RESUMEN
Previous studies have suggested that the effects of androgens on body weight (BW) and appetite are affected by the estrogen milieu in females; however, the mechanism underlying these effects remains unclear. We hypothesized that androgens may affect endogenous oxytocin (OT), which is a hypothalamic anorectic factor, and that these effects of androgens may be altered by the estrogen milieu in females. To investigate this hypothesis, in the present study, we examined the effects of testosterone on peripheral and central OT levels in ovariectomized female rats that did or did not receive estradiol supplementation. Ovariectomized female rats were randomly divided into non-estradiol-supplemented or estradiol-supplemented groups, and half of the rats in each group were concurrently supplemented with testosterone (i.e., rats were divided into four groups, n = 7 per each group). We also measured peripheral and central OT receptor (OTR) gene expression levels. As a result, we found that testosterone increased serum and hypothalamic OT levels and OT receptor mRNA levels in non-estradiol-supplemented rats, whereas it had no effects on these factors in estradiol-supplemented rats. In addition, testosterone reduced food intake, BW gain, and fat weight in non-estradiol-supplemented rats, whereas it did not have any effects on BW, appetite, or fat weight in estradiol-supplemented rats. These findings indicate that the effects of androgens on OT may be affected by the estrogen milieu, and elevated OT levels may be related to the blunting of appetite and prevention of obesity under estrogen-deficient conditions.
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Estradiol , Hipotálamo , Ovariectomía , Oxitocina , Receptores de Oxitocina , Testosterona , Animales , Oxitocina/sangre , Oxitocina/farmacología , Femenino , Testosterona/sangre , Hipotálamo/metabolismo , Hipotálamo/efectos de los fármacos , Estradiol/sangre , Estradiol/farmacología , Ratas , Receptores de Oxitocina/metabolismo , Receptores de Oxitocina/genética , Estrógenos/sangre , Estrógenos/farmacología , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Ratas Sprague-Dawley , Apetito/efectos de los fármacos , ARN Mensajero/metabolismoRESUMEN
This study investigated whether ghrelin mimetics, namely anamorelin and ipamorelin, can alleviate weight loss and inhibition of feeding observed during acute and delayed phases of cisplatin-induced emesis in ferrets. The potential of anamorelin to inhibit electrical field stimulation (EFS)-induced contractions of isolated ferret ileum was compared with ipamorelin. In other experiments, ferrets were administered anamorelin (1-3 mg/kg), ipamorelin (1-3 mg/kg), or vehicle intraperitoneally (i.p.) 30 s before cisplatin (5 mg/kg, i.p.) and then every 24 h, and their behaviour was recorded for up to 72 h. Food and water consumption was measured every 24 h. The effect of anamorelin (10 µg) was also assessed following intracerebroventricular administration. Anamorelin and ipamorelin inhibited EFS-induced contractions of isolated ileum by 94.4 % (half-maximal inhibitory concentration [IC50]=14.0 µM) and 54.4 % (IC50=11.7 µM), respectively. Neither of compounds administered i.p. had any effect on cisplatin-induced acute or delayed emesis, but both inhibited associated cisplatin-induced weight loss on the last day of delayed phase (48-72 h) by approximately 24 %. Anamorelin (10 µg) administered intracerebroventricularly reduced cisplatin-induced acute emesis by 60 % but did not affect delayed emesis. It also improved food and water consumption by approximately 20 %-40 % during acute phase, but not delayed phase, and reduced associated cisplatin-induced weight loss during delayed phase by â¼23 %. In conclusion, anamorelin and ipamorelin administered i.p. had beneficial effects in alleviating cisplatin-induced weight loss during delayed phase, and these effects were seen when centrally administered anamorelin. Anamorelin inhibited cisplatin-induced acute emesis following intracerebroventricular but not intraperitoneal administration, suggesting that brain penetration is important for its anti-emetic mechanism of action.
