Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 211
Filtrar
1.
EMBO Rep ; 25(1): 351-377, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38177913

RESUMO

Hypothalamic Adult Neurogenesis (hAN) has been implicated in regulating energy homeostasis. Adult-generated neurons and adult Neural Stem Cells (aNSCs) in the hypothalamus control food intake and body weight. Conversely, diet-induced obesity (DIO) by high fat diets (HFD) exerts adverse influence on hAN. However, the effects of anti-obesity compounds on hAN are not known. To address this, we administered a lipidized analogue of an anti-obesity neuropeptide, Prolactin Releasing Peptide (PrRP), so-called LiPR, to mice. In the HFD context, LiPR rescued the survival of adult-born hypothalamic neurons and increased the number of aNSCs by reducing their activation. LiPR also rescued the reduction of immature hippocampal neurons and modulated calcium dynamics in iPSC-derived human neurons. In addition, some of these neurogenic effects were exerted by another anti-obesity compound, Liraglutide. These results show for the first time that anti-obesity neuropeptides influence adult neurogenesis and suggest that the neurogenic process can serve as a target of anti-obesity pharmacotherapy.


Assuntos
Neuropeptídeos , Obesidade , Camundongos , Humanos , Animais , Hormônio Liberador de Prolactina/farmacologia , Hormônio Liberador de Prolactina/uso terapêutico , Obesidade/tratamento farmacológico , Peso Corporal , Neurogênese , Hipotálamo
2.
Nature ; 624(7990): 130-137, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37993711

RESUMO

The termination of a meal is controlled by dedicated neural circuits in the caudal brainstem. A key challenge is to understand how these circuits transform the sensory signals generated during feeding into dynamic control of behaviour. The caudal nucleus of the solitary tract (cNTS) is the first site in the brain where many meal-related signals are sensed and integrated1-4, but how the cNTS processes ingestive feedback during behaviour is unknown. Here we describe how prolactin-releasing hormone (PRLH) and GCG neurons, two principal cNTS cell types that promote non-aversive satiety, are regulated during ingestion. PRLH neurons showed sustained activation by visceral feedback when nutrients were infused into the stomach, but these sustained responses were substantially reduced during oral consumption. Instead, PRLH neurons shifted to a phasic activity pattern that was time-locked to ingestion and linked to the taste of food. Optogenetic manipulations revealed that PRLH neurons control the duration of seconds-timescale feeding bursts, revealing a mechanism by which orosensory signals feed back to restrain the pace of ingestion. By contrast, GCG neurons were activated by mechanical feedback from the gut, tracked the amount of food consumed and promoted satiety that lasted for tens of minutes. These findings reveal that sequential negative feedback signals from the mouth and gut engage distinct circuits in the caudal brainstem, which in turn control elements of feeding behaviour operating on short and long timescales.


Assuntos
Regulação do Apetite , Tronco Encefálico , Ingestão de Alimentos , Retroalimentação Fisiológica , Alimentos , Saciação , Estômago , Regulação do Apetite/fisiologia , Tronco Encefálico/citologia , Tronco Encefálico/fisiologia , Ingestão de Alimentos/fisiologia , Vias Neurais/citologia , Vias Neurais/fisiologia , Neurônios/metabolismo , Hormônio Liberador de Prolactina/metabolismo , Saciação/fisiologia , Núcleo Solitário/citologia , Núcleo Solitário/fisiologia , Estômago/fisiologia , Paladar/fisiologia , Fatores de Tempo , Animais , Camundongos
3.
Neuropeptides ; 100: 102349, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37269608

RESUMO

Prolactin-releasing peptide (PrRP) has been investigated as a potential therapeutic for diabetes by the effect of food intake reduction, increasing leptin signaling, and insulin tolerance. Recent studies focused on its synaptogenesis and protective effects against neurodegeneration. Whereas 1,2-diacetylbenzene (DAB), a common metabolite of a neurotoxicant 1,2-diethyl benzene, causes memory impairment and neurotoxicity partly through the inflammatory process. Our present study assessed the effect of PrRP in microglia and its action in balancing the inflammation to protect against DAB. We observed that PrRP modulated NADPH oxidase - regulated NLRP3 inflammasome and PRL signaling pathways differently between physical and toxic conditions in microglia.


