RESUMEN
OBJECTIVE: The satiating effect of protein compared with other nutrients has been well described and is thought to be mediated, in part, by gut hormone release. Previously, it has been shown that oral L-arginine acts as a GLP-1 secretagogue both in vitro and in vivo in rodents. Here, the effect of L-arginine on gut hormone release in humans was investigated. METHODS: The hypothesis was tested in two separate studies. The first study assessed the tolerability of oral L-arginine in healthy human subjects. The second study assessed the effect of oral L-arginine on gut hormone release following an ad libitum meal. Subjects were given L-arginine, glycine (control amino acid), or vehicle control in a randomized double-blind fashion. RESULTS: At a dose of 17.1 mmol, L-arginine was well tolerated and stimulated the release of plasma GLP-1 (P < 0.05) and PYY (P < 0.001) following an ad libitum meal. Food diaries showed a trend toward lower energy intake and particularly fat intake following L-arginine treatment. CONCLUSIONS: L-arginine can significantly elevate GLP-1 and PYY in healthy human volunteers in combination with a meal. Further work is required to investigate whether L-arginine may have utility in the suppression of appetite and food intake.
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Depresores del Apetito/uso terapéutico , Arginina/uso terapéutico , Ingestión de Alimentos/efectos de los fármacos , Péptido 1 Similar al Glucagón/efectos de los fármacos , Péptido YY/efectos de los fármacos , Periodo Posprandial/efectos de los fármacos , Adulto , Depresores del Apetito/farmacología , Arginina/farmacología , Método Doble Ciego , Femenino , Péptido 1 Similar al Glucagón/sangre , Humanos , Masculino , Péptido YY/sangreRESUMEN
A new strategy under development for the treatment of type 2 diabetes and obesity is to mimic some of the effects of bariatric surgery by delivering food-related stimuli to the distal gastrointestinal tract where they should enhance the release of gut hormones such as glucagon-like peptide-1 (GLP-1) and peptideYY (PYY). Methods include inhibition of food digestion and absorption in the upper GI tract, or oral delivery of stimuli in capsules or pelleted form to protect them against gastric degradation. A variety of agents have been tested in humans using capsules, microcapsules or pellets, delivering nutrients, bile acids, fatty acids and bitter compounds. This review examines the outcomes of these different approaches and supporting evidence from intestinal perfusion studies.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Tracto Gastrointestinal/efectos de los fármacos , Incretinas/uso terapéutico , Obesidad/tratamiento farmacológico , Cirugía Bariátrica , Diabetes Mellitus Tipo 2/metabolismo , Interacciones Alimento-Droga , Tracto Gastrointestinal/metabolismo , Péptido 1 Similar al Glucagón/biosíntesis , Péptido 1 Similar al Glucagón/efectos de los fármacos , Humanos , Incretinas/química , Obesidad/metabolismo , Péptido YY/efectos de los fármacos , Péptido YY/metabolismo , SecretagogosRESUMEN
OBJECTIVE: Previous studies have shown that polyunsaturated fats (PUFAs) elicit a greater response in satiety after a single-meal challenge compared with other types of fats. The long-term effects of PUFAs on satiety, however, remain unknown. The aim of this study was to determine subjective and physiological hunger and satiety responses to high-fat (HF) meals before and after a 7-d PUFA-rich diet. METHODS: Twenty-six, healthy weight (body mass index 18-24.9 kg/m2), sedentary adults were randomly assigned to either a 7-d PUFA-rich diet (n = 8 men and n = 8 women) or a 7-d control diet (n = 5 men and n = 5 women). After a 3-d lead-in diet, participants reported for the baseline visit where anthropometrics, fasting visual analog scale (VAS) measurements, and a fasting blood sample were collected. Then, two HF meals (breakfast and lunch) were consumed. Postprandial blood draws and VAS measures were collected approximately every 30 min for 4 h after each meal, for a total of 8 h. RESULTS: From pre- to post-PUFA-rich diet, there was a decrease in fasting ghrelin (P < 0.05) and an increase in fasting peptide YY (PYY; P < 0.05); however, there were no changes in fasting insulin or leptin concentrations. The postprandial response for PYY was higher after the PUFA-rich diet visit compared to baseline (P < 0.01). However, there were no differences in the postprandial response for ghrelin, insulin, leptin, or VAS measures from pre- to post-diet in either the PUFA-rich diet or control (ns). CONCLUSION: A PUFA-rich diet consumed for 7 d favorably altered fasting and postprandial physiological markers of hunger and satiety; yet, did not alter subjective ratings of hunger or fullness.
