RESUMO
Previous studies have proposed a role for neuromedin B (NB), a bombesin-like peptide, in the control of body weight homeostasis. However, the nature of this role is unclear. The actions of NB are mediated preferentially by NB-preferring receptors (NBRs). Here we examined the consequences of targeted deletion of NBRs in female mice on body weight homeostasis in mice fed a normolipid diet (ND) or a high-fat diet (HFD) for 13 weeks. Body weight and food ingestion of neuromedin B receptor knockout (NBR-KO) mice fed a normolipid diet showed no difference in relation to wild-type (WT). However, the high-fat diet induced an 8.9- and 4.8-fold increase in body weight of WT and NBR-KO, respectively, compared to their controls maintained with a normolipid diet, even though the mice ingested the same amount of calories, regardless of genotype. Comparing mice fed the high-fat diet, NBR-KO mice accumulated approximately 45% less fat depot mass than WT, exhibited a lower percentage of fat in their carcasses (19.2 vs. 31.3%), and their adipocytes were less hypertrophied. Serum leptin and leptin mRNA in inguinal and perigonadal fat were lower in HFD NBR-KO than HFD WT, and serum adiponectin was similar among HFD groups and unaltered in comparison to ND-fed mice. HFD-fed WT mice developed glucose intolerance but not the HFD-fed NBR-KO mice, although they had similar glycaemia and insulinaemia. NBR-KO and WT mice on the normolipid diet showed no differences in any parameters, except for a trend to lower insulin levels. Therefore, disruption of the neuromedin B receptor pathway did not change body weight homeostasis in female mice fed a normolipid diet; however, it did result in partial resistance to diet-induced obesity.
Assuntos
Dieta , Obesidade/genética , Receptores da Bombesina/fisiologia , Tecido Adiposo Branco/anatomia & histologia , Animais , Compostos Azo , Composição Corporal/genética , Composição Corporal/fisiologia , Peso Corporal/genética , Peso Corporal/fisiologia , Corantes , Gorduras na Dieta/farmacologia , Ingestão de Energia , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Feminino , Teste de Tolerância a Glucose , Homeostase/genética , Homeostase/fisiologia , Hormônios/sangue , Leptina/biossíntese , Leptina/genética , Lipídeos/sangue , Fígado/química , Fígado/metabolismo , Camundongos , Camundongos Knockout , Receptores da Bombesina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
Neuromedin B (NB), a neuropeptide highly concentrated in pituitary, has been proposed to be an inhibitor of thyrotropin (TSH) secretion. Previous study showed that mice with disruption of neuromedin B receptor (NBR-KO) have higher TSH release in response to thyrotropin-releasing hormone (TRH), although TSH seems to have decreased bioactivity. Here we examined in NBR-KO mice the response of TSH to thyroid hormone (TH) deprivation, obtained by methimazole treatment, or excess, obtained by acute and chronic TH administration. In response to hypothyroidism NBR-KO mice exhibited a lower magnitude increase in serum TSH compared to wild-type (WT) mice (1.7 vs. 3.3-times increase compared to euthyroid values, respectively, P<0.001). One hour after a single T4 injection (0.4 microg/100 g BW), WT and NBR-KO hypothyroid mice presented similar degree of serum TSH reduction (54%, P<0.05). However, 3 h after T4 administration, WT mice presented serum TSH similar to hypothyroid baseline, while NBR-KO mice still had decreased serum TSH (30% reduced in comparison to hypothyroid baseline P<0.05). T3 treatment of euthyroid mice for 21 days, with progressively increasing doses, significantly reduced serum TSH similarly in WT and NBR-KO mice. Also, serum T4 exhibited the same degree of suppression in WT and NBR-KO. In conclusion, disruption of neuromedin B receptor did not interfere with the sensitivity of thyroid hormone-mediated suppression of TSH release, but impaired the ability of thyrotroph to increase serum TSH in hypothyroidism, which highlights the importance of NB in modulating the set point of the hypothalamus-pituitary-thyroid axis at hypothyroidism.
Assuntos
Hipotireoidismo/sangue , Receptores da Bombesina/fisiologia , Tireotropina/sangue , Animais , Hipotireoidismo/induzido quimicamente , Masculino , Camundongos , Camundongos Knockout , Receptores da Bombesina/genética , Tireotropina/metabolismoRESUMO
Bombesin-like peptides (BLP) and its receptors are widely distributed in mammalian peripheral tissues and in the central nervous system. Recently, effects of these peptides on the production and release of cytokines were described both in animal models and humans with inflammatory diseases. Some pathological conditions such as exposure to tobacco smoke, chronic obstructive pulmonary diseases and eosinophilic granuloma have recently been found to be associated with an increase of pulmonary BLP-producing cells. Proinflammatory neuropeptides have a key role in the pathogenesis and maintenance of rheumatoid arthritis and sepsis. Together, these findings support the view that the GRPR should be considered a therapeutic target for a subset of inflammatory diseases.
