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We recently reported that a novel chimeric peptide (GEP44) targeting both the glucagon-like peptide-1 receptor (GLP-1R) and neuropeptide Y1- and Y2 receptor (Y1R and Y2R) reduced energy intake and body weight (BW) in diet-induced obese (DIO) rats. We hypothesized that GEP44 reduces energy intake and BW primarily through a GLP-1R dependent mechanism. To test this hypothesis, GLP-1R+/+ mice and GLP-1R null (GLP-1R-/-) mice were fed a high fat diet for 4 months to elicit diet-induced obesity prior to undergoing a sequential 3-day vehicle period, 3-day drug treatment (5, 10, 20 or 50 nmol/kg; GEP44 vs the selective GLP-1R agonist, exendin-4) and a 3-day washout. Energy intake, BW, core temperature and activity were measured daily. GEP44 (10, 20 and 50 nmol/kg) reduced BW after 3-day treatment in DIO male GLP-1R+/+ mice by -1.5 ± 0.6, -1.3 ± 0.4 and -1.9 ± 0.4 grams, respectively (P<0.05), with similar effects being observed in female GLP-1R+/+ mice. These effects were absent in male and female DIO GLP-1R-/- mice suggesting that GLP-1R signaling contributes to GEP44-elicited reduction of BW. Further, GEP44 decreased energy intake in both male and female DIO GLP-1R+/+ mice, but GEP44 appeared to produce more consistent effects across multiple doses in males. In GLP-1R-/- mice, the effects of GEP44 on energy intake were only observed in males and not females, suggesting that GEP44 may reduce energy intake, in part, through a GLP-1R independent mechanism in males. In addition, GEP44 reduced core temperature and activity in both male and female GLP-1R+/+ mice suggesting that it may also reduce energy expenditure. Lastly, we show that GEP44 reduced fasting blood glucose in DIO male and female mice through GLP-1R. Together, these findings support the hypothesis that the chimeric peptide, GEP44, reduces energy intake, BW, core temperature, and glucose levels in male and female DIO mice primarily through a GLP-1R dependent mechanism.
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Peso Corporal , Dieta Alta en Grasa , Ingestión de Energía , Receptor del Péptido 1 Similar al Glucagón , Ratones Obesos , Obesidad , Animales , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Femenino , Masculino , Ratones , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Dieta Alta en Grasa/efectos adversos , Ingestión de Energía/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Ratones Noqueados , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Gut L-type enteroendocrine cells (EECs) are intestinal chemosensory cells that secrete satiety hormones GLP-1 and PYY in response to activation of G-protein coupled receptors (GPCRs) by luminal components of nutrient digestion and microbial fermentation. Regulator of G-protein Signaling (RGS) proteins are negative regulators of GPCR signaling. The expression profile of RGS in EECs, and their potential role in satiety hormone secretion and obesity is unknown. METHODS: Transcriptomic profiling of RGS was completed in native colonic EECs was completed using single-cell RNA sequencing (scRNA-Seq) in lean and obesity, and human jejunal EECs with data obtained from a publicly available RNAseq dataset (GSE114853). RGS validation studies were completed using whole mucosal intestinal tissue obtained during endoscopy in 61 patients (n = 42 OB, n = 19 Lean); a subset of patients' postprandial plasma was assayed for GLP-1 and PYY. Ex vivo human intestinal cultures and in vitro NCI-H716 cells overexpressing RGS9 were exposed to GLP-1 secretagogues in conjunction with a nonselective RGS-inhibitor and assayed for GLP-1 secretion. FINDINGS: Transcriptomic profiling of colonic and jejunal enteroendocrine cells revealed a unique RGS expression profile in EECs, and further within GLP-1+ L-type EECs. In obesity the RGS expression profile was altered in colonic EECs. Human gut RGS9 expression correlated positively with BMI and negatively with postprandial GLP-1 and PYY. RGS inhibition in human intestinal cultures increased GLP-1 release from EECs ex vivo. NCI-H716 cells overexpressing RGS9 displayed defective nutrient-stimulated GLP-1 secretion. INTERPRETATION: This study introduces the expression profile of RGS in human EECs, alterations in obesity, and suggests a role for RGS proteins as modulators of GLP-1 and PYY secretion from intestinal EECs. FUNDING: AA is supported by the NIH(C-Sig P30DK84567, K23 DK114460), a Pilot Award from the Mayo Clinic Center for Biomedical Discovery, and a Translational Product Development Fund from The Mayo Clinic Center for Clinical and Translational Science Office of Translational Practice in partnership with the University of Minnesota Clinical and Translational Science Institute.
