administered PP suppresses food intake and gastric emptying. On the other hand, central administration of PP elicits food intake and gastric emptying. Therefore, PP actions on food intake may be, in part, attributable to gastric emptying. PP transgenic mice exhibit decreases in both food intake and gastric emptying rate that were clearly reversed by anti-PP antiserum. PP is an anorexigenic signal in the periphery and an orexigenic signal in the central nervous system.
Many different hormones control our weight and appetite. The discovery of another hormone, which suppresses appetite for up to 12 hours, may lead to a better understanding of this complex control system.