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American Journal of Physiology.... May 2019A large number of glucagon-like-peptide-1 (GLP-1)- and peptide-YY (PYY)-producing L cells are located in the colon, but little is known about their contribution to whole...
A large number of glucagon-like-peptide-1 (GLP-1)- and peptide-YY (PYY)-producing L cells are located in the colon, but little is known about their contribution to whole body metabolism. Since bile acids (BAs) increase GLP-1 and PYY release, and since BAs spill over from the ileum to the colon, we decided to investigate the ability of BAs to stimulate colonic GLP-1 and PYY secretion. Using isolated perfused rat/mouse colon as well as stimulation of the rat colon in vivo, we demonstrate that BAs significantly enhance secretion of GLP-1 and PYY from the colon with average increases of 3.5- and 2.9-fold, respectively. Furthermore, we find that responses depend on BA absorption followed by basolateral activation of the BA-receptor Takeda-G protein-coupled-receptor 5. Surprisingly, the apical sodium-dependent BA transporter, which serves to absorb conjugated BAs, was not required for colonic conjugated BA absorption or conjugated BA-induced peptide secretion. In conclusion, we demonstrate that BAs represent a major physiological stimulus for colonic L-cell secretion. By the use of isolated perfused rodent colon preparations we show that bile acids are potent and direct promoters of colonic glucagon-like-peptide 1 and peptide-YY secretion. The study provides convincing evidence that basolateral Takeda-G protein-coupled-receptor 5 activation is mediating the effects of bile acids in the colon and thus add to the existing literature described for L cells in the ileum.
Topics: Animals; Bile Acids and Salts; Carrier Proteins; Colon; Glucagon-Like Peptide 1; Ileum; Intestinal Absorption; L Cells; Membrane Glycoproteins; Mice; Peptide YY; Rats
PubMed: 30767682
DOI: 10.1152/ajpgi.00010.2019 -
Psychoneuroendocrinology Nov 2014Appetite hormones are directly involved in regulating satiety, energy expenditure, and food intake, and accumulating evidence suggests their involvement in regulating...
Appetite hormones are directly involved in regulating satiety, energy expenditure, and food intake, and accumulating evidence suggests their involvement in regulating reward and craving for drugs. This study investigated the ability of peptide YY (PYY) and ghrelin during the initial 24-48 h of a smoking cessation attempt to predict smoking relapse at 4 weeks. Multiple regression analysis indicated that increased PYY was associated with decreased reported craving and increased positive affect. Cox proportional hazard models showed that higher ghrelin levels predicted increased risk of smoking relapse (hazard ratio=2.06, 95% CI=1.30-3.27). These results indicate that circulating PYY may have buffering effects during the early stages of cessation while ghrelin may confer increased risk of smoking relapse. Further investigation of the links between these hormones and nicotine dependence is warranted.
Topics: Adult; Carbon Monoxide; Cotinine; Craving; Female; Ghrelin; Humans; Male; Peptide YY; Recurrence; Risk Factors; Saliva; Smoking Cessation; Substance Withdrawal Syndrome; Young Adult
PubMed: 25127083
DOI: 10.1016/j.psyneuen.2014.07.018 -
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 -
American Journal of Physiology.... Jul 2007
Topics: Animals; Eating; Gastric Emptying; Insulin Resistance; Mice; Peptide Fragments; Peptide YY; Rats; Weight Gain
PubMed: 17491108
DOI: 10.1152/ajpregu.00311.2007 -
Endocrinology Apr 2018The lipid sensor G protein-coupled receptor 119 (GPR119) is highly expressed by enteroendocrine L-cells and pancreatic β-cells that release the hormones, peptide YY...