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Evaluation of weight loss drugs is usually performed in diet-induced obese mice housed at â¼22°C. This is a cold stress that increases energy expenditure by â¼35% compared to thermoneutrality (â¼30°C), which may overestimate drug-induced weight loss. We investigated five anti-obesity mechanisms that have been in clinical development, comparing weight loss in mice housed at 22°C vs. 30°C. Glucagon-like peptide-1 (GLP-1), human fibroblast growth factor 21 (hFGF21), and melanocortin-4 receptor (MC4R) agonist induced similar weight losses. Peptide YY elicited greater vehicle-subtracted weight loss at 30°C (7.2% vs. 1.4%), whereas growth differentiation factor 15 (GDF15) was more effective at 22°C (13% vs. 6%). Independent of ambient temperature, GLP-1 and hFGF21 prevented the reduction in metabolic rate caused by weight loss. There was no simple rule for a better prediction of human drug efficacy based on ambient temperature, but since humans live at thermoneutrality, drug testing using mice should include experiments near thermoneutrality.
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Dietary restriction slows aging in many animals, while in some cases the sensory signals from diet alone are sufficient to retard or accelerate lifespan. The digestive tract is a candidate location to sense nutrients, where neuropeptides secreted by enteroendocrine cells (EEC) produce systemic signals in response to food. Here we measure how Drosophila neuropeptide F (NPF) is secreted into adult circulation by enteroendocrine cells and find that specific enteroendocrine cells differentially respond to dietary sugar and yeast. Lifespan is increased when gut NPF is genetically depleted, and this manipulation is sufficient to blunt the longevity benefit conferred by dietary restriction. Depletion of NPF receptors at insulin producing neurons of the brain also increases lifespan, consistent with observations where loss of gut NPF decreases neuronal insulin secretion. The longevity conferred by repressing gut NPF and brain NPF receptors is reversed by treating adults with a juvenile hormone (JH) analog. JH is produced by the adult corpora allata, and inhibition of the insulin receptor at this tissue decreases JH titer and extends lifespan, while this longevity is restored to wild type by treating adults with a JH analog. Overall, enteroendocrine cells of the gut modulate Drosophila aging through interorgan communication mediated by a gut-brain-corpora allata axis, and insulin produced in the brain impacts lifespan through its control of JH titer. These data suggest that we should consider how human incretins and their analogs, which are used to treat obesity and diabetes, may impact aging.
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The consumption of protein-rich foods stimulates satiety more than other macronutrient-rich foods; however, the underlying mechanisms-of-action are not well-characterized. The objective of this study was to identify the direct and indirect effects of postprandial amino acid (AA) responses on satiety. Seventeen women (mean ± SEM, age: 33 ± 1 year; BMI: 27.8 ± 0.1 kg/m2) consumed a eucaloric, plant-based diet containing two servings of lean beef/day (i.e., 7.5 oz (207 g)) for 7 days. During day 6, the participants completed a 12 h controlled-feeding, clinical testing day including repeated satiety questionnaires and blood sampling to assess pre- and postprandial plasma AAs, PYY, and GLP-1. Regression and mediation analyses were completed to assess AA predictors and hormonal mediators. Total plasma AAs explained 41.1% of the variance in perceived daily fullness (p < 0.001), 61.0% in PYY (p < 0.001), and 66.1% in GLP-1 (p < 0.001) concentrations, respectively. Several individual AAs significantly predicted fluctuations in daily fullness, PYY, and GLP-1. In completing mediation analyses, the effect of plasma leucine on daily fullness was fully mediated by circulating PYY concentrations (indirect effect = B: 0.09 [Boot 95% CI: 0.032, 0.17]) as no leucine-fullness direct effect was observed. No other mediators were identified. Although a number of circulating AAs predict satiety, leucine was found to do so through changes in PYY concentrations in middle-aged women.
