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Science (New York, N.Y.) Aug 2023The mammalian gut secretes a family of multifunctional peptides that affect appetite, intestinal secretions, and motility whereas others regulate the microbiota. We have...
The mammalian gut secretes a family of multifunctional peptides that affect appetite, intestinal secretions, and motility whereas others regulate the microbiota. We have found that peptide YY (PYY), but not endocrine PYY, acts as an antimicrobial peptide (AMP) expressed by gut epithelial paneth cells (PC). PC-PYY is packaged into secretory granules and is secreted into and retained by surface mucus, which optimizes PC-PYY activity. Although PC-PYY shows some antibacterial activity, it displays selective antifungal activity against virulent hyphae-but not the yeast form. PC-PYY is a cationic molecule that interacts with the anionic surfaces of fungal hyphae to cause membrane disruption and transcriptional reprogramming that selects for the yeast phenotype. Hence, PC-PYY is an antifungal AMP that contributes to the maintenance of gut fungal commensalism.
Topics: Animals; Antifungal Agents; Antimicrobial Peptides; Candida; Paneth Cells; Peptide Fragments; Peptide YY; Symbiosis; Humans; Mice
PubMed: 37535745
DOI: 10.1126/science.abq3178 -
The Journal of Physiological Sciences :... Feb 2024Many hormones act on the hypothalamus to control hunger and satiety through various pathways closely associated with several factors. When food is present in the gastro... (Review)
Review
Many hormones act on the hypothalamus to control hunger and satiety through various pathways closely associated with several factors. When food is present in the gastro intestinal (GI) tract, enteroendocrine cells (EECs) emit satiety signals such as cholecystokinin (CCK), glucagon like peptide-1 (GLP-1) and peptide YY (PYY), which can then communicate with the vagus nerve to control food intake. More specifically, satiety has been shown to be particularly affected by the GLP-1 hormone and its receptor agonists that have lately been acknowledged as a promising way to reduce weight. In addition, there is increasing evidence that normal flora is also involved in the peripheral, central, and reward system that impact satiety. Moreover, neurologic pathways control satiety through neurotransmitters. In this review, we discuss the different roles of each of the GLP-1 hormone and its agonist, gut microbiomes, as well as neurotransmitters and their interconnected relation in the regulation of body's satiety homeostasis.
Topics: Cholecystokinin; Glucagon-Like Peptide 1; Peptide YY; Brain; Neurotransmitter Agents
PubMed: 38368346
DOI: 10.1186/s12576-024-00904-9 -
Physiological Reviews Jan 2017The efficacy of Roux-en-Y gastric-bypass (RYGB) and other bariatric surgeries in the management of obesity and type 2 diabetes mellitus and novel developments in... (Review)
Review
The efficacy of Roux-en-Y gastric-bypass (RYGB) and other bariatric surgeries in the management of obesity and type 2 diabetes mellitus and novel developments in gastrointestinal (GI) endocrinology have renewed interest in the roles of GI hormones in the control of eating, meal-related glycemia, and obesity. Here we review the nutrient-sensing mechanisms that control the secretion of four of these hormones, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide tyrosine tyrosine [PYY(3-36)], and their contributions to the controls of GI motor function, food intake, and meal-related increases in glycemia in healthy-weight and obese persons, as well as in RYGB patients. Their physiological roles as classical endocrine and as locally acting signals are discussed. Gastric emptying, the detection of specific digestive products by small intestinal enteroendocrine cells, and synergistic interactions among different GI loci all contribute to the secretion of ghrelin, CCK, GLP-1, and PYY(3-36). While CCK has been fully established as an endogenous endocrine control of eating in healthy-weight persons, the roles of all four hormones in eating in obese persons and following RYGB are uncertain. Similarly, only GLP-1 clearly contributes to the endocrine control of meal-related glycemia. It is likely that local signaling is involved in these hormones' actions, but methods to determine the physiological status of local signaling effects are lacking. Further research and fresh approaches are required to better understand ghrelin, CCK, GLP-1, and PYY(3-36) physiology; their roles in obesity and bariatric surgery; and their therapeutic potentials.