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Dieta Alta en Grasa/métodos , Grasas de la Dieta/farmacología , Ácidos Grasos Insaturados/farmacología , Hambre/efectos de los fármacos , Respuesta de Saciedad/efectos de los fármacos , Adolescente , Adulto , Grasas de la Dieta/sangre , Ácidos Grasos Insaturados/sangre , Femenino , Ghrelina/sangre , Ghrelina/efectos de los fármacos , Humanos , Masculino , Péptido YY/sangre , Péptido YY/efectos de los fármacos , Saciedad/efectos de los fármacos , Adulto JovenRESUMEN
There is considerable interest in the effect of foods containing high intensity sweeteners on satiation. However, less is known about low-calorie bulk sweeteners such as erythritol. In this randomized three-way crossover study, we studied 10 lean and 10 obese volunteers who consumed three test meals on separate occasions: (a) control sucrose meal; (b) isovolumic meal with partial replacement of sucrose by erythritol; (c) isocaloric meal which contained more erythritol but equivalent calories to the control meal. We measured gut hormone levels, hunger and satiety scores, ad libitum food intake, sucrose preference and intake after the manipulations. There was a greater post-prandial excursion in glucose and insulin levels after sucrose than after the erythritol meals. There was no difference in GLP-1/PYY levels or subsequent energy intake and sucrose preference between sucrose control and isovolumic erythritol meals. In lean (but not obese) participants, hunger decreased to a greater extent after the isocaloric erythritol meal compared to the control meal (p = 0.003) reflecting the larger volume of this meal. Replacing sucrose with erythritol leads to comparable hunger and satiety scores, GLP-1 and PYY levels, and subsequent sucrose preference and intake.
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Eritritol/farmacología , Péptido 1 Similar al Glucagón/efectos de los fármacos , Edulcorantes no Nutritivos/farmacología , Obesidad/metabolismo , Péptido YY/efectos de los fármacos , Adulto , Estudios Cruzados , Femenino , Péptido 1 Similar al Glucagón/metabolismo , Humanos , Hambre/efectos de los fármacos , Masculino , Comidas/efectos de los fármacos , Persona de Mediana Edad , Péptido YY/metabolismo , Periodo Posprandial , Saciedad/efectos de los fármacos , Sacarosa/farmacología , Edulcorantes/farmacologíaRESUMEN
We investigated the effects of a long-duration glucagon-like peptide-1 (GLP-1) receptor agonist, GSK2374697, on postprandial endogenous total GLP-1 and peptide YY (PYY). Two cohorts of healthy subjects, one normal/overweight and one obese, were randomized to receive GSK2374697 2 mg (n = 8 each) or placebo (n = 4 and n = 2) subcutaneously on days 1, 4 and 7. Samples for plasma endogenous GLP-1 and PYY were collected after breakfast on days -1 and 12. Weighted mean area under the curve (0-4 h) of total GLP-1 and PYY in treated subjects was reduced compared with placebo. The least squares mean difference for change from baseline was -1.24 pmol/l [95% confidence interval (CI) -2.33, -0.16] and -4.47 pmol/l (95% CI -8.74, -0.20) for total GLP-1 and PYY, respectively, in normal/overweight subjects (p < 0.05 for both), and -1.56 (95% CI -2.95, -0.16) and -3.02 (95% CI -8.58, 2.55), respectively, in obese subjects (p < 0.05 for GLP-1). In healthy subjects, GSK2374697 reduced postprandial total GLP-1 and PYY levels, suggesting feedback suppression of enteroendocrine L-cell secretion of these peptides.
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Péptido 1 Similar al Glucagón/efectos de los fármacos , Péptido YY/efectos de los fármacos , Periodo Posprandial/efectos de los fármacos , Proteínas Recombinantes de Fusión/farmacología , Adulto , Anciano , Desayuno , Femenino , Péptido 1 Similar al Glucagón/sangre , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Péptido YY/sangre , Adulto JovenRESUMEN
BACKGROUND: Medium chain triglycerides (MCT) enhance thermogenesis and may reduce food intake relative to long chain triglycerides (LCT). The goal of this study was to establish the effects of MCT on appetite and food intake and determine whether differences were due to differences in hormone concentrations. METHODS: Two randomized, crossover studies were conducted in which overweight men consumed 20 g of MCT or corn oil (LCT) at breakfast. Blood samples were obtained over 3 h. In Study 1 (n=10), an ad lib lunch was served after 3 h. In Study 2 (n=7), a preload containing 10 g of test oil was given at 3 h and lunch was served 1 h later. Linear mixed model analyses were performed to determine the effects of MCT and LCT oil on change in hormones and metabolites from fasting, adjusting for body weight. Correlations were computed between differences in hormones just before the test meals and differences in intakes after the two oils for Study 1 only. RESULTS: Food intake at the lunch test meal after the MCT preload (Study 2) was (mean±s.e.m.) 532±389 kcal vs 804±486 kcal after LCT (P<0.05). MCT consumption resulted in a lower rise in triglycerides (P=0.014) and glucose (P=0.066) and a higher rise in peptide YY (PYY, P=0.017) and leptin (P=0.036) compared with LCT (combined data). Correlations between differences in hormone levels (glucagon-like peptide (GLP-1), PYY) and differences in food intake were in the opposite direction to expectations. CONCLUSIONS: MCT consumption reduced food intake acutely but this does not seem to be mediated by changes in GLP-1, PYY and insulin.