Assuntos
Hormônios Hipotalâmicos , Doenças Neuroinflamatórias , Humanos , Hormônio Liberador de Prolactina/farmacologia , Prolactina/metabolismo , Hormônios Hipotalâmicos/metabolismo
4.
Arch Razi Inst ; 78(1): 181-184, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-37312715

RESUMO

PrRP, also known as prolactoliberin, is a bovine hypothalamic extract neurohormone that stimulates prolactin synthesis in a rat pituitary adenoma cell line and lactating rat pituitary cells. PrRP has been shown to control the intake of food and energy expenditure, but it may also have a role in stress sensitivity, reproduction, cardia productivity, secretion of endocrine components, and lately, neuroprotective characteristics, among others. The current study was performed to identify if prolactin-releasing peptide (PrRP) had any effect in increasing anxiety clinical features in rats as an animal model. The study included 114 Wistar handling-acclimated male rats (160 gm, 2 months old); divided randomly into three major groups. The rats were divided randomly into three major groups (38-control animals (38C), and 38-PrRP animals (38P), both were examined using the EPM test to test for stress-related signs, such as fear of height (5 mins duration for each rat). The maze was cleaned with water to eliminate the previous rat odor after the experiment for each rat was completed. The tests were performed between 13:00 to 17:00 of the day. Then, a week later, 38 (19-PrRP animals (19P) and 19-control animals (19C)) were examined using the SP test conducted between 13:00 to 16:00 of the day. Fifteen minutes before EPM, the 38C received intranasal 0.9%-10µl NaCl (per nostril), and 38P received intranasal 10-10mol/l-10 µl PrRP (per nostril), and the anxiety-related signs, such as time spent in open arms (less time means more anxious), during the EPM test were recorded. The 19P and 19C received 10-10mol/l-10µl PrRP and 0.9%-10µl NaCl, respectively, (intranasal, per nostril, and 15 minutes before the SP test, where a stranger rat was placed in a specific cage in front of each of the 19P and 19C animals in a separate cage, in which both cages provided visual and olfactory but no confrontational contact). The results showed that PrRP significantly (P<0.05) decreased the time spent by the treated rats on the open arms. In addition, PrRP revealed significant (P<0.05) decreases in the time spent close to the stranger rat, which means increased anxiety levels. The current findings revealed that prolactin-releasing peptide increases anxiety and decreases sociality in the studied male rats.


Assuntos
Ansiedade , Hormônio Liberador de Prolactina , Animais , Bovinos , Masculino , Ratos , Hormônio Liberador de Prolactina/farmacologia , Ratos Wistar
5.
Nutrients ; 15(2)2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36678151

RESUMO

Prolactin-releasing peptide (PrRP) is an anorexigenic neuropeptide that has potential for the treatment of obesity and its complications. Recently, we designed a palmitoylated PrRP31 analog (palm11-PrRP31) that is more stable than the natural peptide and able to act centrally after peripheral administration. This analog acted as an anti-obesity and glucose-lowering agent, attenuating lipogenesis in rats and mice with high-fat (HF) diet-induced obesity. In Wistar Kyoto (WKY) rats fed a HF diet for 52 weeks, we explored glucose intolerance, but also prediabetes, liver steatosis and insulin resistance-related changes, as well as neuroinflammation in the brain. A potential beneficial effect of 6 weeks of treatment with palm11-PrRP31 and liraglutide as comparator was investigated. Liver lipid profiles, as well as urinary and plasma metabolomic profiles, were measured by lipidomics and metabolomics, respectively. Old obese WKY rats showed robust glucose intolerance that was attenuated by palm11-PrRP31, but not by liraglutide treatment. On the contrary, liraglutide had a beneficial effect on insulin resistance parameters. Despite obesity and prediabetes, WKY rats did not develop steatosis owing to HF diet feeding, even though liver lipogenesis was enhanced. Plasma triglycerides and cholesterol were not increased by HFD feeding, which points to unincreased lipid transport from the liver. The liver lipid profile was significantly altered by a HF diet that remained unaffected by palm11-PrRP31 or liraglutide treatment. The HF-diet-fed WKY rats revealed astrogliosis in the brain cortex and hippocampus, which was attenuated by treatment. In conclusion, this study suggested multiple beneficial anti-obesity-related effects of palm11-PrRP31 and liraglutide in both the periphery and brain.