The lipid sensor G protein-coupled receptor 119 (GPR119) is highly expressed by enteroendocrine L-cells and pancreatic β-cells that release the hormones, peptide YY (PYY) and glucagonlike peptide 1, and insulin, respectively. Endogenous oleoylethanolamide (OEA) and the dietary metabolite, 2-monoacylglycerol (2-OG), can each activate GPR119. Here, we compared mucosal responses with selective, synthetic GPR119 agonists (AR440006 and AR231453) and the lipids, OEA, 2-OG, and N-oleoyldopamine (OLDA), monitoring epithelial ion transport as a readout for L-cell activity in native mouse and human gastrointestinal (GI) mucosae. We also assessed GPR119 modulation of colonic motility in wild-type (WT), GPR119-deficient (GPR119-/-), and PYY-deficient (PYY-/-) mice. The water-soluble GPR119 agonist, AR440006 (that cannot traverse epithelial tight junctions), elicited responses, when added apically or basolaterally in mouse and human colonic mucosae. In both species, GPR119 responses were PYY, Y1 receptor mediated, and glucose dependent. AR440006 efficacy matched the GI distribution of L-cells in WT tissues but was absent from GPR119-/- tissue. OEA and 2-OG responses were significantly reduced in the GPR119-/- colon, but OLDA responses were unchanged. Alternative L-cell activation via free fatty acid receptors 1, 3, and 4 and the G protein-coupled bile acid receptor TGR5 or by the melanocortin 4 receptor, was unchanged in GPR119-/- tissues. The GPR119 agonist slowed transit in WT but not the PYY-/- colon in vitro. AR440006 (intraperitoneally) slowed WT colonic and upper-GI transit significantly in vivo. These data indicate that luminal or blood-borne GPR119 agonism can stimulate L-cell PYY release with paracrine consequences and slower motility. We suggest that this glucose-dependent L-cell response to a gut-restricted GPR119 stimulus has potential therapeutic advantage in modulating insulinotropic signaling with reduced risk of hypoglycemia.
Topics: Animals; Colon; Dopamine; Endocannabinoids; Gastrointestinal Motility; Glucose; Humans; Intestinal Mucosa; Ion Transport; Mice; Mice, Knockout; Monoglycerides; Oleic Acids; Oxadiazoles; Peptide YY; Pyrimidines; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 29471473
DOI: 10.1210/en.2017-03172 -
Clinical Endocrinology Sep 2023Peptide tyrosine tyrosine (PYY) exists as two species, PYY and PYY , with distinct effects on insulin secretion and appetite regulation. The detailed effects of...
OBJECTIVES
Peptide tyrosine tyrosine (PYY) exists as two species, PYY and PYY , with distinct effects on insulin secretion and appetite regulation. The detailed effects of bariatric surgery on PYY and PYY secretion are not known as previous studies have used nonspecific immunoassays to measure total PYY. Our objective was to characterize the effect of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on fasting and postprandial PYY and PYY secretion using a newly developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay.
DESIGN AND SUBJECTS
Observational study in 10 healthy nonobese volunteers and 30 participants with obesity who underwent RYGB (n = 24) or SG (n = 6) at the Imperial Weight Centre [NCT01945840]. Participants were studied using a standardized mixed meal test (MMT) before and 1 year after surgery. The outcome measures were PYY and PYY concentrations.
RESULTS
Presurgery, the fasting and postprandial levels of PYY and PYY were low, with minimal responses to the MMT, and these did not differ from healthy nonobese volunteers. The postprandial secretion of both PYY and PYY at 1 year was amplified after RYGB, but not SG, with the response being significantly higher in RYGB compared with SG.
CONCLUSIONS
There appears to be no difference in PYY secretion between nonobese and obese volunteers at baseline. At 1 year after surgery, RYGB, but not SG, is associated with increased postprandial secretion of PYY and PYY , which may account for long-term differences in efficacy and adverse effects between the two types of surgery.
Topics: Humans; Gastric Bypass; Peptide YY; Chromatography, Liquid; Blood Glucose; Tandem Mass Spectrometry; Obesity; Gastrectomy; Tyrosine
PubMed: 36345253
DOI: 10.1111/cen.14846 -
Toxins Jun 2020The trichothecene mycotoxins contaminate cereal grains and have been related to alimentary toxicosis resulted in emetic response. This family of mycotoxins comprises...