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Apetito/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Sobrepeso/sangre , Triglicéridos/administración & dosificación , Adulto , Glucemia/efectos de los fármacos , Aceite de Maíz/metabolismo , Estudios Cruzados , Ghrelina/sangre , Ghrelina/efectos de los fármacos , Péptido 1 Similar al Glucagón/sangre , Péptido 1 Similar al Glucagón/efectos de los fármacos , Humanos , Insulina/sangre , Leptina/sangre , Masculino , Persona de Mediana Edad , Péptido YY/sangre , Péptido YY/efectos de los fármacos , Método Simple Ciego , Triglicéridos/química , Triglicéridos/metabolismo , Adulto JovenRESUMEN
INTRODUCTION: The present study was undertaken to determine if patients with schizophrenia on clozapine monotherapy have lower serum levels of peptide YY [PYY(1-36)], which is an endogenous inhibitor of food intake, comparing to healthy controls. METHODS: Data for 24 patients (mean age 38.8 years) with paranoid schizophrenia on clozapine monotherapy and 24 healthy subjects (gender- and age-matched; mean age 39.9 years) were analyzed. RESULTS: Fasting serum levels of PYY(1-36) were lower in the clozapine group (178.4±138.4 vs. 277.4±218.1 pg/mL, p=0.034). In the whole study sample PYY(1-36) levels were lower in subjects with body mass index≥25 kg/m(2) (p=0.03) and in subjects with abdominal obesity defined using International Diabetes Foundation criteria (p=0.04). There were no significant differences for metabolic syndrome, smoking, impaired fasting glucose, dyslipidemia, and homeostatic model assessment (HOMA) defined insulin resistance. DISCUSSION: RESULTS suggest that weight is asso-ciated with levels of PYY. Patients on clozapine had higher body mass index, but not fat mass index or body weight, therefore lower levels of PYY(1-36) in patients taking clozapine may result from clozapine-induced weight gain and central -obesity.
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Antipsicóticos/farmacología , Clozapina/farmacología , Péptido YY/sangre , Péptido YY/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Adulto , Composición Corporal , Índice de Masa Corporal , Peso Corporal/efectos de los fármacos , Impedancia Eléctrica , Femenino , Humanos , Masculino , Síndrome Metabólico , Persona de Mediana Edad , FumarRESUMEN
AIM: Inhibition of diacylglycerol acyltransferase 1 (DGAT1) is a potential treatment modality for patients with type 2 diabetes mellitus and obesity, based on preclinical data suggesting it is associated with insulin sensitization and weight loss. This randomized, placebo-controlled, phase 1 study in 62 overweight or obese men explored the effects and tolerability of AZD7687, a reversible and selective DGAT1 inhibitor. METHODS: Multiple doses of AZD7687 (1, 2.5, 5, 10 and 20 mg/day, n = 6 or n = 12 for each) or placebo (n = 20) were administered for 1 week. Postprandial serum triacylglycerol (TAG) was measured for 8 h after a standardized 45% fat meal. Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were measured and a paracetamol challenge was performed to assess gastric emptying. RESULTS: Dose-dependent reductions in postprandial serum TAG were demonstrated with AZD7687 doses ≥5 mg compared with placebo (p < 0.01). Significant (p < 0.001) increases in plasma GLP-1 and PYY levels were seen at these doses, but no clear effect on gastric emptying was demonstrated at the end of treatment. With AZD7687 doses >5 mg/day, gastrointestinal (GI) side effects increased; 11/18 of these participants discontinued treatment owing to diarrhoea. CONCLUSIONS: Altered lipid handling and hormone secretion in the gut were demonstrated during 1-week treatment with the DGAT1 inhibitor AZD7687. However, the apparent lack of therapeutic window owing to GI side effects of AZD7687, particularly diarrhoea, makes the utility of DGAT1 inhibition as a novel treatment for diabetes and obesity questionable.