Assuntos
Intolerância à Glucose , Resistência à Insulina , Estado Pré-Diabético , Ratos , Camundongos , Animais , Ratos Endogâmicos WKY , Intolerância à Glucose/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Hormônio Liberador de Prolactina/farmacologia , Estado Pré-Diabético/tratamento farmacológico , Obesidade/tratamento farmacológico , Lipídeos , Dieta Hiperlipídica/efeitos adversos
6.
Neuropeptides ; 98: 102319, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36669365

RESUMO

Prolactin-releasing peptide (PrRP) is an anorexigenic neuropeptide that attenuates food intake and increases energy expenditure. We designed three series of new lipidized PrRP31 analogs of different lengths of fatty acids attached at amino acids 1 or 11 directly or via linkers, part of them acetylated at the N-terminus and/or modified with dichlorophenylalanine (PheCl2) at the C-terminus. We tested their affinity for and activation of signaling pathways relevant to receptors GPR10, NPFF-R2, and NPFF-R1, effect on food intake in fasted or freely fed mice and rats, and stability in rat plasma. We aimed to select a strong dual GPR10/NPFF-R2 agonist whose affinity for NPFF-1 was not enhanced. The selected potent analog was then tested for body weight-lowering potency after chronic administration in mice with diet-induced obesity. PrRP31 analogs lipidized by monocarboxylic fatty acids showed strong dual affinity for both GPR10 and NPFF-R2 and activated MAPK/ERK1/2, Akt and CREB in cells overexpressing GPR10 and NPFF-R2. The selected analog stabilized at N- and C-termini and palmitoylated through the TTDS linker to Lys11 is a powerful dual agonist GPR10/NPFF-R2 at not enhanced affinity for NPFF-R1. It showed strong anti-obesity properties in mice with diet-induced obesity and became a potential compound for further studies.


Assuntos
Neuropeptídeos , Obesidade , Ratos , Camundongos , Animais , Hormônio Liberador de Prolactina/metabolismo , Hormônio Liberador de Prolactina/farmacologia , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Dieta , Ácidos Graxos
7.
J Neurosci ; 43(5): 846-862, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36564184