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Aminoácidos , Sobrepeso , Péptido YY , Periodo Posprandial , Carne Roja , Saciedad , Humanos , Femenino , Adulto , Aminoácidos/sangre , Péptido YY/sangre , Saciedad/efectos de los fármacos , Sobrepeso/sangre , Péptido 1 Similar al Glucagón/sangre , Biomarcadores/sangre , Comidas , Animales , Bovinos , Respuesta de Saciedad/efectos de los fármacosRESUMEN
The approval of the glucagon-like peptide 1 (GLP-1) mimetics semaglutide and liraglutide for management of obesity, independent of type 2 diabetes (T2DM), has initiated a resurgence of interest in gut-hormone derived peptide therapies for the management of metabolic diseases, but side-effect profile is a concern for these medicines. However, the recent approval of tirzepatide for obesity and T2DM, a glucose-dependent insulinotropic polypeptide (GIP), GLP-1 receptor co-agonist peptide therapy, may provide a somewhat more tolerable option. Despite this, an increasing number of non-incretin alternative peptides are in development for obesity, and it stands to reason that other hormones will take to the limelight in the coming years, such as peptides from the neuropeptide Y family. This narrative review outlines the therapeutic promise of the neuropeptide Y family of peptides, comprising of the 36 amino acid polypeptides neuropeptide Y (NPY), peptide tyrosine-tyrosine (PYY) and pancreatic polypeptide (PP), as well as their derivatives. This family of peptides exerts a number of metabolically relevant effects such as appetite regulation and can influence pancreatic beta-cell survival. Although some of these actions still require full translation to the human setting, potential therapeutic application in obesity and type 2 diabetes is conceivable. However, like GLP-1 and GIP, the endogenous NPY, PYY and PP peptide forms are subject to rapid in vivo degradation and inactivation by the serine peptidase, dipeptidyl-peptidase 4 (DPP-4), and hence require structural modification to prolong circulating half-life. Numerous protective modification strategies are discussed in this regard herein, alongside related impact on biological activity profile and therapeutic promise.
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Diabetes Mellitus Tipo 2 , Neuropéptido Y , Obesidad , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Neuropéptido Y/metabolismo , Animales , Péptidos Similares al Glucagón/uso terapéutico , Liraglutida/uso terapéutico , Liraglutida/farmacología , Polipéptido Pancreático/metabolismo , Péptido YY/metabolismo , Péptido YY/uso terapéutico , Polipéptido Inhibidor Gástrico/uso terapéutico , Polipéptido Inhibidor Gástrico/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Péptido 1 Similar al Glucagón/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Receptor del Péptido 2 Similar al GlucagónRESUMEN
Bone is a highly dynamic organ that changes with the daily circadian rhythm. During the day, bone resorption is suppressed due to eating, while it increases at night. This circadian rhythm of the skeleton is regulated by gut hormones. Until now, gut hormones that have been found to affect skeletal homeostasis include glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucose-dependent insulinotropic polypeptide (GIP), and peptide YY (PYY), which exerts its effects by binding to its cognate receptors (GLP-1R, GLP-2R, GIPR, and Y1R). Several studies have shown that GLP-1, GLP-2, and GIP all inhibit bone resorption, while GIP also promotes bone formation. Notably, PYY has a strong bone resorption-promoting effect. In addition, gut microbiota (GM) plays an important role in maintaining bone homeostasis. This review outlines the roles of GLP-1, GLP-2, GIP, and PYY in bone metabolism and discusses the roles of gut hormones and the GM in regulating bone homeostasis and their potential mechanisms.
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Obesity is a critical health condition worldwide that increases the risks of comorbid chronic diseases, but it can be managed with weight loss. However, conventional interventions relying on diet and exercise are inadequate for achieving and maintaining weight loss, thus there is significant market interest for pharmaceutical anti-obesity agents. For decades, receptor agonists for the gut peptide glucagon-like peptide 1 (GLP-1) featured prominently in anti-obesity medications by suppressing appetite and food reward to elicit rapid weight loss. As the neurocircuitry underlying food motivation overlaps with that for drugs of abuse, GLP-1 receptor agonism has also been shown to decrease substance use and relapse, thus its therapeutic potential may extend beyond weight management to treat addictions. However, as prolonged use of anti-obesity drugs may increase the risk of mood-related disorders like anxiety and depression, and individuals taking GLP-1-based medication commonly report feeling demotivated, the long-term safety of such drugs is an ongoing concern. Interestingly, current research now focuses on dual agonist approaches that include GLP-1 receptor agonism to enable synergistic effects on weight loss or associated functions. GLP-1 is secreted from the same intestinal cells as the anorectic gut peptide, Peptide YY3-36 (PYY3-36), thus this review assessed the therapeutic potential and underlying neural circuits targeted by PYY3-36 when administered independently or in combination with GLP-1 to curb the appetite for food or drugs of abuse like opiates, alcohol, and nicotine. Additionally, we also reviewed animal and human studies to assess the impact, if any, for GLP-1 and/or PYY3-36 on mood-related behaviors in relation to anxiety and depression. As dual agonists targeting GLP-1 and PYY3-36 may produce synergistic effects, they can be effective at lower doses and offer an alternative approach for therapeutic benefits while mitigating undesirable side effects.