Asunto(s)
Acetatos/uso terapéutico , Fármacos Antiobesidad/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Diarrea/inducido químicamente , Obesidad/tratamiento farmacológico , Pirazinas/uso terapéutico , Acetatos/efectos adversos , Adulto , Fármacos Antiobesidad/efectos adversos , Diacilglicerol O-Acetiltransferasa/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Vaciamiento Gástrico/efectos de los fármacos , Péptido 1 Similar al Glucagón/efectos de los fármacos , Humanos , Absorción Intestinal/efectos de los fármacos , Masculino , Persona de Mediana Edad , Péptido YY/efectos de los fármacos , Pirazinas/efectos adversos , Resultado del Tratamiento , Pérdida de Peso/efectos de los fármacosRESUMEN
The gastrointestinal (GI) tract is a specialized sensory system that detects and responds to constant changes in nutrient- and bacterial-derived intestinal signals, thus contributing to controls of food intake. Chronic exposure to dietary fat causes morphological, physiological and metabolic changes leading to disruptions in the regulatory feeding pathways promoting more efficient fat absorption and utilization, blunted satiation signals and excess adiposity. Accumulating evidence demonstrates that impaired gastrointestinal signals following long-term high fat consumption are, at least partially, responsible for increased caloric intake. This review focuses on the role of dietary fat in modulating oral and post-oral chemosensory signaling elements responsible for lipid detection and responses, including changes in sensitivity to satiation signals, such as GLP-1, PYY and CCK and their impact on food intake and weight gain. Furthermore, the influence of the gut microbiota on mechanisms controlling energy regulation in the face of excessive fat exposure will be explored. The profound influence of dietary fats on altering complex regulatory feeding pathways can result in dysregulation of body weight and development of obesity, while restoration or manipulation of satiation signaling may prove an effective tool in prevention and treatment of obesity.
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Grasas de la Dieta/administración & dosificación , Tracto Gastrointestinal/fisiología , Obesidad/metabolismo , Transducción de Señal/efectos de los fármacos , Adiposidad , Animales , Antígenos CD36/fisiología , Colecistoquinina/metabolismo , Ingestión de Energía/fisiología , Tracto Gastrointestinal/microbiología , Ghrelina/fisiología , Péptido 1 Similar al Glucagón/efectos de los fármacos , Péptido 1 Similar al Glucagón/metabolismo , Humanos , Absorción Intestinal/efectos de los fármacos , Microbiota/fisiología , Péptido YY/efectos de los fármacos , Péptido YY/metabolismo , Receptores Acoplados a Proteínas G/fisiología , Saciedad/fisiología , Gusto/fisiología , Aumento de PesoRESUMEN
Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), secreted by enteroendocrine L-cells located most densely in the colon and rectum, are of fundamental importance in blood glucose and appetite regulation. In animal models, colonic administration of bile acids can stimulate GLP-1 and PYY by TGR5 receptor activation. We evaluated the effects of taurocholic acid (TCA), administered as an enema, on plasma GLP-1 and PYY, as well as gastrointestinal sensations in 10 healthy male subjects, and observed that rectal administration of TCA promptly stimulated secretion of both GLP-1 and PYY, and increased fullness, in a dose-dependent manner. These observations confirm that topical application of bile acids to the distal gut may have potential for the management of type 2 diabetes and obesity.
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Péptido 1 Similar al Glucagón/efectos de los fármacos , Péptido 1 Similar al Glucagón/metabolismo , Péptido YY/efectos de los fármacos , Péptido YY/metabolismo , Ácido Taurocólico/administración & dosificación , Ácido Taurocólico/farmacología , Administración Rectal , Adulto , Regulación del Apetito/efectos de los fármacos , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Índice de Masa Corporal , Colagogos y Coleréticos/administración & dosificación , Colagogos y Coleréticos/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/fisiopatología , Enema , Humanos , Masculino , Obesidad/tratamiento farmacológico , Obesidad/fisiopatología , Resultado del TratamientoRESUMEN
OBJECTIVE: Significant weight gain is a problematic side effect of treatment with the antipsychotic drug olanzapine (OLA). Previous studies in rats suggest that one of the contributing factors is an impairment in satiation that results in increased food intake. However, the mechanisms underlying this impairment in satiation remain largely unclear. METHODS AND RESULTS: In this study, we determined the effect of OLA on levels of leptin, insulin, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1, peptide YY and amylin in male rats that had received a fixed amount of food. OLA did not affect the secretion of any of these hormones, except for ghrelin levels, which were increased compared with controls. Furthermore, when ghrelin levels were determined in rats just before they received their meal, OLA caused a significant increase in ghrelin levels compared with controls, whereas OLA failed to affect baseline ghrelin levels. Next, we investigated the effect of OLA on the efficacy of CCK to reduce meal size. With coadministration, OLA pretreatment counteracted the reduction in meal size by CCK, although there was no significant interaction between the treatments. Finally, telemetry measurements revealed that acute OLA treatment causes a temporary decrease in both locomotor activity and body core temperature. CONCLUSION: Taken together, this study shows that acute injection of OLA selectively increases meal-related ghrelin secretion and this may partially underlie the impairment in satiation by OLA.