Assuntos
Inflamação/tratamento farmacológico , Receptores da Bombesina/antagonistas & inibidores , Animais , Bombesina/análogos & derivados , Bombesina/farmacologia , Bombesina/uso terapêutico , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Interleucina-1/metabolismo , Modelos Biológicos , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/uso terapêutico , Receptores da Bombesina/metabolismo , Receptores da Bombesina/fisiologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Gastrin-releasing peptide (GRP) is a mammalian counterpart of the amphibian peptide bombesin (BB) that stimulates cell proliferation, acts as a growth factor in the pathogenesis of many types of cancer, and regulates several aspects of neuroendocrine function. BB and GRP act by binding to the GRP-preferring type of BB receptor (GRPR, also known as BB2 receptor), a member of the superfamily of G-protein coupled membrane receptors. This review summarizes recent evidence from animal and human studies indicating that abnormalities in GRPR function in the brain might play a role in the pathogenesis of neurological and psychiatric disorders, and suggesting that BB, GRP, and GRPR antagonists might display therapeutic actions in central nervous system diseases. Recent patent applications on GRPR-related methods for treating brain disorders are introduced.
Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Receptores da Bombesina/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Peptídeo Liberador de Gastrina/fisiologia , Humanos , Camundongos , Dados de Sequência Molecular , Receptores da Bombesina/química , Receptores da Bombesina/fisiologia , Transdução de SinaisRESUMO
The gastrin-releasing peptide receptor (GRPR) has been implicated in central nervous system (CNS) diseases, including neurodevelopmental disorders associated with autism. In the present study we examined the effects of GRPR blockade during the neonatal period on behavioral measures relevant to animal models of neurodevelopmental disorders. Male Wistar rats were given an intraperitoneal (i.p.) injection of either saline (SAL) or the GRPR antagonist [D-Tpi(6), Leu(13) psi(CH(2)NH)-Leu(14)] bombesin (6-14) (RC-3095; 1 or 10mg/kg) twice daily for 10days from postnatal days (PN) 1 to 10. Animals treated with RC-3095 showed pronounced deficits in social interaction when tested at PN 30-35 and impaired 24-h retention of memory for both novel object recognition (NOR) and inhibitory avoidance (IA) tasks tested at PN 60-71. Neither short-term memory tested 1.5h posttraining nor open field behavior were affected by neonatal GRPR blockade. The implications of the findings for animal models of neurodevelopmental disorders are discussed.
Assuntos
Bombesina/análogos & derivados , Transtornos da Memória/induzido quimicamente , Fragmentos de Peptídeos , Receptores da Bombesina/antagonistas & inibidores , Receptores da Bombesina/fisiologia , Transtornos do Comportamento Social/induzido quimicamente , Fatores Etários , Animais , Animais Recém-Nascidos , Aprendizagem da Esquiva/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Feminino , Inibição Psicológica , Injeções Intraperitoneais/métodos , Locomoção/efeitos dos fármacos , Masculino , Transtornos da Memória/fisiopatologia , Atividade Motora/efeitos dos fármacos , Gravidez , Ratos , Ratos Wistar , Transtornos do Comportamento Social/fisiopatologiaRESUMO
Although the gastrin-releasing peptide receptor has been implicated in memory consolidation, previous studies have not examined whether it is involved in extinction. Here we show that gastrin-releasing peptide receptor blockade in the hippocampus disrupts extinction of aversive memory. Male rats were trained in inhibitory avoidance conditioning and then returned repeatedly to the training context without shock on a daily basis for 3 days. Infusion of a gastrin-releasing peptide receptor antagonist or the protein synthesis inhibitor anisomycin into the dorsal hippocampus immediately after the first extinction session blocked extinction. These drugs did not affect performance in subsequent sessions when the first extinction session (1 day after training) was omitted. The results indicate that hippocampal gastrin-releasing peptide receptors are involved in memory extinction.
Assuntos
Aprendizagem da Esquiva/fisiologia , Extinção Psicológica/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Receptores da Bombesina/fisiologia , Animais , Anisomicina/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal , Bombesina/análogos & derivados , Bombesina/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Extinção Psicológica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Receptores da Bombesina/antagonistas & inibidores , Estatísticas não Paramétricas , Fatores de TempoRESUMO
Although the gastrin-releasing peptide-preferring bombesin receptor (GRPR) has been implicated in memory formation, the underlying molecular events are poorly understood. In the present study, we examined interactions between the GRPR and cellular signaling pathways in influencing memory consolidation in the hippocampus. Male Wistar rats received bilateral infusions of bombesin (BB) into the dorsal hippocampus immediately after inhibitory avoidance (IA) training. Intermediate doses of BB enhanced, whereas a higher dose impaired, 24-h IA memory retention. The BB-induced memory enhancement was prevented by pretraining infusions of a GRPR antagonist or inhibitors of protein kinase C (PKC), mitogen-activated protein kinase (MAPK) kinase and protein kinase A (PKA), but not by a neuromedin B receptor (NMBR) antagonist. We next further investigated the interactions between the GRPR and the PKA pathway. BB-induced enhancement of consolidation was potentiated by coinfusion of activators of the dopamine D1/D5 receptor (D1R)/cAMP/PKA pathway and prevented by a PKA inhibitor. We conclude that memory modulation by hippocampal GRPRs is mediated by the PKC, MAPK, and PKA pathways. Furthermore, pretraining infusion of BB prevented beta-amyloid peptide (25-35)-induced memory impairment, supporting the view that the GRPR is a target for the development of cognitive enhancers for dementia.