RESUMO

Stress disorders impair sleep and quality of life; however, their pathomechanisms are unknown. Prolactin-releasing peptide (PrRP) is a stress mediator; we therefore hypothesized that PrRP may be involved in the development of stress disorders. PrRP is produced by the medullary A1/A2 noradrenaline (NA) cells, which transmit stress signals to forebrain centers, and by non-NA cells in the hypothalamic dorsomedial nucleus. We found in male rats that both PrRP and PrRP-NA cells innervate melanin-concentrating hormone (MCH) producing neurons in the dorsolateral hypothalamus (DLH). These cells serve as a key hub for regulating sleep and affective states. Ex vivo, PrRP hyperpolarized MCH neurons and further increased the hyperpolarization caused by NA. Following sleep deprivation, intracerebroventricular PrRP injection reduced the number of REM sleep-active MCH cells. PrRP expression in the dorsomedial nucleus was upregulated by sleep deprivation, while downregulated by REM sleep rebound. Both in learned helplessness paradigm and after peripheral inflammation, impaired coping with sustained stress was associated with (1) overactivation of PrRP cells, (2) PrRP protein and receptor depletion in the DLH, and (3) dysregulation of MCH expression. Exposure to stress in the PrRP-insensitive period led to increased passive coping with stress. Normal PrRP signaling, therefore, seems to protect animals against stress-related disorders. PrRP signaling in the DLH is an important component of the PrRP's action, which may be mediated by MCH neurons. Moreover, PrRP receptors were downregulated in the DLH of human suicidal victims. As stress-related mental disorders are the leading cause of suicide, our findings may have particular translational relevance.SIGNIFICANCE STATEMENT Treatment resistance to monoaminergic antidepressants is a major problem. Neuropeptides that modulate the central monoaminergic signaling are promising targets for developing alternative therapeutic strategies. We found that stress-responsive prolactin-releasing peptide (PrRP) cells innervated melanin-concentrating hormone (MCH) neurons that are crucial in the regulation of sleep and mood. PrRP inhibited MCH cell activity and enhanced the inhibitory effect evoked by noradrenaline, a classic monoamine, on MCH neurons. We observed that impaired PrRP signaling led to failure in coping with chronic/repeated stress and was associated with altered MCH expression. We found alterations of the PrRP system also in suicidal human subjects. PrRP dysfunction may underlie stress disorders, and fine-tuning MCH activity by PrRP may be an important part of the mechanism.


Assuntos
Hormônios Hipotalâmicos , Privação do Sono , Ratos , Masculino , Humanos , Animais , Hormônio Liberador de Prolactina/farmacologia , Hormônio Liberador de Prolactina/metabolismo , Privação do Sono/metabolismo , Transtornos do Humor/etiologia , Qualidade de Vida , Ratos Wistar , Hormônios Hipotalâmicos/metabolismo , Sono/fisiologia , Neurônios/fisiologia , Norepinefrina/metabolismo
8.
Nutr Diabetes ; 12(1): 26, 2022 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-35589696

RESUMO

BACKGROUND/OBJECTIVE: Anorexigenic palmitoylated prolactin-releasing peptide (palm11-PrRP) is able to act centrally after peripheral administration in rat and mouse models of obesity, type 2 diabetes mellitus and/or neurodegeneration. Functional leptin and intact leptin signaling pathways are necessary for the body weight reducing and glucose tolerance improving effect of palm11-PrRP. We have previously shown that palm11-PrRP31 had glucose-lowering properties but not anti-obesity effect in Koletsky rats with leptin signaling disturbances, so improvements in glucose metabolism appear to be completely independent of leptin signaling. The purpose of this study was to describe relationship between metabolic and neurodegenerative pathologies and explore if palm11-PrRP31 could ameliorate them in obese fa/fa rat model with leptin signaling disruption. SUBJECT/METHODS: The fa/fa rats and their age-matched lean controls at the age 32 weeks were used for this study. The rats were infused for 2 months with saline or palm11-PrRP31 (n = 7-8 per group) at a dose of 5 mg/kg per day using Alzet osmotic pumps. During the dosing period food intake and body weight were monitored. At the end of experiment the oral glucose tolerance test was performed; plasma and tissue samples were collected and arterial blood pressure was measured. Then, markers of leptin and insulin signaling, Tau phosphorylation, neuroinflammation, and synaptogenesis were measured by western blotting and immunohistochemistry. RESULTS: Fa/fa rats developed obesity, mild glucose intolerance, and peripheral insulin resistance but not hypertension while palm11-PrRP31 treatment neither lowered body weight nor attenuated glucose tolerance but ameliorated leptin and insulin signaling and synaptogenesis in hippocampus. CONCLUSION: We demonstrated that palm11-PrRP31 had neuroprotective features without anti-obesity and glucose lowering effects in fa/fa rats. This data suggest that this analog has the potential to exert neuroprotective effect despite of leptin signaling disturbances in this rat model.