Asunto(s)
Antipsicóticos/farmacología , Benzodiazepinas/farmacología , Temperatura Corporal/efectos de los fármacos , Colecistoquinina/efectos de los fármacos , Ghrelina/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Péptido YY/efectos de los fármacos , Análisis de Varianza , Animales , Colecistoquinina/metabolismo , Ingestión de Alimentos , Ghrelina/metabolismo , Péptido 1 Similar al Glucagón/efectos de los fármacos , Péptido 1 Similar al Glucagón/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/efectos de los fármacos , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Masculino , Olanzapina , Péptido YY/metabolismo , Ratas , Ratas Wistar , Saciedad/efectos de los fármacosRESUMEN
BACKGROUND: The endocannabinoid system is a potential pharmacotherapy target for obesity. However, the role of this system in human food intake regulation is currently unknown. METHODS: To test whether circulating endocannabinoids might functionally respond to food intake and verify whether these orexigenic signals are deregulated in obesity alongside with anorexigenic ones, we measured plasma anandamide (AEA), 2-arachidonoylglycerol (2-AG) and peptide YY (PYY) changes in response to a meal in 12 normal-weight and 12 non-diabetic, insulin-resistant obese individuals. RESULTS: Both normal-weight and obese subjects had a significant preprandial AEA peak. Postprandially, AEA levels significantly decreased in normal-weight, whereas no significant changes were observed in obese subjects. Similarly, PYY levels significantly increased in normal-weight subjects only. No meal-related changes were found for 2-AG. Postprandial AEA and PYY changes inversely correlated with waist circumference, and independently explained 20.7 and 21.3% of waist variance. Multiple regression analysis showed that postprandial AEA and PYY changes explained 34% of waist variance, with 8.2% of the variance commonly explained. CONCLUSION: These findings suggest that AEA might be a physiological meal initiator in humans and furthermore show that postprandially AEA and PYY are concomitantly deregulated in obesity.
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Regulación del Apetito/efectos de los fármacos , Ácidos Araquidónicos/sangre , Moduladores de Receptores de Cannabinoides/sangre , Endocannabinoides , Glicéridos/sangre , Obesidad/sangre , Obesidad/tratamiento farmacológico , Péptido YY/sangre , Alcamidas Poliinsaturadas/sangre , Adulto , Índice de Masa Corporal , Ingestión de Alimentos/efectos de los fármacos , Femenino , Humanos , Resistencia a la Insulina , Masculino , Péptido YY/efectos de los fármacos , Periodo PosprandialRESUMEN
The incidence of type 2 diabetes mellitus is increasing worldwide. Several G-protein-coupled receptor agonists are being studied for their efficacy as antidiabetes agents. JNJ-38431055 is a novel, potent, and orally available selective agonist of the glucose-dependent insulinotropic (GPR119) receptor. Double-blind, randomized, placebo-controlled studies were conducted to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of JNJ-38431055 (2.5-800 mg) in healthy male volunteers. The systemic exposure of JNJ-38431055 in plasma increased in proportion to the dose and was not influenced by coadministration of food. The terminal elimination half-life was ~13 h when administered as an oral suspension formulation. JNJ-38431055 was well tolerated and was not associated with hypoglycemia. As compared with placebo, single-dose oral JNJ-38431055 increased postmeal plasma glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) concentrations but did not significantly decrease glucose excursion or increase insulin secretion. However, in a graded glucose infusion study, JNJ-38431055 was shown to induce a higher insulin secretion rate (ISR) relative to placebo at elevated plasma glucose levels. These studies provide evidence for the potential efficacy of JNJ-38431055 as an antidiabetes agent in humans.
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Glucemia/efectos de los fármacos , Hipoglucemiantes/farmacología , Receptores Acoplados a Proteínas G/agonistas , Administración Oral , Adulto , Método Doble Ciego , Polipéptido Inhibidor Gástrico/sangre , Polipéptido Inhibidor Gástrico/efectos de los fármacos , Péptido 1 Similar al Glucagón/sangre , Péptido 1 Similar al Glucagón/efectos de los fármacos , Semivida , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacocinética , Insulina/metabolismo , Secreción de Insulina , Masculino , Persona de Mediana Edad , Péptido YY/sangre , Péptido YY/efectos de los fármacosRESUMEN
This study tested the effects of (1â3),(1â4) ß-D-glucan from oats, on activation of the gut-hypothalamic (PYY3â36-NPY) axis, satiety, and weight loss in diet-induced obesity (DIO) mice. DIO mice were fed standard lab chow diets or varied doses of ß-glucan for 6 weeks. Energy intake, satiety, body weight changes and peptide Y-Y3â36 (PYY3â36) were measured together with a satiety test and measurement of neuropeptide Y (NPY) mRNA expression in the hypothalamic arcuate nucleus (Arc). The average energy intake (-13%, p<0.05) and body weight gain was lower with increasing ß-glucan over 6 wk with acute suppression of energy intake over 4 h. The highest ß-glucan diet significantly increased plasma PYY3â36, with suppression of Arc NPY mRNA.