Assuntos
Hipocampo/fisiologia , Memória , Receptores da Bombesina/fisiologia , Peptídeos beta-Amiloides/farmacologia , Animais , Bombesina/farmacologia , AMP Cíclico/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Hipocampo/efeitos dos fármacos , Masculino , Quinases de Proteína Quinase Ativadas por Mitógeno/fisiologia , Fragmentos de Peptídeos/farmacologia , Proteína Quinase C/fisiologia , Ratos , Ratos Wistar , Receptores da Bombesina/agonistas , Receptores de Dopamina D5/agonistas , Transdução de SinaisRESUMO
The level of thyrotropin (TSH) secretion is determined by the balance of TSH-releasing hormone (TRH) and thyroid hormones. However, neuromedin B (NB), a bombesin-like peptide, highly concentrated in the pituitary, has been postulated to be a tonic inhibitor of TSH secretion. We studied the pituitary-thyroid axis in adult male mice lacking NB receptor (NBR-KO) and their wild-type (WT) littermates. At basal state, NBR-KO mice presented serum TSH slightly higher than WT (18%, P< 0.05), normal intra-pituitary TSH content, and no significant changes in alpha and beta TSH mRNA levels. Serum thyroxine was normal but serum triiodothyronine (T3) was reduced by 24% (P< 0.01) in NBR-KO mice. Pituitaries of NBR-KO mice exhibited no alteration in prolactin mRNA expression but type I and II deiodinase mRNA levels were reduced by 53 and 42% respectively (P< 0.05), while TRH receptor mRNA levels were importantly increased (78%, P< 0.05). The TSH-releasing effect of TRH was significantly higher in NBR-KO than in WT mice (7.1-and 4.0-fold respectively), but, while WT mice presented a 27% increase in serum T3 (P< 0.05) after TRH, NBR-KO mice showed no change in serum T3 after TRH. NBR-KO mice did not respond to exogenous NB, while WT showed a 30% reduction in serum TSH. No compensatory changes in mRNA expression of NB or other bombesin-related peptides and receptors (gastrin-releasing peptide (GRP), GRP-receptor and bombesin receptor subtype-3) were found in the pituitary of NBR-KO mice. Therefore, the data suggest that NB receptor pathways are importantly involved in thyrotroph gene regulation and function, leading to a state where TSH release is facilitated especially in response to TRH, but probably with a less-bioactive TSH. Therefore, the study highlights the important role of NB as a physiological regulator of pituitary-thyroid axis function and gene expression.
Assuntos
Hipófise/fisiologia , Receptores da Bombesina/fisiologia , Glândula Tireoide/fisiologia , Animais , Sequência de Bases , Primers do DNA , Masculino , Camundongos , Camundongos Knockout , Hormônios Hipofisários/sangue , Hormônios Hipofisários/genética , Hormônios Hipofisários/fisiologia , RNA Mensageiro/genética , Receptores da Bombesina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Hormônios Tireóideos/fisiologiaAssuntos
Neoplasias Colorretais/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Receptores da Bombesina/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Bombesina/análogos & derivados , Bombesina/farmacologia , Sistemas de Liberação de Medicamentos , Humanos , Fragmentos de Peptídeos/farmacologia , Ratos , Receptores da Bombesina/antagonistas & inibidores , Receptores da Bombesina/fisiologiaRESUMO
Several receptor and intracellular signalling systems in the basolateral amygdala (BLA) regulate memory formation. In the present study, we show that bombesin/gastrin-releasing peptide (GRP) receptors in the BLA are involved in the consolidation of affectively motivated memory. Adult male rats were trained in a single-trial step-down inhibitory avoidance task and tested for retention 24 h later. Post-training systemic injection of the bombesin/GRP receptor antagonist (D-Tpi6, Leu13 psi[CH2NH]-Leu14) bombesin (6-14) (RC-3095) impaired memory retention. In rats implanted under thionembutal anaesthesia with guide cannulae aimed at the BLA, post-training bilateral infusion of RC-3095 into the BLA dose-dependently impaired retention. Pre-training unilateral muscimol inactivation of the BLA blocked the memory-impairing effect of post-training systemic administration of RC-3095. The results suggest that bombesin/GRP receptors in the BLA are involved in the consolidation of aversive memory, and the BLA mediates the memory-impairing effect of systemic bombesin/GRP receptor blockade.