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Cisplatino , Hurones , Pérdida de Peso , Animales , Pérdida de Peso/efectos de los fármacos , Masculino , Ingestión de Alimentos/efectos de los fármacos , Receptores de Ghrelina/agonistas , Receptores de Ghrelina/antagonistas & inhibidores , Vómitos/inducido químicamente , Vómitos/prevención & control , Vómitos/tratamiento farmacológico , Antieméticos/farmacología , Oligopéptidos/farmacología , Íleon/efectos de los fármacos , Ingestión de Líquidos/efectos de los fármacos , Relación Dosis-Respuesta a DrogaRESUMEN
Despite the therapeutic potential of chemogenetics, the method lacks comprehensive preclinical validation, hindering its progression to human clinical trials. We aimed to validate a robust but simple in vivo efficacy assay in rats which could support chemogenetic drug discovery by providing a quick, simple and reliable animal model. Key methodological parameters such as adeno-associated virus (AAV) serotype, actuator drug, dose, and application routes were investigated by measuring the food-intake-reducing effect of chemogenetic inhibition of the lateral hypothalamus (LH) by hM4D(Gi) designer receptor stimulation. Subcutaneous deschloroclozapine in rats transfected with AAV9 resulted in a substantial reduction of food-intake, comparable to the efficacy of exenatide. We estimated that the effect of deschloroclozapine lasts 1-3 h post-administration. AAV5, oral administration of deschloroclozapine, and clozapine-N-oxide were also effective but with slightly less potency. The strongest effect on food-intake occurred within the first 30 min after re-feeding, suggesting this as the optimal experimental endpoint. This study demonstrates that general chemogenetic silencing of the LH can be utilized as an optimal, fast and reliable in vivo experimental model for conducting preclinical proof-of-concept studies in order to validate the in vivo effectiveness of novel chemogenetic treatments. We also hypothesize based on our results that universal LH silencing with existing and human translatable genetic neuroengineering techniques might be a viable strategy to affect food intake and influence obesity.
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Clozapina , Dependovirus , Ingestión de Alimentos , Área Hipotalámica Lateral , Prueba de Estudio Conceptual , Animales , Clozapina/análogos & derivados , Clozapina/farmacología , Ratas , Ingestión de Alimentos/efectos de los fármacos , Área Hipotalámica Lateral/efectos de los fármacos , Dependovirus/genética , Masculino , Exenatida/farmacología , HumanosRESUMEN
BACKGROUND: Antipsychotics are indispensable in the treatment of severe mental illneses, however adverse metabolic effects including diabetes, weight gain, dyslipidemia, and related cardiovascular morbidity are common, and current pharmacological strategies for their management are unsatisfactory. Glucagon-like 1 peptide receptor agonists (GLP-1 RAs) are approved for the treatment of type 2 diabetes and obesity hold promise for the management of antipsychotic-associated adverse metabolic effects. METHODS: To characterize the molecular effects and identify biomarkers for GLP-1 RA preventive treatment, Sprague-Dawley female rats were treated with long-acting formulations of the antipsychotic olanzapine and the GLP-1 RA dulaglutide for 8 days. A pair-feeding protocol evaluated the combined effects of dulaglutide and food restriction on an olanzapine-induced metabolic phenotype. Body weight and food consumption were recorded. Biochemical analysis included a lipid profile, a spectrum of gastrointestinal and adipose tissue-derived hormones, and fibroblast growth factor 21 serum levels. RESULTS: Olanzapine induced hyperphagia, weight gain, increased serum triglycerides and HDL cholesterol. Food restriction affected the OLA-induced phenotype but not serum markers. Dulaglutide led to a modest decrease in food intake, with no effect on weight gain, and did not reverse the OLA-induced changes in serum lipid parameters. Concomitant dulaglutide and food restriction resulted in weight loss, decreased feed efficiency, and lower total and HDL cholesterol. CONCLUSIONS: A combined strategy of dulaglutide and food restriction manifested a massive synergistic benefit. GLP-1RAs represent a promising strategy and deserve thorough future research. Our findings underline the potential importance of lifestyle intervention in addition to GLP-1 RA treatment.
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Péptidos Similares al Glucagón , Fragmentos Fc de Inmunoglobulinas , Olanzapina , Ratas Sprague-Dawley , Proteínas Recombinantes de Fusión , Animales , Fragmentos Fc de Inmunoglobulinas/farmacología , Péptidos Similares al Glucagón/análogos & derivados , Péptidos Similares al Glucagón/farmacología , Olanzapina/farmacología , Olanzapina/efectos adversos , Femenino , Proteínas Recombinantes de Fusión/farmacología , Ratas , Antipsicóticos/farmacología , Antipsicóticos/efectos adversos , Ingestión de Alimentos/efectos de los fármacos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Aumento de Peso/efectos de los fármacos , Modelos Animales de Enfermedad , Benzodiazepinas/farmacología , Benzodiazepinas/efectos adversos , Peso Corporal/efectos de los fármacos , Restricción Calórica/métodosRESUMEN
The serotonin 2C receptor (5-HT2CR)-melanocortin pathway plays well-established roles in the regulation of feeding behavior and body weight homeostasis. Dysfunctions in this system, such as loss-of-function mutations in the Htr2c gene, can lead to hyperphagia and obesity. In this study, we aimed to investigate the potential therapeutic strategies for ameliorating hyperphagia, hyperglycemia, and obesity associated with a loss-of-function mutation in the Htr2c gene (Htr2cF327L/Y). We demonstrated that reexpressing functional 5-HT2CR solely in hypothalamic pro-opiomelanocortin (POMC) neurons is sufficient to reduce food intake and body weight in Htr2cF327L/Y mice subjected to a high-fat diet (HFD). In addition, 5-HT2CR expression restores the responsiveness of POMC neurons to lorcaserin, a selective agonist for 5-HT2CR. Similarly, administration of melanotan II, an agonist of the melanocortin receptor 4 (MC4R), effectively suppresses feeding and weight gain in Htr2cF327L/Y mice. Strikingly, promoting wheel-running activity in Htr2cF327L/Y mice results in a decrease in HFD consumption and improved glucose homeostasis. Together, our findings underscore the crucial role of the melanocortin system in alleviating hyperphagia and obesity related to dysfunctions of the 5-HT2CR, and further suggest that MC4R agonists and lifestyle interventions might hold promise in counteracting hyperphagia, hyperglycemia, and obesity in individuals carrying rare variants of the Htr2c gene.