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Péptido 1 Similar al Glucagón , Péptido YY , Humanos , Animales , Péptido YY/metabolismo , Péptido YY/farmacología , Péptido 1 Similar al Glucagón/metabolismo , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Fragmentos de Péptidos/farmacología , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismoRESUMEN
Circulating insulin levels are known to be increased in people with higher body mass index (BMI) due to effects of adiposity on insulin resistance, whilst gut hormones have a more complex relationship, with fasting peptideYY (PYY) reported to be inversely related to BMI. This study aimed to further explore fasting and post prandial pancreatic and gut hormone concentrations in plasma samples from obese and non-obese participants. Participants with healthy BMI (n=15), overweight BMI (n=29) and obesity (n=161) had samples taken fasting and 30â¯min post mixed liquid meal for analysis of glucagon-like peptide-1 (GLP-1), PYY, glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon. Data visualiation used linear discriminant analysis for dimensionality reduction, to visualise the data and assess scaling of each hormone. Fasting levels of insulin, GIP and PYY were shown to be key classifiers between the 3 groups on ANCOVA analysis, with an observation of increased GIP levels in overweight, but not obese participants. In non-obese subjects, fasting GIP, PYY and insulin correlated with BMI, whereas in subjects with obesity only the pancreatic hormones glucagon and insulin correlated with BMI. Concentrations of total GLP-1 in the fasting state correlated strongly with glucagon levels, highlighting potential assay cross-reactivities. The study, which included a relatively large number of subjects with severe obesity, supported previous evidence of BMI correlating negatively with fasting PYY and positively with fasting insulin. The observation of increased fasting GIP levels in overweight but not obese participants deserves further validation and mechanistic investigation.
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Índice de Masa Corporal , Ayuno , Polipéptido Inhibidor Gástrico , Péptido 1 Similar al Glucagón , Insulina , Obesidad , Péptido YY , Humanos , Obesidad/sangre , Masculino , Femenino , Adulto , Ayuno/sangre , Péptido YY/sangre , Persona de Mediana Edad , Péptido 1 Similar al Glucagón/sangre , Polipéptido Inhibidor Gástrico/sangre , Insulina/sangre , Periodo Posprandial , Glucagón/sangre , Hormonas Gastrointestinales/sangreRESUMEN
(1) Background: Modulators of the Neuropeptide Y (NPY) system are involved in energy metabolism, but the effect of NPY receptor antagonists on metabolic-dysfunction-associated steatotic liver disease (MASLD), a common obesity-related comorbidity, are largely unknown. In this study, we report on the effects of antagonists of the NPY-2 receptor (Y2R) in comparison with empagliflozin and semaglutide, substances that are known to be beneficial in MASLD. (2) Methods: Diet-induced obese (DIO) male Wistar rats were randomized into the following treatment groups: empagliflozin, semaglutide ± PYY3-36, the Y2R antagonists JNJ 31020028 and a food-restricted group, as well as a control group. After a treatment period of 8 weeks, livers were weighed and histologically evaluated. QrtPCR was performed to investigate liver inflammation and de novo lipogenesis (in liver and adipose tissue). Serum samples were analysed for metabolic parameters. (3) Results: Semaglutide + PYY3-36 led to significant weight loss, reduced liver steatosis (p = 0.05), and decreased inflammation, insulin resistance, and leptin levels. JNJ-31020028 prevented steatosis (p = 0.03) without significant weight loss. Hepatic downregulation of de novo lipogenesis-regulating genes (SREBP1 and MLXIPL) was observed in JNJ-31020028-treated rats (p ≤ 0.0001). Food restriction also resulted in significantly reduced weight, steatosis, and hepatic de novo lipogenesis. (4) Conclusions: Body weight reduction (e.g., by food restriction or drugs like semaglutide ± PYY3-36) is effective in improving liver steatosis in DIO rats. Remarkably, the body-weight-neutral Y2R antagonists may be effective in preventing liver steatosis through a reduction in de novo lipogenesis, making this drug class a candidate for the treatment of (early) MASLD.