Asunto(s)
Avena/química , Obesidad/fisiopatología , beta-Glucanos/farmacología , Animales , Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Núcleo Arqueado del Hipotálamo/metabolismo , Peso Corporal/efectos de los fármacos , Dieta , Relación Dosis-Respuesta a Droga , Ingestión de Energía/efectos de los fármacos , Tracto Gastrointestinal/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Neuropéptido Y/efectos de los fármacos , Neuropéptido Y/genética , Obesidad/dietoterapia , Fragmentos de Péptidos , Péptido YY/análisis , Péptido YY/efectos de los fármacos , ARN Mensajero , Respuesta de Saciedad/efectos de los fármacosRESUMEN
BACKGROUND AND AIMS: Dietary fibre (DF) may play an important role in weight control. The amount, type and way of processing of DF modify food structure and subsequent postprandial appetitive, metabolic and hormonal effects, but current understanding about the magnitude of effects that specific types and amounts of DF exert are still poorly understood. METHODS AND RESULTS: We investigated the effects of wheat and oat brans alone and as combination in semisolid food matrix on postprandial appetite profile and gastrointestinal (GI) hormonal responses. Twenty healthy, normal-weight subjects (5 male/15 female, aged 23.3 ± 0.85y) participated in the study. Isoenergetic and isovolumic (1250 kJ, 300 g) puddings with different insoluble and soluble DF content were tested in a randomised order: pudding with 1) no added fibre, 2) 10 g wheat bran DF, 3) 10 g oat bran DF and 4) combination including 5 g wheat bran DF + 5 g oat bran DF. Blood samples were drawn before and 15, 30, 45, 60, 90, 120 and 180 min after the test meals to determine plasma glucose, ghrelin, peptide YY (PYY) and serum insulin concentrations. Subjective profiles of appetite were assessed using visual analogue scales (VAS). Plasma glucose (P = 0.001) and serum insulin (P < 0.001) responses were the lowest after the pudding with the greatest amount of ß-glucan. In contrast, postprandial ghrelin or PYY responses or appetite sensations did not differ among the meals. CONCLUSION: Oat ß-glucan decreased postprandial plasma glucose and serum insulin responses, yet had no significant effects on GI peptide responses or appetite ratings.
Asunto(s)
Avena/química , Glucemia/efectos de los fármacos , Insulina/sangre , Adulto , Apetito/efectos de los fármacos , Estudios Cruzados , Fibras de la Dieta/administración & dosificación , Ingestión de Energía , Femenino , Tracto Gastrointestinal/metabolismo , Ghrelina/sangre , Ghrelina/efectos de los fármacos , Humanos , Masculino , Péptido YY/sangre , Péptido YY/efectos de los fármacos , Periodo Posprandial/efectos de los fármacos , Método Simple Ciego , Triticum/química , Adulto JovenRESUMEN
In animals, colonic infusion of SCFA does not affect glucagon-like peptide-1 (GLP-1) release whereas intravenous infusion does and SCFA may directly stimulate peptide YY (PYY) release. It is unknown whether SCFA and their route of administration affect human blood concentrations of GLP-1 and PYY. Our aim was to conduct a pilot study to determine the effects of intravenous and rectal acetate on blood concentrations of GLP-1, PYY, ghrelin, adiponectin and TNF-alpha in hyperinsulinaemic human subjects. Six hyperinsulinaemic female subjects were given 20 mmol sodium acetate intravenously, 60 mmol acetate rectally, or normal saline rectally or intravenously on four separate occasions in randomised order, with blood samples collected at 0, 10, 15, 30, 45 and 60 min. Change in plasma PYY was significantly higher after acetate and rectal infusions (9.69 and 13.78 pg/ml) compared with saline and intravenous (0.60 and - 3.1 pg/ml; P < 0.01), respectively. Change in plasma GLP-1 was increased by rectal and acetate infusions (0.25 and 0.23 mmol/l) v. intravenous and saline ( - 0.26 and - 0.19 mmol/l; P < 0.01). Acetate decreased TNF-alpha v. saline ( - 0.8 and 0.15 pg/ml; P < 0.05). Rectal infusions increased TNF-alpha and ghrelin (0.2 and 98.27 pg/ml) v. intravenous ( - 0.9 and - 40 pg/ml; P < 0.01). There was no effect of treatment on plasma adiponectin. These preliminary results suggest that acetate raises plasma PYY and GLP-1, and suppresses TNF-alpha. Also, distending the rectum increases PYY, GLP-1, TNF-alpha and ghrelin in hyperinsulinaemic females. Increasing colonic fermentation products, particularly acetate, could yield a new mechanism for modifying weight gain.