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Dieta Alta en Grasa , Hiperfagia , Obesidad , Proopiomelanocortina , Receptor de Melanocortina Tipo 4 , Receptor de Serotonina 5-HT2C , Animales , Receptor de Serotonina 5-HT2C/metabolismo , Receptor de Serotonina 5-HT2C/genética , Masculino , Ratones , Hiperfagia/metabolismo , Hiperfagia/genética , Proopiomelanocortina/metabolismo , Proopiomelanocortina/genética , Obesidad/metabolismo , Obesidad/genética , Receptor de Melanocortina Tipo 4/genética , Receptor de Melanocortina Tipo 4/metabolismo , Receptor de Melanocortina Tipo 4/agonistas , alfa-MSH/farmacología , alfa-MSH/análogos & derivados , Mutación con Pérdida de Función , Hipotálamo/metabolismo , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Ingestión de Alimentos/genética , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Modelos Animales de Enfermedad , Hiperglucemia/metabolismo , Hiperglucemia/genética , Ratones Endogámicos C57BL , Benzazepinas , Péptidos CíclicosRESUMEN
INTRODUCTION: GLP-1 receptor agonists are the number one drug prescribed for the treatment of obesity and type 2 diabetes. These drugs are not, however, without side effects, and in an effort to maximize therapeutic effect while minimizing adverse effects, gut hormone co-agonists received considerable attention as new drug targets in the fight against obesity. Numerous previous reports identified the neuropeptide oxytocin (OXT) as a promising anti-obesity drug. The aims of this study were to evaluate OXT as a possible co-agonist for GLP-1 and examine the effects of its co-administration on food intake (FI) and body weight (BW) in mice. METHODS: FI and c-Fos levels were measured in the feeding centers of the brain in response to an intraperitoneal injection of saline, OXT, GLP-1, or OXT/GLP-1. The action potential frequency and cytosolic Ca2+ ([Ca2+]i) in response to OXT, GLP-1, or OXT/GLP-1 were measured in ex vivo paraventricular nucleus (PVN) neuronal cultures. Finally, FI and BW changes were compared in diet-induced obese mice treated with saline, OXT, GLP-1, or OXT/GLP-1 for 13 days. RESULTS: Single injection of OXT/GLP-1 additively decreased FI and increased c-Fos expression specifically in the PVN and supraoptic nucleus. Seventy percent of GLP-1 receptor-positive neurons in the PVN also expressed OXT receptors, and OXT/GLP-1 co-administration dramatically increased firing and [Ca2+]i in the PVN OXT neurons. The chronic OXT/GLP-1 co-administration decreased BW without changing FI. CONCLUSION: Chronic OXT/GLP-1 co-administration decreases BW, possibly via the activation of PVN OXT neurons. OXT might be a promising candidate as an incretin co-agonist in obesity treatment.