The trichothecene mycotoxins contaminate cereal grains and have been related to alimentary toxicosis resulted in emetic response. This family of mycotoxins comprises type A to D groups of toxic sesquiterpene chemicals. Diacetoxyscirpenol (DAS), one of the most toxic type A trichothecenes, is considered to be a potential risk for human and animal health by the European Food Safety Authority. Other type A trichothecenes, T-2 toxin and HT-2 toxin, as well as type B trichothecene deoxynivalenol (DON), have been previously demonstrated to induce emetic response in the mink, and this response has been associated with the plasma elevation of neurotransmitters peptide YY (PYY) and serotonin (5-hydroxytryptamine, 5-HT). However, it is found that not all the type A and type B trichothecenes have the capacity to induce PYY and 5-HT. It is necessary to identify the roles of these two emetogenic mediators on DAS-induced emesis. The goal of this study was to determine the emetic effect of DAS and relate this effect to PYY and 5-HT, using a mink bioassay. Briefly, minks were fasted one day before experiment and given DAS by intraperitoneally and orally dosing on the experiment day. Then, emetic episodes were calculated and blood collection was employed for PYY and 5-HT test. DAS elicited robust emetic responses that corresponded to upraised PYY and 5-HT. Blocking the neuropeptide Y2 receptor (NPY2R) diminished emesis induction by PYY and DAS. The serotonin 3 receptor (5-HT3R) inhibitor granisetron totally restrained the induction of emesis by serotonin and DAS. In conclusion, our findings demonstrate that PYY and 5-HT have critical roles in DAS-induced emetic response.
Topics: Animals; Antiemetics; Disease Models, Animal; Female; Granisetron; Mink; Peptide YY; Receptors, Gastrointestinal Hormone; Receptors, Serotonin, 5-HT3; Secretory Pathway; Serotonin; Serotonin 5-HT3 Receptor Antagonists; Trichothecenes; Up-Regulation; Vomiting
PubMed: 32630472
DOI: 10.3390/toxins12060419 -
Advances in Nutrition (Bethesda, Md.) May 2012Proteins are suspected to have a greater satiating effect than the other 2 macronutrients. After protein consumption, peptide hormones released from the gastrointestinal... (Review)
Review
Proteins are suspected to have a greater satiating effect than the other 2 macronutrients. After protein consumption, peptide hormones released from the gastrointestinal tract (mainly anorexigenic gut peptides such as cholecystokinin, glucagon peptide 1, and peptide YY) communicate information about the energy status to the brain. These hormones and vagal afferents control food intake by acting on brain regions involved in energy homeostasis such as the brainstem and the hypothalamus. In fact, a high-protein diet leads to greater activation than a normal-protein diet in the nucleus tractus solitarius and in the arcuate nucleus. More specifically, neural mechanisms triggered particularly by leucine consumption involve 2 cellular energy sensors: the mammalian target of rapamycin and AMP-activated protein kinase. In addition, reward and motivation aspects of eating behavior, controlled mainly by neurons present in limbic regions, play an important role in the reduced hedonic response of a high-protein diet. This review examines how metabolic signals emanating from the gastrointestinal tract after protein ingestion target the brain to control feeding, energy expenditure, and hormones. Understanding the functional roles of brain areas involved in the satiating effect of proteins and their interactions will demonstrate how homeostasis and reward are integrated with the signals from peripheral organs after protein consumption.
Topics: AMP-Activated Protein Kinases; Animals; Arcuate Nucleus of Hypothalamus; Cholecystokinin; Diet; Dietary Proteins; Eating; Energy Metabolism; Feeding Behavior; Gastrointestinal Tract; Glucagon-Like Peptide 1; Homeostasis; Humans; Hypothalamus; Peptide Hormones; Peptide YY; Satiation; TOR Serine-Threonine Kinases
PubMed: 22585905
DOI: 10.3945/an.112.002071 -
The Journal of Nutrition May 2023The role of fat-free mass loss (FFML) in modulating weight regain in individuals with obesity, as well as the potential mechanisms involved, remain inconsistent.
BACKGROUND
The role of fat-free mass loss (FFML) in modulating weight regain in individuals with obesity, as well as the potential mechanisms involved, remain inconsistent.
OBJECTIVES
The aim of this study was to determine if % FFML following weight loss (WL) is a predictor of weight regain and to investigate the association between %FFML and changes in appetite markers.