Assuntos
Diabetes Mellitus Tipo 2 , Leptina , Animais , Peso Corporal , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose , Insulina/uso terapêutico , Camundongos , Obesidade/metabolismo , Hormônio Liberador de Prolactina/farmacologia , Hormônio Liberador de Prolactina/uso terapêutico , Ratos
9.
Sci Rep ; 12(1): 1696, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35105898

RESUMO

Prolactin-releasing peptide (PrRP) is an endogenous neuropeptide involved in appetite regulation and energy homeostasis. PrRP binds with high affinity to G-protein coupled receptor 10 (GPR10) and with lesser activity towards the neuropeptide FF receptor type 2 (NPFF2R). The present study aimed to develop long-acting PrRP31 analogues with potent anti-obesity efficacy. A comprehensive series of C18 lipidated PrRP31 analogues was characterized in vitro and analogues with various GPR10 and NPFF2R activity profiles were profiled for bioavailability and metabolic effects following subcutaneous administration in diet-induced obese (DIO) mice. PrRP31 analogues acylated with a C18 lipid chain carrying a terminal acid (C18 diacid) were potent GPR10-selective agonists and weight-neutral in DIO mice. In contrast, acylation with aliphatic C18 lipid chain (C18) resulted in dual GPR10-NPFF2R co-agonists that suppressed food intake and promoted a robust weight loss in DIO mice, which was sustained for at least one week after last dosing. Rapid in vivo degradation of C18 PrRP31 analogues gave rise to circulating lipidated PrRP metabolites maintaining dual GPR10-NPFF2R agonist profile and long-acting anti-obesity efficacy in DIO mice. Combined GPR10 and NPFF2R activation may therefore be a critical mechanism for obtaining robust anti-obesity efficacy of PrRP31 analogues.


Assuntos
Fármacos Antiobesidade/administração & dosagem , Obesidade/tratamento farmacológico , Hormônio Liberador de Prolactina/análogos & derivados , Hormônio Liberador de Prolactina/administração & dosagem , Receptores Acoplados a Proteínas G/agonistas , Receptores de Neuropeptídeos/agonistas , Redução de Peso/efeitos dos fármacos , Acilação , Animais , Regulação do Apetite/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Ingestão de Alimentos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/metabolismo , Hormônio Liberador de Prolactina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Resultado do Tratamento
10.
Endocrinology ; 163(3)2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35085394

RESUMO

Prolactin (PRL), a hormone involved in lactation, is mainly produced and secreted by the lactotrophs of the anterior pituitary (AP) gland. We previously reported a method to generate functional adrenocorticotropic hormone-producing cells by differentiating the AP and hypothalamus simultaneously from human induced pluripotent stem cells (iPSCs). However, PRL-producing cells in the induced AP have not been investigated. Here, we confirmed the presence of PRL-producing cells and evaluated their endocrine functions. We differentiated pituitary cells from human iPSCs using serum-free floating culture of embryoid-like aggregates with quick reaggregation (SFEB-q) method and evaluated the appearance and function of PRL-producing cells. Secretion of PRL from the differentiated aggregates was confirmed, which increased with further culture. Fluorescence immunostaining and immunoelectron microscopy revealed PRL-producing cells and PRL-positive secretory granules, respectively. PRL secretion was promoted by various prolactin secretagogues such as thyrotropin-releasing hormone, vasoactive intestinal peptide, and prolactin-releasing peptide, and inhibited by bromocriptine. Moreover, the presence of tyrosine hydroxylase-positive dopaminergic nerves in the hypothalamic tissue area around the center of the aggregates connecting to PRL-producing cells indicated the possibility of recapitulating PRL regulatory mechanisms through the hypothalamus. In conclusion, we generated pituitary lactotrophs from human iPSCs; these displayed similar secretory responsiveness as human pituitary cells in vivo. In the future, this is expected to be used as a model of human PRL-producing cells for various studies, such as drug discovery, prediction of side effects, and elucidation of tumorigenic mechanisms using disease-specific iPSCs. Furthermore, it may help to develop regenerative medicine for the pituitary gland.