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Peso Corporal , Ingestión de Alimentos , Péptido 1 Similar al Glucagón , Ratones Endogámicos C57BL , Oxitocina , Oxitocina/administración & dosificación , Oxitocina/farmacología , Oxitocina/metabolismo , Animales , Péptido 1 Similar al Glucagón/metabolismo , Masculino , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Ratones , Peso Corporal/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/metabolismo , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismoRESUMEN
Nicotine use produces psychoactive effects, and chronic use is associated with physiological and psychological symptoms of addiction. However, chronic nicotine use is known to decrease food intake and body weight gain, suggesting that nicotine also affects central metabolic and appetite regulation. We recently showed that acute nicotine self-administration in nicotine-dependent animals produces a short-term increase in food intake, contrary to its long-term decrease of feeding behavior. As feeding behavior is regulated by complex neural signaling mechanisms, this study aimed to test the hypothesis that nicotine intake in animals exposed to chronic nicotine may increase activation of pro-feeding regions and decrease activation of pro-satiety regions to produce the acute increase in feeding behavior. FOS immunohistochemistry revealed that acute nicotine intake in nicotine self-administering animals increased activation of the pro-feeding arcuate and lateral hypothalamic nuclei and decreased activation of the pro-satiety parabrachial nucleus. Regional correlational analysis also showed that acute nicotine changes the functional connectivity of the hunger/satiety network. Further dissection of the role of the arcuate nucleus using electrophysiology found that putative POMC neurons in animals given chronic nicotine exhibited decreased firing following acute nicotine application. These brain-wide central signaling changes may contribute to the acute increase in feeding behavior we see in rats after acute nicotine and provide new areas of focus for studying both nicotine addiction and metabolic regulation.
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Encéfalo , Nicotina , Animales , Nicotina/farmacología , Masculino , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ratas , Ratas Sprague-Dawley , Agonistas Nicotínicos/farmacología , Conducta Alimentaria/efectos de los fármacos , Proopiomelanocortina/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Autoadministración , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Anorexia/inducido químicamenteRESUMEN
Cobalt protoporphyrin (CoPP) is a synthetic heme analog that has been observed to reduce food intake and promote sustained weight loss. While the precise mechanisms responsible for these effects remain elusive, earlier research has hinted at the potential involvement of nitric oxide synthase in the hypothalamus. This study aimed to delve into CoPP's impact on the activities of crucial antioxidant enzymes: superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST) across seven distinct brain regions (hippocampus, hypothalamus, prefrontal cortex, motor cortex, striatum, midbrain, and cerebellum), as well as in the liver and kidneys. Female Wistar rats weighing 180 to 200 grams received a single subcutaneous dose of 25 µmol/kg CoPP. After six days, brain tissue was extracted to assess the activities of antioxidant enzymes and quantify malondialdehyde levels. Our findings confirm that CoPP administration triggers the characteristic effects of decreased food intake and reduced body weight. Moreover, it led to an increase in SOD activity in the hypothalamus, a pivotal brain region associated with food intake regulation. Notably, CoPP-treated rats exhibited elevated enzymatic activity of catalase, GR, and GST in the motor cortex without concurrent signs of heightened oxidative stress. These results underscore a strong connection between the antioxidant system and food intake regulation. They also emphasize the need for further investigation into the roles of antioxidant enzymes in modulating food intake and the ensuing weight loss, using CoPP as a valuable research tool.
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Antioxidantes , Hipotálamo , Corteza Motora , Protoporfirinas , Animales , Femenino , Ratas , Antioxidantes/metabolismo , Peso Corporal/efectos de los fármacos , Catalasa/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Glutatión Peroxidasa/efectos de los fármacos , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/efectos de los fármacos , Glutatión Reductasa/metabolismo , Glutatión Transferasa/efectos de los fármacos , Glutatión Transferasa/metabolismo , Hipotálamo/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/enzimología , Malondialdehído/metabolismo , Corteza Motora/efectos de los fármacos , Corteza Motora/metabolismo , Corteza Motora/enzimología , Estrés Oxidativo/efectos de los fármacos , Protoporfirinas/farmacología , Ratas Wistar , Superóxido Dismutasa/efectos de los fármacos , Superóxido Dismutasa/metabolismoRESUMEN
Our previous research identified interleukin-4 (IL-4) as a key regulator of glucose/lipid metabolism, circulatory leptin levels, and insulin action, suggesting its potential as a therapeutic target for obesity and related complications. This study aimed to further elucidate the role of IL-4 in regulating hypothalamic appetite-controlling neuropeptides using leptin dysfunctional Leptin145E/145E mice as the experimental model. IL-4 significantly reduces body weight, food intake, and serum glucose levels. Our data demonstrated that IL-4 exhibits multiple functions in regulating hypothalamic appetite control, including downregulating orexigenic agouti-related peptide and neuropeptide Y levels, promoting expression of anorexigenic proopiomelanocortin, alleviating microenvironmental hypothalamic inflammation, enhancing leptin and insulin pathway, and attenuating insulin resistance. Furthermore, IL-4 promotes uncoupling protein 1 expression of white adipose tissue (WAT), suggesting its role in triggering WAT-beige switch. In summary, this study uncovers novel function of IL-4 in mediating food-intake behaviors and metabolic efficiency by regulating hypothalamic appetite-control and WAT browning activities. These findings support the therapeutic potential of targeting hypothalamic inflammation and reducing adiposity through IL-4 intervention for tackling the pandemic increasing prevalence of obesity and associated metabolic disorders.