Topics: Blood Glucose; Cholecystokinin; Eating; Gastric Bypass; Ghrelin; Glucagon-Like Peptide 1; Humans; Obesity; Peptide Fragments; Peptide YY
PubMed: 28003328
DOI: 10.1152/physrev.00031.2014 -
Physiology & Behavior Sep 2021Food intake is tightly controlled by homeostatic signals sensitive to metabolic need for the regulation of body weight. This review focuses on the peripherally-secreted... (Review)
Review
Food intake is tightly controlled by homeostatic signals sensitive to metabolic need for the regulation of body weight. This review focuses on the peripherally-secreted gastrointestinal peptides (i.e., ghrelin, cholecystokinin, glucagon-like peptide 1, and peptide tyrosine tyrosine) that contribute to the control of appetite and discusses how these peptides or the signals arising from their release are disrupted in eating-related disorders across the weight spectrum, namely anorexia nervosa, bulimia nervosa, and obesity, and whether they are normalized following weight restoration or weight loss treatment. Further, the role of gut peptides in the pathogenesis and treatment response in human weight conditions as identified by rodent models are discussed. Lastly, we review the incretin- and hormone-based pharmacotherapies available for the treatment of obesity and eating-related disorders.
Topics: Appetite; Cholecystokinin; Eating; Ghrelin; Glucagon-Like Peptide 1; Peptide YY
PubMed: 33989649
DOI: 10.1016/j.physbeh.2021.113456 -
Diabetes Jul 2022The induction of nausea and emesis is a major barrier to maximizing the weight loss profile of obesity medications, and therefore, identifying mechanisms that improve...
The induction of nausea and emesis is a major barrier to maximizing the weight loss profile of obesity medications, and therefore, identifying mechanisms that improve tolerability could result in added therapeutic benefit. The development of peptide YY (PYY)-based approaches to treat obesity are no exception, as PYY receptor agonism is often accompanied by nausea and vomiting. Here, we sought to determine whether glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) agonism reduces PYY-induced nausea-like behavior in mice. We found that central and peripheral administration of a GIPR agonist reduced conditioned taste avoidance (CTA) without affecting hypophagia mediated by a PYY analog. The receptors for GIP and PYY (Gipr and Npy2r) were found to be expressed by the same neurons in the area postrema (AP), a brainstem nucleus involved in detecting aversive stimuli. Peripheral administration of a GIPR agonist induced neuronal activation (cFos) in the AP. Further, whole-brain cFos analyses indicated that PYY-induced CTA was associated with augmented neuronal activity in the parabrachial nucleus (PBN), a brainstem nucleus that relays aversive/emetic signals to brain regions that control feeding behavior. Importantly, GIPR agonism reduced PYY-mediated neuronal activity in the PBN, providing a potential mechanistic explanation for how GIPR agonist treatment reduces PYY-induced nausea-like behavior. Together, the results of our study indicate a novel mechanism by which GIP-based therapeutics may have benefit in improving the tolerability of weight loss agents.
Topics: Animals; Anti-Obesity Agents; Mice; Nausea; Obesity; Peptide YY; Receptors, Gastrointestinal Hormone
PubMed: 35499381
DOI: 10.2337/db21-0848 -
European Journal of Nutrition Dec 2020The gut-brain axis could be a possible key factor in the pathophysiology of anorexia nervosa. The neuropeptide peptide YY, secreted by endocrine L cells of the...
PURPOSE
The gut-brain axis could be a possible key factor in the pathophysiology of anorexia nervosa. The neuropeptide peptide YY, secreted by endocrine L cells of the gastrointestinal tract, is a known regulator of appetite and food intake. The objective of this study was to investigate peptide YY plasma concentrations at different stages of anorexia nervosa in a combined cross-sectional and longitudinal design to differentiate between effects of acute undernutrition and more enduring characteristics.
METHODS
We measured fasting plasma peptide YY concentrations in young patients with acute anorexia nervosa (n = 47) and long-term recovered patients (n = 35) cross-sectionally in comparison to healthy control participants (n = 58), and longitudinally over the course of inpatient treatment. Physical activity was controlled as it may modulate peptide YY secretion.