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Benzamidas , Compuestos de Bencidrilo , Hígado Graso , Péptidos Similares al Glucagón , Glucósidos , Piperazinas , Receptores de Neuropéptido Y , Ratas , Masculino , Animales , Receptores de Neuropéptido Y/metabolismo , Ratas Wistar , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Dieta , Hígado Graso/tratamiento farmacológico , Hígado Graso/etiología , Hígado Graso/prevención & control , Pérdida de Peso , InflamaciónRESUMEN
It has been known since 2005 that the secretion of several gut hormones changes radically after gastric bypass operations and, although more moderately, after sleeve gastrectomy but not after gastric banding. It has therefore been speculated that increased secretion of particularly GLP-1 and Peptide YY (PYY), which both inhibit appetite and food intake, may be involved in the weight loss effects of surgery and for improvements in glucose tolerance. Experiments involving inhibition of hormone secretion with somatostatin, blockade of their actions with antagonists, or blockade of hormone formation/activation support this notion. However, differences between results of bypass and sleeve operations indicate that distinct mechanisms may also be involved. Although the reductions in ghrelin secretion after sleeve gastrectomy would seem to provide an obvious explanation, experiments with restoration of ghrelin levels pointed towards effects on insulin secretion and glucose tolerance rather than on food intake. It seems clear that changes in GLP-1 secretion are important for insulin secretion after bypass and appear to be responsible for postbariatric hypoglycemia in glucose-tolerant individuals; however, with time the improvements in insulin sensitivity, which in turn are secondary to the weight loss, may be more important. Changes in bile acid metabolism do not seem to be of particular importance in humans.
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Gastrectomía , Derivación Gástrica , Péptido 1 Similar al Glucagón , Péptido YY , Pérdida de Peso , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/cirugía , Gastrectomía/métodos , Hormonas Gastrointestinales/metabolismo , Ghrelina/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Insulina/metabolismo , Péptido YY/metabolismoRESUMEN
Peptide YY (PYY3-36) is a post-prandially released gut hormone with potent appetite-reducing activity, the mechanism of action of which is not fully understood. Unravelling how this system physiologically regulates food intake may help unlock its therapeutic potential, whilst minimising unwanted effects. Here we demonstrate that germline and post-natal targeted knockdown of the PYY3-36 preferring receptor (neuropeptide Y (NPY) Y2 receptor (Y2R)) in the afferent vagus nerve is required for the appetite inhibitory effects of physiologically-released PYY3-36, but not peripherally administered pharmacological doses. Post-natal knockdown of the Y2R results in a transient body weight phenotype that is not evident in the germline model. Loss of vagal Y2R signalling also results in altered meal patterning associated with accelerated gastric emptying. These results are important for the design of PYY-based anti-obesity agents.
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Hormonas Gastrointestinales , Péptido YY , Péptido YY/fisiología , Apetito/fisiología , Nervio Vago , Ingestión de AlimentosRESUMEN
OBJECTIVE: This study was designed to compare basal concentrations of the gastrointestinal appetite modulators ghrelin, peptide tyrosine tyrosine (PYY), and glucagon-like peptide 1 (GLP-1) between obesity classes and obesity classes and controls. METHODS: The study included 49 healthy controls with body mass index (BMI) between 18.5 and 29.9 kg/m² and 62 individuals with obesity with BMI ≥30 kg/m². Basal ghrelin, PYY, and GLP-1 concentrations of the samples were analyzed by an enzyme-linked immunosorbent assay commercial kit (SunRed Human). Other biochemical parameters were measured by a clinical chemistry autoanalyzer (Beckman Coulter AU 5800) in the biochemistry laboratory. RESULTS: Compared with the control group, ghrelin, PYY, and GLP-1 levels were significantly lower in the obese group (P < .05). The PYY concentration was significantly different between obese groups (P < .05). The PYY and GLP-1 levels were significantly different between obesity class I and obesity class III. In addition, ghrelin levels were significantly different between obesity class II and obesity class III. Correlation analysis revealed a negative correlation between BMI and serum ghrelin, GLP-1, and PYY concentrations. CONCLUSION: Low basal ghrelin, GLP-1, and PYY hormones in the obese group compared with the control group indicate impaired appetite regulation in this population. The significant difference in PYY levels between obese groups was associated with increasing obesity grade.