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Hipotálamo , Insulina , Interleucina-4 , Leptina , Transducción de Señal , Animales , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Interleucina-4/metabolismo , Ratones , Transducción de Señal/efectos de los fármacos , Leptina/metabolismo , Insulina/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Masculino , Quinasas Janus/metabolismo , Regulación del Apetito/efectos de los fármacos , Apetito/efectos de los fármacos , Factores de Transcripción STAT/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismoRESUMEN
Amylin, a pancreatic hormone, is well-established to suppress feeding by enhancing satiation. Pramlintide, an amylin analog that is FDA-approved for the treatment of diabetes, has also been shown to produce hypophagia. However, the behavioral mechanisms underlying the ability of pramlintide to suppress feeding are unresolved. We hypothesized that systemic pramlintide administration in rats would reduce energy intake, specifically by reducing meal size. Male rats were given b.i.d. administration of intraperitoneal pramlintide or vehicle for 1 week, and chow intake, meal patterns, and body weight were monitored throughout the test period. Consistent with our hypothesis, pramlintide decreased chow intake mainly via suppression of meal size, with corresponding reductions in meal duration on several days. Fewer effects on meal number or feeding rate were detected. Pramlintide also reduced weight gain over the 1-week study. These results highlight that the behavioral mechanisms by which pramlintide produces hypophagia are similar to those driven by amylin itself, and provide important insight into the ability of this pharmacotherapy to promote negative energy balance over a period of chronic administration.
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Conducta Alimentaria , Polipéptido Amiloide de los Islotes Pancreáticos , Animales , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Masculino , Ratas , Conducta Alimentaria/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Ratas Sprague-Dawley , Peso Corporal/efectos de los fármacos , Ingestión de Energía/efectos de los fármacosRESUMEN
The first oral form of the glucagon-like peptide-1 receptor agonist, oral semaglutide, has recently been launched and potently controls glycemia and body weight in subjects with type 2 diabetes. This drug carries the absorption enhancer and requires specific protocols of administration. The mechanism of action of oral semaglutide is not fully understood, for which an appropriate experimental model is required. This study explores the metabolic effects of oral semaglutide in mice under human protocols and doses. Oral semaglutide was bolus and once daily injected into high-fat diet-induced obese (DIO) mice under human protocols, followed by monitoring blood glucose, food intake, and body weight. Oral semaglutide 0.23 mg/kg, a comparable human dose (14 mg) in a small volume of water under human protocols rapidly decreased blood glucose and food intake and continuously reduced food intake and weight gain for 3 days in DIO mice. At 0.7 mg/kg (42 mg), this drug was somewhat more potent. Oral semaglutide with human protocols and doses rapidly reduces blood glucose and food intake and continuously suppresses feeding and weight in DIO mice. This study establishes mice as a model suitable for analyzing the mechanism of anti-obesity/diabetes actions of oral semaglutide.
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Dieta Alta en Grasa , Ingestión de Alimentos , Péptidos Similares al Glucagón , Ratones Obesos , Péptidos Similares al Glucagón/administración & dosificación , Péptidos Similares al Glucagón/farmacología , Ingestión de Alimentos/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Glucemia/efectos de los fármacos , Animales , RatonesRESUMEN
Several triggers can trigger a migraine attack, including food. By the way, food only triggers headache in migraine sufferers. The foods that most trigger headache attacks are these: cheese, chocolate, citrus fruits and some sweet fruits, such as watermelon.
Vários gatilhos podem desencadear uma crise de enxaqueca, incluindo alimentos. Aliás, a comida só provoca dor de cabeça em quem sofre de enxaqueca. Os alimentos que mais desencadeiam as crises de dor de cabeça são estes: queijo, chocolate, frutas cítricas e algumas frutas doces, como a melancia.
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Humanos , Masculino , Femenino , Ingestión de Alimentos/efectos de los fármacos , Frutas/efectos adversos , Cefalea/diagnóstico , Trastornos Migrañosos/clasificaciónRESUMEN
Elevated circulating levels of growth differentiation factor 15 (GDF15) have been shown to reduce food intake and lower body weight through activation of hindbrain receptor glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) in rodents and nonhuman primates, thus endogenous induction of this peptide holds promise for obesity treatment. Here, through in silico drug-screening methods, we found that small molecule Camptothecin (CPT), a previously identified drug with potential antitumor activity, is a GDF15 inducer. Oral CPT administration increases circulating GDF15 levels in diet-induced obese (DIO) mice and genetic ob/ob mice, with elevated Gdf15 expression predominantly in the liver through activation of integrated stress response. In line with GDF15's anorectic effect, CPT suppresses food intake, thereby reducing body weight, blood glucose, and hepatic fat content in obese mice. Conversely, CPT loses these beneficial effects when Gdf15 is inhibited by a neutralizing antibody or AAV8-mediated liver-specific knockdown. Similarly, CPT failed to reduce food intake and body weight in GDF15's specific receptor GFRAL-deficient mice despite high levels of GDF15. Together, these results indicate that CPT is a promising anti-obesity agent through activation of GDF15-GFRAL pathway.