RESULTS
There was no group difference in peptide YY concentration among young acutely underweight anorexia nervosa patients, long-term recovered anorexia nervosa patients, and healthy control participants. Longitudinally, there was no change in peptide YY concentration after short-term weight rehabilitation. For acute anorexia nervosa patients at admission to treatment, there was a negative correlation between peptide YY concentration and body mass index.
CONCLUSIONS
The current study provides additional evidence for a normal basal PYY concentration in AN. Future studies should study multiple appetite-regulating peptides and their complex interplay and also use research designs including a food challenge.
Topics: Anorexia Nervosa; Appetite; Body Mass Index; Cross-Sectional Studies; Humans; Peptide YY; Thinness
PubMed: 32166384
DOI: 10.1007/s00394-020-02210-7 -
Gut Nov 2015The colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
The colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite regulation. We hypothesised that colonic delivery of propionate would increase peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion in humans, and reduce energy intake and weight gain in overweight adults.
DESIGN
To investigate whether propionate promotes PYY and GLP-1 secretion, a primary cultured human colonic cell model was developed. To deliver propionate specifically to the colon, we developed a novel inulin-propionate ester. An acute randomised, controlled cross-over study was used to assess the effects of this inulin-propionate ester on energy intake and plasma PYY and GLP-1 concentrations. The long-term effects of inulin-propionate ester on weight gain were subsequently assessed in a randomised, controlled 24-week study involving 60 overweight adults.
RESULTS
Propionate significantly stimulated the release of PYY and GLP-1 from human colonic cells. Acute ingestion of 10 g inulin-propionate ester significantly increased postprandial plasma PYY and GLP-1 and reduced energy intake. Over 24 weeks, 10 g/day inulin-propionate ester supplementation significantly reduced weight gain, intra-abdominal adipose tissue distribution, intrahepatocellular lipid content and prevented the deterioration in insulin sensitivity observed in the inulin-control group.
CONCLUSIONS
These data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans.
TRIAL REGISTRATION NUMBER
NCT00750438.
Topics: Adiposity; Appetite Regulation; Body Weight Maintenance; Cells, Cultured; Colon; Cross-Over Studies; Double-Blind Method; Female; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; Overweight; Peptide YY; Propionates
PubMed: 25500202
DOI: 10.1136/gutjnl-2014-307913 -
International Journal of Molecular... Jun 2023Currently available data on the involvement of neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) and their receptors (YRs) in cancer are updated.... (Review)
Review
Currently available data on the involvement of neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) and their receptors (YRs) in cancer are updated. The structure and dynamics of YRs and their intracellular signaling pathways are also studied. The roles played by these peptides in 22 different cancer types are reviewed (e.g., breast cancer, colorectal cancer, Ewing sarcoma, liver cancer, melanoma, neuroblastoma, pancreatic cancer, pheochromocytoma, and prostate cancer). YRs could be used as cancer diagnostic markers and therapeutic targets. A high Y1R expression has been correlated with lymph node metastasis, advanced stages, and perineural invasion; an increased Y5R expression with survival and tumor growth; and a high serum NPY level with relapse, metastasis, and poor survival. YRs mediate tumor cell proliferation, migration, invasion, metastasis, and angiogenesis; YR antagonists block the previous actions and promote the death of cancer cells. NPY favors tumor cell growth, migration, and metastasis and promotes angiogenesis in some tumors (e.g., breast cancer, colorectal cancer, neuroblastoma, pancreatic cancer), whereas in others it exerts an antitumor effect (e.g., cholangiocarcinoma, Ewing sarcoma, liver cancer). PYY or its fragments block tumor cell growth, migration, and invasion in breast, colorectal, esophageal, liver, pancreatic, and prostate cancer. Current data show the peptidergic system's high potential for cancer diagnosis, treatment, and support using Y2R/Y5R antagonists and NPY or PYY agonists as promising antitumor therapeutic strategies. Some important research lines to be developed in the future will also be suggested.