METHODS
Seventy individuals with obesity (BMI: 36 ± 4 kg/m; age: 44 ± 9 y; 29 males) underwent 8 wk of a very low energy diet (550-660 kcal/d), followed by 4 wk of gradual refeeding and weight stabilization and a 9-mo maintenance program (eucaloric diet). The primary outcomes were body weight and body composition (fat mass and fat-free mass). The secondary outcomes were plasma concentrations of β-hydroxybutyrate (a marker of ketosis) in fasting and appetite-related hormones (ghrelin, glucagon-like peptide 1, peptide YY, and cholecystokinin) and subjective appetite feelings during fasting and every 30 min after a fixed breakfast for 2.5 h. All were measured at baseline, week 9, and 1 y [week 13 in 35 subjects (25 males)]. The association between FFML, weight regain, and changes in appetite was assessed by linear regression.
RESULTS
WL at week 9 was 17.5 ± 4.3kg and %FFML 20.4 ± 10.6%. Weight regain at 1 y was 1.7 ± 8.2 kg (8.8 ± 45.0%). After adjusting for WL and fat mass at baseline, %FFML at week 9 was not a significant predictor of weight regain. Similar results were seen at week 13. The greater the %FFML at week 9, but not 13, the smaller the reduction, or greater the increase in basal ghrelin concentration (β: -3.2; 95% CI: -5.0, -1.1; P = 0.003), even after adjusting for WL and β-hydroxybutyrate.
CONCLUSIONS
%FFML was not a significant predictor of weight regain at 1 y in individuals with obesity. However, a greater %FFML was accompanied by a greater increase in ghrelin secretion under ketogenic conditions, suggesting a link between fat-free mass and appetite regulation. This trial was registered at clinicaltrials.gov as NCT01834859.
Topics: Male; Humans; Adult; Middle Aged; Appetite; Ghrelin; 3-Hydroxybutyric Acid; Obesity; Weight Loss; Peptide YY; Weight Gain
PubMed: 36963504
DOI: 10.1016/j.tjnut.2023.03.026 -
Molecular Metabolism Jan 2022Obesity-linked type 2 diabetes (T2D) is a worldwide health concern and many novel approaches are being considered for its treatment and subsequent prevention of serious...
Peptide-YY/glucagon-like peptide-1 combination treatment of obese diabetic mice improves insulin sensitivity associated with recovered pancreatic β-cell function and synergistic activation of discrete hypothalamic and brainstem neuronal circuitries.
OBJECTIVE
Obesity-linked type 2 diabetes (T2D) is a worldwide health concern and many novel approaches are being considered for its treatment and subsequent prevention of serious comorbidities. Co-administration of glucagon like peptide 1 (GLP-1) and peptide YY (PYY) renders a synergistic decrease in energy intake in obese men. However, mechanistic details of the synergy between these peptide agonists and their effects on metabolic homeostasis remain relatively scarce.
METHODS
In this study, we utilized long-acting analogues of GLP-1 and PYY (via Fc-peptide conjugation) to better characterize the synergistic pharmacological benefits of their co-administration on body weight and glycaemic regulation in obese and diabetic mouse models. Hyperinsulinemic-euglycemic clamps were used to measure weight-independent effects of Fc-PYY + Fc-GLP-1 on insulin action. Fluorescent light sheet microscopy analysis of whole brain was performed to assess activation of brain regions.
RESULTS
Co-administration of long-acting Fc-IgG/peptide conjugates of Fc-GLP-1 and Fc-PYY (specific for PYY receptor-2 (Y2R)) resulted in profound weight loss, restored glucose homeostasis, and recovered endogenous β-cell function in two mouse models of obese T2D. Hyperinsulinemic-euglycemic clamps in C57BLKS/J db/db and diet-induced obese Y2R-deficient (Y2RKO) mice indicated Y2R is required for a weight-independent improvement in peripheral insulin sensitivity and enhanced hepatic glycogenesis. Brain cFos staining demonstrated distinct temporal activation of regions of the hypothalamus and hindbrain following Fc-PYY + Fc-GLP-1R agonist administration.
CONCLUSIONS
These results reveal a therapeutic approach for obesity/T2D that improved insulin sensitivity and restored endogenous β-cell function. These data also highlight the potential association between the gut-brain axis in control of metabolic homeostasis.
Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet; Eating; Energy Intake; Energy Metabolism; Gastric Bypass; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypothalamus; Insulin Resistance; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Peptide YY; Weight Loss
PubMed: 34781035
DOI: 10.1016/j.molmet.2021.101392