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Camptotecina/farmacología , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Factor 15 de Diferenciación de Crecimiento/genética , Obesidad/prevención & control , Animales , Peso Corporal/efectos de los fármacos , Peso Corporal/genética , Camptotecina/farmacocinética , Línea Celular , Línea Celular Tumoral , Dieta Alta en Grasa/efectos adversos , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/genética , Regulación de la Expresión Génica/efectos de los fármacos , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Factor 15 de Diferenciación de Crecimiento/metabolismo , Células HEK293 , Células HL-60 , Humanos , Células MCF-7 , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Obesos , Obesidad/etiología , Obesidad/genética , Células PC-3RESUMEN
AIMS: To evaluate whether the potent hypophagic and weight-suppressive effects of growth differentiation factor-15 (GDF15) and semaglutide combined would be a more efficacious antiobesity treatment than either treatment alone by examining whether the neural and behavioural mechanisms contributing to their anorectic effects were common or disparate. MATERIALS/METHODS: Three mechanisms were investigated to determine how GDF15 and semaglutide induce anorexia: the potentiation of the intake suppression by gastrointestinal satiation signals; the reduction in motivation to feed; and the induction of visceral malaise. We then compared the effects of short-term, combined GDF15 and semaglutide treatment on weight loss to the individual treatments. Rat pharmaco-behavioural experiments assessed whether GDF15 or semaglutide added to the satiating effects of orally gavaged food and exogenous cholecystokinin (CCK). A progressive ratio operant paradigm was used to examine whether GDF15 or semaglutide reduced feeding motivation. Pica behaviour (ie, kaolin intake) and conditioned affective food aversion testing were used to evaluate visceral malaise. Additionally, fibre photometry studies were conducted in agouti-related protein (AgRP)-Cre mice to examine whether GDF15 or semaglutide, alone or in combination with CCK, modulate calcium signalling in hypothalamic AgRP neurons. RESULTS: Semaglutide reduced food intake by amplifying the feeding-inhibitory effect of CCK or ingested food, inhibited the activity of AgRP neurons when combined with CCK, reduced feeding motivation and induced malaise. GDF15 induced visceral malaise but, strikingly, did not affect feeding motivation, the satiating effect of ingested food or CCK signal processing. Combined GDF15 and semaglutide treatment produced greater food intake and body weight suppression than did either treatment alone, without enhancing malaise. CONCLUSIONS: GDF15 and semaglutide reduce food intake and body weight through largely distinct processes that produce greater weight loss and feeding suppression when combined.
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Ingestión de Alimentos , Péptidos Similares al Glucagón , Factor 15 de Diferenciación de Crecimiento , Pérdida de Peso , Proteína Relacionada con Agouti/metabolismo , Animales , Anorexia/tratamiento farmacológico , Anorexia/metabolismo , Peso Corporal/efectos de los fármacos , Colecistoquinina/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Péptidos Similares al Glucagón/farmacología , Factor 15 de Diferenciación de Crecimiento/farmacología , Ratones , Ratas , Pérdida de Peso/efectos de los fármacosRESUMEN
There has been a concern that sodium-glucose cotransporter 2 (SGLT2) inhibitors could reduce skeletal muscle mass and function. Here, we examine the effect of canagliflozin (CANA), an SGLT2 inhibitor, on slow and fast muscles from nondiabetic C57BL/6J mice. In this study, mice were fed with or without CANA under ad libitum feeding, and then evaluated for metabolic valuables as well as slow and fast muscle mass and function. We also examined the effect of CANA on gene expressions and metabolites in slow and fast muscles. During SGLT2 inhibition, fast muscle function is increased, as accompanied by increased food intake, whereas slow muscle function is unaffected, although slow and fast muscle mass is maintained. When the amount of food in CANA-treated mice is adjusted to that in vehicle-treated mice, fast muscle mass and function are reduced, but slow muscle was unaffected during SGLT2 inhibition. In metabolome analysis, glycolytic metabolites and ATP are increased in fast muscle, whereas glycolytic metabolites are reduced but ATP is maintained in slow muscle during SGLT2 inhibition. Amino acids and free fatty acids are increased in slow muscle, but unchanged in fast muscle during SGLT2 inhibition. The metabolic effects on slow and fast muscles are exaggerated when food intake is restricted. This study demonstrates the differential effects of an SGLT2 inhibitor on slow and fast muscles independent of impaired glucose metabolism, thereby providing new insights into how they should be used in patients with diabetes, who are at a high risk of sarcopenia.