Asunto(s)
Acetatos/sangre , Acetato de Sodio/farmacología , Adiponectina/sangre , Administración Rectal , Adulto , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Estudios Cruzados , Femenino , Ghrelina/sangre , Ghrelina/efectos de los fármacos , Péptido 1 Similar al Glucagón/sangre , Péptido 1 Similar al Glucagón/efectos de los fármacos , Humanos , Inyecciones Intravenosas , Insulina/sangre , Cinética , Persona de Mediana Edad , Selección de Paciente , Péptido YY/sangre , Péptido YY/efectos de los fármacos , Distribución Aleatoria , Acetato de Sodio/administración & dosificación , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/efectos de los fármacosRESUMEN
BACKGROUND: Oleic acid premeal supplements have been described as a method to trigger the ileal brake and thus lengthen transit time and the opportunity for nutrient absorption. The aims of this study were to determine whether oleic acid supplements would lengthen transit time and improve absorption of nutrients in study participants with short bowel syndrome as well as affect diarrhea or patient weight. METHODS: A double-blind, controlled, random-order crossover trial was conducted in 8 study participants with longstanding and severe short bowel syndrome, employing blue food color appearance, breath hydrogen testing, and radio-opaque markers as measures of transit time. Absorption of energy, protein, fat, and fluid was conducted by classic nutrient balance methods. Diarrhea was estimated by daily stool weight and number of bowel actions. Although 8 patients were enrolled, only 7 completed the study. RESULTS: Transit time was not significantly different between oleic acid and placebo treatment, although peptide YY levels trended higher with the oleic acid treatment. Energy absorption was reduced 14% by oleic acid, significantly more than the 3% reduction by placebo. Fat, protein, and fluid absorption was not changed significantly. Neither diarrhea nor patient body weight was changed by oleic acid. CONCLUSIONS: Energy absorption is reduced by oleic acid supplements in severe short bowel syndrome. The study may have lacked power to determine whether oleic acid affects diarrhea or body weight.
Asunto(s)
Ingestión de Energía/efectos de los fármacos , Tránsito Gastrointestinal/efectos de los fármacos , Absorción Intestinal/efectos de los fármacos , Ácido Oléico/uso terapéutico , Síndrome del Intestino Corto/tratamiento farmacológico , Adulto , Anciano , Estudios Cruzados , Diarrea/prevención & control , Suplementos Dietéticos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Alimentos , Humanos , Masculino , Persona de Mediana Edad , Péptido YY/efectos de los fármacos , Estudios Prospectivos , Síndrome del Intestino Corto/metabolismo , Síndrome del Intestino Corto/fisiopatología , Factores de TiempoRESUMEN
BACKGROUND & AIMS: Patients receiving parenteral nutrition (PN) still feel hungry despite adequate provision of calories intravenously. It is not known whether PN or its constituent macronutrients acutely affect appetite and to what degree this may be mediated by ghrelin and peptide YY (PYY). METHODS: Six medically stable patients (four men) with intestinal failure receiving PN received an isocaloric 200 kcal infusion on three separate occasions following a 12 h fast. The infusions consisted of either carbohydrate (10% dextrose), fat (10% intralipid) or mixed protein/carbohydrate (PN). Changes in ghrelin and peptide YY levels and changes in subjective symptoms of hunger, satiety and nausea during each macronutrient infusion were assessed. RESULTS: None of the three infusions acutely affected subjective symptoms of hunger, satiety and nausea (P>0.05 ANOVA). Ghrelin levels decreased significantly during dextrose [-19.1 (-35.9, -12.4), regression coefficient (95% CI), P<0.001] and parenteral nutrition infusions [-18.2 (-26.8, -9.6), P<0.001]. Lipid infusion had no effect on ghrelin levels but led to a significant decrease in PYY [-0.076 (-0.0123, -0.028), P=0.004]. Dextrose and PN infusion had no significant effect on PYY levels. CONCLUSIONS: Dextrose and PN infusions decrease ghrelin levels. Lipid infusion does not affect ghrelin levels but in contrast to oral nutrients leads to a significant decrease in PYY. Despite these changes, in patients receiving PN, macronutrient infusions do no acutely affect appetite.