Topics: Male; Humans; Neuropeptide Y; Sarcoma, Ewing; Receptors, Neuropeptide Y; Neoplasm Recurrence, Local; Peptide YY; Breast Neoplasms; Neuroblastoma; Pancreatic Neoplasms; Prostatic Neoplasms; Liver Neoplasms; Colorectal Neoplasms
PubMed: 37373115
DOI: 10.3390/ijms24129962 -
British Journal of Pharmacology Dec 2017Free fatty acid receptors FFA1 and FFA4 are located on enteroendocrine L cells with the highest gastrointestinal (GI) expression in descending colon. Their activation... (Comparative Study)
Comparative Study
BACKGROUND AND PURPOSE
Free fatty acid receptors FFA1 and FFA4 are located on enteroendocrine L cells with the highest gastrointestinal (GI) expression in descending colon. Their activation causes the release of glucagon-like peptide 1 and peptide YY (PYY) from L cells. Additionally, FFA1 agonism releases insulin from pancreatic β cells. As these receptors are modulators of nutrient-stimulated glucose regulation, the aim of this study was to compare the pharmacology of commercially available agonists (TUG424, TUG891, GW9508) with proven selective agonists (JTT, TAK-875, AZ423, Metabolex-36) in mice.
EXPERIMENTAL APPROACH
Mouse mucosa was mounted in Ussing chambers, voltage-clamped and the resultant short-circuit current (I ) was recorded continuously. Pretreatments included antagonists of FFA1, Y or Y receptors. Glucose sensitivity was investigated by mannitol replacement apically, and colonic and upper GI transit was assessed in vitro and in vivo.
KEY RESULTS
FFA1 and FFA4 agonism required glucose and reduced I in a PYY-Y receptor-dependent manner. The novel compounds were more potent than GW9508. The FFA1 antagonists (GW1100 and ANT825) blocked FFA1 activity only and revealed FFA1 tonic activity. The FFA4 agonist, Metabolex-36, slowed colonic transit in vitro but increased small intestinal transit in vivo.
CONCLUSIONS AND IMPLICATIONS
The selective FFA1 and FFA4 agonists were more potent at reducing I than GW9508, a dual FFA1 and FFA4 agonist. A paracrine epithelial mechanism involving PYY-stimulated Y receptors mediated their responses, which were glucose sensitive, potentially limiting hypoglycaemia. ANT825 revealed tonic activity and the possibility of endogenous FFA1 ligands causing PYY release. Finally, FFA4 agonism induced regional differences in transit.
Topics: Animals; Biphenyl Compounds; Colon; Female; Glucose; Intestinal Mucosa; Male; Methylamines; Mice; Mice, Inbred C57BL; Patch-Clamp Techniques; Peptide YY; Phenylpropionates; Propionates; Receptors, G-Protein-Coupled
PubMed: 28971469
DOI: 10.1111/bph.14054 -
Physiology & Behavior Nov 2011Peptidergic and neural signals arising from the presence of food in the gastrointestinal track provide feedback signals to the brain about the nature and quantity of... (Review)
Review
Peptidergic and neural signals arising from the presence of food in the gastrointestinal track provide feedback signals to the brain about the nature and quantity of consumed nutrients. Peptide secreting cells are differentially distributed along the gastrointestinal tract. How ingested nutrients activate or inhibit peptide secretion is complex and depends upon local, hormonal and neural mechanisms. The mode of action of the various peptides is equally complex involving endocrine, paracrine and neurocrine signaling. The success of bariatric surgical approaches to obesity treatment is secondary to alterations in gastrointestinal feedback signaling and roles of increased secretion of lower gut peptides such as peptide YY (PYY) and glucagon like peptide 1 (GLP-1) in mediating the superior effects of Roux-en-Y gastric bypass (RYGB) surgery are becoming evident. Direct nutrient delivery to jejunal sites that models the site of gastric-jejunal anastamosis in RYGB is especially effective at inhibiting food intake. Such infusions also stimulate the release of lower gut peptides suggesting a role for increased gut peptide signaling in sustaining such feeding inhibitions. Thus, gut peptides are clear targets for future obesity therapeutic developments.
Topics: Animals; Cholecystokinin; Feedback, Physiological; Ghrelin; Glucagon-Like Peptide 1; Humans; Intestines; Peptide YY; Satiation
PubMed: 21315751
DOI: 10.1016/j.physbeh.2011.02.005