Assuntos
Diferenciação Celular , Células-Tronco Pluripotentes Induzidas/fisiologia , Lactotrofos/fisiologia , Adeno-Hipófise/citologia , Prolactina/biossíntese , Técnicas de Cultura de Células , Linhagem Celular , Proliferação de Células , Células Cultivadas , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Lactotrofos/efeitos dos fármacos , Hormônio Liberador de Prolactina/farmacologia , Hormônio Liberador de Tireotropina/farmacologia , Peptídeo Intestinal Vasoativo/farmacologia
11.
Br J Pharmacol ; 179(4): 642-658, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34050926

RESUMO

Neuroendocrine, behavioural and autonomic responses to stressful stimuli are orchestrated by complex neural circuits. The caudal nucleus of the solitary tract (cNTS) in the dorsomedial hindbrain is uniquely positioned to integrate signals of both interoceptive and psychogenic stress. Within the cNTS, glucagon-like peptide-1 (GLP-1) and prolactin-releasing peptide (PrRP) neurons play crucial roles in organising neural responses to a broad range of stressors. In this review we discuss the anatomical and functional overlap between PrRP and GLP-1 neurons. We outline their co-activation in response to stressful stimuli and their importance as mediators of behavioural and physiological stress responses. Finally, we review evidence that PrRP neurons are downstream of GLP-1 neurons and outline unexplored areas of the research field. Based on the current state-of-knowledge, PrRP and GLP-1 neurons may be compelling targets in the treatment of stress-related disorders. LINKED ARTICLES: This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc.


Assuntos
Peptídeo 1 Semelhante ao Glucagon , Núcleo Solitário , Neurônios/metabolismo , Hormônio Liberador de Prolactina/metabolismo , Núcleo Solitário/metabolismo , Estresse Fisiológico/fisiologia
12.
Front Endocrinol (Lausanne) ; 12: 762826, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34803923

RESUMO

Prolactin-releasing peptide (PrRP), a sort of vital hypothalamic neuropeptide, has been found to exert an enormous function on the food intake of mammals. However, little is known about the functional role of PrRP in teleost. In the present study, two PrRP isoforms and four PrRP receptors were isolated from grass carp. Ligand-receptor selectivity displayed that PrRP1 preferentially binds with PrRP-R1a and PrRP-R1b, while PrRP-R2a and PrRP-R2b were special receptors for PrRP2. Tissue distribution indicated that both PrRPs and PrRP-Rs were highly expressed in the hypothalamus-pituitary-gonad axis and intestine, suggesting a latent function on food intake and reproduction. Using grass carp as a model, we found that food intake could significantly induce hypothalamus PrRP mRNA expression, which suggested that PrRP should be also an anorexigenic peptide in teleost. Interestingly, intraperitoneal (IP) injection of PrRPs could significantly induce serum luteinizing hormone (LH) secretion and pituitary LHß and GtHα mRNA expression in grass carp. Moreover, using primary culture grass carp pituitary cells as a model, we further found that PrRPs could directly induce pituitary LH secretion and synthesis mediated by AC/PKA, PLC/IP3/PKC, and Ca2+/CaM/CaMK-II pathways. Finally, estrogen treatment of prepubertal fish elicited increases in PrRPs and PrPR receptors expression in primary cultured grass carp hypothalamus cells, which further confirmed that the PrRP/PrRPR system may participate in the neuroendocrine control of fish reproduction. These results, taken together, suggest that PrRPs might act as a coupling factor in feeding metabolism and reproductive activities in teleost.