Asunto(s)
Apetito/efectos de los fármacos , Emulsiones Grasas Intravenosas/farmacología , Glucosa/farmacología , Nutrición Parenteral , Hormonas Peptídicas/sangre , Péptido YY/sangre , Adulto , Anciano , Apetito/fisiología , Área Bajo la Curva , Glucemia/metabolismo , Método Doble Ciego , Femenino , Ghrelina , Humanos , Insulina/metabolismo , Enfermedades Intestinales/terapia , Masculino , Persona de Mediana Edad , Náusea/epidemiología , Hormonas Peptídicas/efectos de los fármacos , Péptido YY/efectos de los fármacos , Proteínas/farmacología , Respuesta de Saciedad/efectos de los fármacosRESUMEN
Many peptides are synthesised and released from the gastrointestinal tract. Whilst their roles in regulation of gastrointestinal function have been known for some time, it is now evident that they also influence eating behaviour and thus potential anti obesity targets. Peptide YY (PYY) is released post prandially from the gastrointestinal L-cells with glucagon-like peptide 1 (GLP-1) and oxyntomodulin. Following peripheral administration of PYY 3-36, the circulating form of PYY, to mouse, rat or human there is marked inhibition of food intake. PYY 3-36 is thought to mediate its actions through the NPY Y2 GPCR. Obese subjects have lower basal fasting PYY levels and have a smaller post prandial rise. However, obesity does not appear to be associated with resistance to PYY (as it is with leptin) and exogenous infusion of PYY 3-36 results in a reduction in food intake by 30% in an obese group and 31% in a lean group. GLP-1 or oxyntomodulin, products of the prepreglucagon gene, decrease food intake when administered either peripherally or directly into the CNS. In addition, both have been shown to decrease food intake in humans. These effects are thought to be mediated by the GLP-1 receptor. Ghrelin, a huger hormone produced by the stomach, increases in the circulation following a period of fasting. Administration of ghrelin either peripherally or directly into the CNS increases food intake and chronic administration leads to obesity. Further infusion into normal healthy volunteers increases both food intake and appetite. Ghrelin is thought to act through the growth hormone secretagogue receptor (GHS-R). Obesity is the current major cause of premature death in the UK, killing almost 1000 people a week. Worldwide its prevalence is accelerating. The administration of the naturally occurring gut hormone may offer a long-term therapeutic approach to weight control. Here we consider the therapeutic potential of some gut hormones, and the GPCR's through which they act, in the treatment of obesity.
Asunto(s)
Fármacos Antiobesidad/clasificación , Regulación del Apetito/fisiología , Hormonas Gastrointestinales/metabolismo , Obesidad/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animales , Fármacos Antiobesidad/farmacología , Fármacos Antiobesidad/uso terapéutico , Regulación del Apetito/efectos de los fármacos , Diseño de Fármacos , Hormonas Gastrointestinales/agonistas , Hormonas Gastrointestinales/antagonistas & inhibidores , Ghrelina , Glucagón/efectos de los fármacos , Glucagón/metabolismo , Péptido 1 Similar al Glucagón , Péptidos Similares al Glucagón/efectos de los fármacos , Péptidos Similares al Glucagón/metabolismo , Humanos , Ratones , Obesidad/tratamiento farmacológico , Oxintomodulina , Polipéptido Pancreático/efectos de los fármacos , Polipéptido Pancreático/metabolismo , Fragmentos de Péptidos/efectos de los fármacos , Fragmentos de Péptidos/metabolismo , Hormonas Peptídicas/efectos de los fármacos , Hormonas Peptídicas/metabolismo , Péptido YY/efectos de los fármacos , Péptido YY/metabolismo , Precursores de Proteínas/efectos de los fármacos , Precursores de Proteínas/metabolismo , Ratas , Receptores Acoplados a Proteínas G/efectos de los fármacosRESUMEN
BACKGROUND: Whether or not peptide YY (PYY)-induced hyperphagia is modified by the histaminergic system in the brain is not yet known. METHODS: We investigated the effect on feeding of intracerebroventricular (ICV) administration of a specific histamine H3 receptor antagonist prior to ICV administration of PYY in rats. RESULTS: PYY (1, 3, and 10 micrograms/10 microL) strongly induced feeding behavior in a dose-dependent manner in sated rats. The 4-hour food intake induced by 3 micrograms/10 microL of PYY was equal to that induced by a 16-hour fast. The ICV administration of thioperamide (40.8, 122.4, and 408.5 micrograms/10 microL) did not suppress the 4-hour food intake induced by 16-hour fasting; however, thioperamide produced dose-dependent and strong inhibition of hyperphagia induced by a 3-microgram dose of PYY. CONCLUSIONS: These results suggest that the effect of PYY on appetite is different than that induced by fasting and may involve a histaminergic mechanism.