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Objective: Combination therapies with gut hormone analogs represent promising treatment strategies for obesity. This pilot study investigates the therapeutic potential of modulators of the glucagon-like peptide 1 (GLP-1) and neuropeptide Y (NPY) system using GLP-1 receptor agonists (semaglutide) and antagonists (exendin 9-39), as well as non-selective and NPY-Y2-receptor selective peptide tyrosine tyrosine (PYY) analogs (PYY3-36/NNC0165-0020 and NNC0165-1273) and an NPY-Y2 receptor antagonist (JNJ31020028). Methods: High-fat diet (HFD)-induced obese rats were randomized into following treatment groups: group 1, nonselective PYY analog + semaglutide (n = 4); group 2, non-selective and NPY-Y2 receptor selective PYY analog + semaglutide (n = 2); group 3, GLP-1 receptor antagonist + NPY-Y2 receptor antagonist (n = 3); group 4, semaglutide (n = 5); and group 5, control (n = 5). Animals had free access to HFD and low-fat diet. Food intake, HFD preference and body weight were measured daily. Results: A combinatory treatment with a non-selective PYY analog and semaglutide led to a maximum body weight loss of 14.0 ± 4.9% vs 9.9 ± 1.5% with semaglutide alone. Group 2 showed a maximum weight loss of 20.5 ± 2.4%. While HFD preference was decreased in group 2, a strong increase in HFD preference was detected in group 3. Conclusions: PYY analogs (especially NPY-Y2 selective receptor agonists) could represent a promising therapeutic approach for obesity in combination with GLP-1 receptor agonists. Additionally, combined GLP-1 and PYY3-36 receptor agonists might have beneficial effects on food preference.
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PURPOSE: Bariatric surgery remains the most efficient treatment to achieve a sustained weight loss. However, a large proportion of patients experience suboptimal weight loss (SWL). The exact mechanisms involved remain to be fully elucidated, but the homeostatic appetite control system seems to be involved. The aim of this study was, therefore, to compare the plasma concentration of gastrointestinal hormones, and appetite ratings, between those experiencing SWL and optimal weight loss (OWL) after Roux-en-Y gastric bypass (RYGB). MATERIALS AND METHODS: Fifty participants from the Bariatric Surgery Observation Study (BAROBS) experiencing either SWL or OWL (< or ≥ 50% of excess weight loss (EWL), respectively) > 13 years post-RYGB were compared to 25 non-surgical controls. Plasma concentrations of acylated ghrelin (AG), total glucagon-like peptide-1 (GLP-1), total peptide YY (PYY), cholecystokinin (CCK), and subjective ratings of hunger, fullness, desire to eat (DTE), and prospective food consumption (PFC) were assessed in the fasting and postprandial (area under the curve (AUC)) states. RESULTS: Those experiencing OWL presented with higher basal AG and GLP-1 iAUC, and lower AG iAUC compared with SWL and controls. Additionally, both bariatric groups presented with higher PYY and CCK iAUC compared to controls. PFC tAUC was also lower in OWL compared to the SWL group. Total weight loss was positively correlated with GLP-1 tAUC and negatively correlated with fasting and tAUC DTE and PFC tAUC. CONCLUSIONS: SWL > 13 years post-RYGB is associated with lower basal ghrelin, as well as a weaker satiety response to a meal. Future studies should investigate the causality of these associations.
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Derivación Gástrica , Obesidad Mórbida , Humanos , Apetito/fisiología , Ghrelina , Obesidad Mórbida/cirugía , Pérdida de Peso/fisiología , Péptido YY , Péptido 1 Similar al Glucagón , ColecistoquininaRESUMEN
Appendiceal neuroendocrine neoplasms (NENs) can present with various growth patterns including the traditional triad of histologic patterns-insular, trabecular and tubular. A small cluster pattern was also found in this study and the literature on this specific morphology is limited. In this study, we conducted a comprehensive review of appendiceal NENs from our institution over a ten-year period. Clinical and demographic data were obtained from medical records. Immunohistochemical stains were performed with antibodies specific for synaptophysin, chromogranin, INSM1, CD56, serotonin and peptide YY. The small cluster pattern was found in 29.4 % of all cases evaluated. The tumor cells in these cases were predominantly located at the distal tip of the appendix, associated with fibrous obliteration. These tumors were smaller in size and tended towards less advanced tumor stage, with reduced incidence of lymphovascular and/or perineural invasion. Chromogranin expression was identified in 76 % of these cases. There is a heterogeneous hormone profile with 46.7 % serotonin and 33.3 % peptide YY. In conclusion, the small cluster pattern NENs present with unique histological features and hormone expression profile. Among the various neuroendocrine markers, INSM1 showed superior diagnostic performance, with high sensitivity and minimal non-specific staining.