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Fibras Musculares de Contracción Rápida/efectos de los fármacos , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Adenilato Quinasa/biosíntesis , Adenilato Quinasa/genética , Tejido Adiposo Blanco/efectos de los fármacos , Aminoácidos/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Canagliflozina/farmacología , Ingestión de Alimentos/efectos de los fármacos , Ácidos Grasos no Esterificados/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Ontología de Genes , Glucólisis , Fuerza de la Mano , Hígado/efectos de los fármacos , Masculino , Metaboloma/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Fibras Musculares de Contracción Rápida/metabolismo , Músculo Esquelético/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transportador 2 de Sodio-Glucosa/fisiología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Serina-Treonina Quinasas TOR/biosíntesis , Serina-Treonina Quinasas TOR/genéticaRESUMEN
Coffee beans contain high polyphenol content, which have the potential to modulate the intestinal microbiota, and possibly attenuate weight gain and the associated dyslipidemia. This study investigated the effect of freeze-dried coffee solution (FCS) consumption on physiological parameters, lipid profile, and microbiota of Wistar rats fed a high-fat diet (HF) or control diet (CT). FCS combined with a high-fat diet increased the fecal and cecal Bifidobacterium spp. population and decreased the cecal Escherichia coli population and intestinal Il1b mRNA level. Regardless of the diet type, FCS increased the serum high-density lipoprotein cholesterol (HDL-C); however, it did not affect body weight, food intake, low-density lipoprotein, triglycerides, fecal bile acids, and intestinal Il6 mRNA levels. The high-fat diet increased weight gain, hepatic cholesterol and triglycerides, fecal bile acids, and the fecal and cecal Lactobacillus spp. population, and reduced food intake, the fecal E. coli population, and intestinal Il6 mRNA level. The results suggest that FCS consumption exhibits positive health effects in rats fed a high-fat diet by increasing Bifidobacterium spp. population and HDL-C reverse cholesterol transport, and by reducing Il1b mRNA level. However, FCS administration at a dose of 0.39 g/100 g diet over an eight-week period was not effective in controlling food intake, and consequently, preventing weight gain in rats of high-fat diet-induced obesity model.
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Café , Microbioma Gastrointestinal/efectos de los fármacos , Inflamación/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Lípidos/sangre , Obesidad/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Ingestión de Alimentos/efectos de los fármacos , Masculino , Obesidad/etiología , Ratas , Ratas WistarRESUMEN
Dual activation of the glucagon-like peptide 1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor has potential as a novel strategy for treatment of diabesity. Here, we created a hybrid peptide which we named 19W, and show that it is more stable in presence of murine plasma than exendin-4 is. In vitro studies were performed to reveal that 19W could stimulate insulin secretion from INS-1 cells in a dose-dependent manner, just like the native peptide GIP and exendin-4 do. 19W effectively evoked dose-dependent cAMP production in cells targeting both GLP-1R and GIPR. In healthy C57BL/6J mice, the single administration of 19W significantly improved glucose tolerance. When administered in combination with sodium deoxycholate (SDC), its oral hypoglycemic activity was enhanced. Pharmacokinetics studies in Wistar rats revealed that 19W was absorbed following oral uptake, while SDC increased its bioavailability. A long-term (28 days) exposure study of twice-daily oral administration to high fat-fed (HFF) mice showed that 19W significantly reduced animal food intake, body weight, fasting blood glucose, total serum cholesterol (T-CHO), non-esterified free fatty acids (NEFA), and low-density lipoprotein cholesterol (LDL-C) levels. It also significantly improved glucose tolerance and the pancreatic ß/α cell ratio, and decreased the area of liver fibrosis. These results clearly demonstrate the beneficial action of this novel oral GLP-1/GIP dual receptor agonist to reduce adiposity and hyperglycemia in diabetic mice and to ameliorate liver fibrosis associated with obesity. This dual-acting peptide can be considered a good candidate for novel oral therapy to treat obesity and diabetes.
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Péptido 1 Similar al Glucagón/metabolismo , Hipoglucemiantes/farmacología , Secreción de Insulina/efectos de los fármacos , Obesidad , Receptores de la Hormona Gastrointestinal/metabolismo , Animales , AMP Cíclico/biosíntesis , Diabetes Mellitus Experimental , Ingestión de Alimentos/efectos de los fármacos , Exenatida/farmacología , Polipéptido Inhibidor Gástrico/metabolismo , Incretinas/farmacología , Insulina/metabolismo , Enfermedades Metabólicas/tratamiento farmacológico , Enfermedades Metabólicas/metabolismo , Ratones , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , RatasRESUMEN
Growth differentiation factor 15 (GDF15), a TGFß superfamily cytokine, acts through its receptor, cell line-derived neurotrophic factorfamily receptor α-like (GFRAL), to suppress food intake and promote nausea. GDF15 is broadly expressed at low levels but increases in states of disease such as cancer, cachexia, and sepsis. Whether GDF15 is necessary for inducing sepsis-associated anorexia and body weight loss is currently unclear. To test this we used a model of moderate systemic infection in GDF15KO and GFRALKO mice with lipopolysaccharide (LPS) treatment to define the role of GDF15 signaling in infection-mediated physiologic responses. Since physiological responses to LPS depend on housing temperature, we tested the effects of subthermoneutral and thermoneutral conditions on eliciting anorexia and inducing GDF15. Our data demonstrate a conserved LPS-mediated increase in circulating GDF15 levels in mouse, rat, and human. However, we did not detect differences in LPS-induced anorexia between WT and GDF15KO or GFRALKO mice. Furthermore, there were no differences in anorexia or circulating GDF15 levels at either thermoneutral or subthermoneutral housing conditions in LPS-treated mice. These data demonstrate that GDF15 is not necessary to drive food intake suppression in response to moderate doses of LPS.NEW & NOTEWORTHY Although many responses to LPS depend on housing temperature, the anorexic response to LPS does not. LPS results in a potent and rapid increase in circulating levels of GDF15 in mice, rats, and humans. Nevertheless, GDF15 and its receptor (GFRAL) are not required for the anorexic response to systemic LPS administration. The anorexic response to LPS likely involves a myriad of complex physiological alterations.
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Anorexia/metabolismo , Factor 15 de Diferenciación de Crecimiento/efectos de los fármacos , Factor 15 de Diferenciación de Crecimiento/metabolismo , Lipopolisacáridos/farmacología , Animales , Ingestión de Alimentos/efectos de los fármacos , Humanos , Ratones , Náusea/inducido químicamente , Ratas , Pérdida de Peso/efectos de los fármacosRESUMEN
Cholecystokinin (CCK) increases core body temperature via CCK2 receptors when administered intracerebroventricularly (icv). The mechanisms of CCK-induced hyperthermia are unknown, and it is also unknown whether CCK contributes to the fever response to systemic inflammation. We studied the interaction between central CCK signaling and the cyclooxygenase (COX) pathway. Body temperature was measured in adult male Wistar rats pretreated with intraperitoneal infusion of the nonselective COX enzyme inhibitor metamizol (120 mg/kg) or a selective COX-2 inhibitor, meloxicam, or etoricoxib (10 mg/kg for both) and, 30 min later, treated with intracerebroventricular CCK (1.7 µg/kg). In separate experiments, CCK-induced neuronal activation (with and without COX inhibition) was studied in thermoregulation- and feeding-related nuclei with c-Fos immunohistochemistry. CCK increased body temperature by â¼0.4°C from 10 min postinfusion, which was attenuated by metamizol. CCK reduced the number of c-Fos-positive cells in the median preoptic area (by â¼70%) but increased it in the dorsal hypothalamic area and in the rostral raphe pallidus (by â¼50% in both); all these changes were completely blocked with metamizol. In contrast, CCK-induced satiety and neuronal activation in the ventromedial hypothalamus were not influenced by metamizol. CCK-induced hyperthermia was also completely blocked with both selective COX-2 inhibitors studied. Finally, the CCK2 receptor antagonist YM022 (10 µg/kg icv) attenuated the late phases of fever induced by bacterial lipopolysaccharide (10 µg/kg; intravenously). We conclude that centrally administered CCK causes hyperthermia through changes in the activity of "classical" thermoeffector pathways and that the activation of COX-2 is required for the development of this response.NEW & NOTEWORTHY An association between central cholecystokinin signaling and the cyclooxygenase-prostaglandin E pathway has been proposed but remained poorly understood. We show that the hyperthermic response to the central administration of cholecystokinin alters the neuronal activity within efferent thermoeffector pathways and that these effects are fully blocked by the inhibition of cyclooxygenase. We also show that the activation of cyclooxygenase-2 is required for the hyperthermic effect of cholecystokinin and that cholecystokinin is a modulator of endotoxin-induced fever.