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Neoplasias del Apéndice , Carcinoma Neuroendocrino , Neoplasias Intestinales , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Neoplasias Gástricas , Humanos , Tumores Neuroendocrinos/patología , Biomarcadores de Tumor/metabolismo , Cromograninas , Péptido YY , Serotonina , Proteínas Represoras/metabolismo , Sensibilidad y Especificidad , Sinaptofisina/metabolismo , Neoplasias del Apéndice/diagnóstico , Carcinoma Neuroendocrino/patologíaRESUMEN
The prevalence of obesity has increased significantly over the last several decades, and with its increase comes a wide variety of comorbidities, such as diabetes and cardiovascular disease. Traditionally, diet and exercise have been prescribed for individuals to try and regain control of their weight and health status. Despite this successful method, the compliance rate is significantly below the desired amount. Over the last few decades, a new treatment has been offered to significantly decrease an individual's weight to an optimal BMI between 18 and 25 kg/m2. Bariatric surgery has been proposed to be the most appropriate treatment for obesity, and there are several different types of bariatric surgery: Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion with duodenal switch (BPD-DS), adjustable gastric band (AGB), and sleeve gastrectomy (SG). Hormones may be significantly involved in losing and maintaining weight loss. This paper aims to evaluate hormone changes in appetite suppression, appetite activation, glycemic control, and lipid metabolism and how these impact overall weight loss concerning the most prominent surgeries. The hormones assessed were ghrelin, insulin, leptin, GLP-1, PYY, and adiponectin, and their levels before and after each surgery were compared. RYGB is one of the most successful types of bariatric surgeries, and this correlates with it having the most suppressed levels of ghrelin, insulin, and leptin following surgery with a slow return to normal. RYGB has also led to the most significant increased levels of PYY, pre- and post-prandial GLP-1, and adiponectin. Hormones following SG followed the hormone trend after RYGB but were not as prominent. BDP-DS has the highest success rate. However, numerous adverse effects have limited the amount of studies assessing the surgery. What was present was not as significant as RYGB, possibly due to manipulation.
RESUMEN
BACKGROUND: Weight loss is associated with a disproportionate reduction in energy expenditure, along with increases in hunger feelings and ghrelin concentrations. These changes are presumed to be homeostatic mechanisms to counteract the energy deficit. The possibility that these 2 components of the energy balance equation are mechanistically linked has never been examined. OBJECTIVE: This study aimed to determine if the disproportionate reduction in resting metabolic rate (RMR) seen with weight loss is associated with changes in the plasma concentration of gastrointestinal hormones involved in appetite regulation and subjective appetite ratings. METHODS: This was a longitudinal study with repeated measurements. Fifty-six individuals with obesity (body mass index [BMI]: 34.5±0.5 kg/m2; age: 47±1 y; 26 males) underwent an 8 wk low-energy diet, followed by 4 wk of refeeding and weight stabilization. The RMR, respiratory quotient (RQ), body composition, plasma concentrations of ghrelin, glucagon-like peptide 1, peptide YY, cholecystokinin, insulin, and appetite ratings in the fasting and postprandial states were measured at baseline, Wk9 and 13. Metabolic adaptation was defined as significantly lower when measured versus the predicted RMR (pRMR) (from own regression model using baseline data). RESULTS: A 14.2±0.6 kg weight loss was seen at Wk9 and maintained at Wk13. RQ was significantly reduced at Wk9 (0.82±0.06 vs. 0.76±0.05, P< 0.001) but returned to baseline at Wk13. Metabolic adaptation was seen at Wk9, but not Wk13 (-341±58, P <0.001 and -75±72 kJ/d, P = 0.305, respectively). The larger the difference between measured and predicted RMR at both timepoints, the greater the increase in hunger, desire to eat, and composite appetite score (fasting and postprandial at Wk9, postprandial only at Wk13), even after adjusting for weight loss and RQ. CONCLUSION: A larger metabolic adaptation during weight loss is accompanied by a greater drive to eat. This might help explain the interindividual differences in weight loss outcomes to dietary interventions.