Assuntos
Comportamento Alimentar/fisiologia , Hormônio Liberador de Prolactina/biossíntese , Hormônio Liberador de Prolactina/genética , Reprodução/fisiologia , Sequência de Aminoácidos , Animais , Carpas , Células Cultivadas , Clonagem Molecular/métodos , Feminino , Células HEK293 , Humanos , Hipotálamo/metabolismo , Masculino , Hipófise/metabolismo
13.
Probl Endokrinol (Mosk) ; 67(5): 29-33, 2021 09 19.
Artigo em Russo | MEDLINE | ID: mdl-34766487

RESUMO

BACKGROUND: Prolactin-releasing peptide(Prl-RP), in addition to stimulating the production of prolactin, interacts with various parts of the central nervous system, participating in the implementation of many functions that are reflected in behavior. AIM: The effect of Prl-RP on the anxiety of white Wistar rats was studied since there were no data in the literature on the relationship between Prl-RP and anxiety. MATERIALS AND METHODS: Anxiety was assessed in two tests. In the elevated plus-maze (EPM), the time spent in the open arms and the number of edge reactions were recorded. In the social preference test, the time spent near a stranger, near a familiar individual, and in neutral territory were recorded. RESULTS: The administration of Prl-RP at a dose of 10-10 M with a volume of 10 µl in each nostril reduced the time spent by the animals in the open arms of the EPM, and the number of edge reactions. For testing the social interaction, animals were pre-selected for high or low levels of anxiety in the EPM. In rats with initially low levels of anxiety, Prl-RP reduced the time spent near a stranger, indicating an increase in anxiety levels. The behavior of rats with initially high levels of anxiety did not change after application of the Prl-RP. CONCLUSION: The results of our experiments indicate that the intranasal administration of Prl-RP increases the anxiety of rats.


Assuntos
Ansiedade , Comportamento Animal , Animais , Comportamento Animal/fisiologia , Prolactina/farmacologia , Hormônio Liberador de Prolactina/farmacologia , Ratos , Ratos Wistar
14.
Curr Alzheimer Res ; 18(8): 607-622, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34551697

RESUMO

BACKGROUND: Prolactin-releasing peptide (PrRP) is a potential drug for the treatment of obesity and associated Type 2 Diabetes Mellitus (T2DM) due to its strong anorexigenic and antidiabetic properties. In our recent study, the lipidized PrRP analog palm11-PrRP31 was proven to exert beneficial effects in APP/PS1 mice, a model of Alzheimer´s Disease (AD)-like amyloid-ß (Aß) pathology, reducing the Aß plaque load, microgliosis and astrocytosis in the hippocampus and cortex. OBJECTIVE: In this study, we focused on the neuroprotective and anti-inflammatory effects of palm11-PrRP31 and its possible impact on synaptogenesis in the cerebellum of APP/PS1 mice, because others have suggested that cerebellar Aß plaques contribute to cognitive deficits in AD. METHODS: APP/PS1 mice were treated subcutaneously with palm11-PrRP31 for 2 months, then immunoblotting and immunohistochemistry were used to quantify pathological markers connected to AD, compared to control mice. RESULTS: In the cerebella of 8 months old APP/PS1 mice, we found widespread Aß plaques surrounded by activated microglia detected by ionized calcium-binding adapter molecule (Iba1), but no increase in astrocytic marker Glial Fibrillary Acidic Protein (GFAP) compared to controls. Interestingly, no difference in both presynaptic markers syntaxin1A and postsynaptic marker spinophilin was registered between APP/PS1 and control mice. Palm11-PrRP31 treatment significantly reduced the Aß plaque load and microgliosis in the cerebellum. Furthermore, palm11-PrRP31 increased synaptogenesis and attenuated neuroinflammation and apoptosis in the hippocampus of APP/PS1 mice. CONCLUSION: These results suggest palm11-PrRP31 is a promising agent for the treatment of neurodegenerative disorders.


Assuntos
Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Cerebelo , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Placa Amiloide/patologia , Presenilina-1/genética , Presenilina-1/metabolismo , Hormônio Liberador de Prolactina/metabolismo , Hormônio Liberador de Prolactina/farmacologia
15.
Nat Commun ; 12(1): 5175, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34462445

RESUMO

Calcitonin receptor (Calcr)-expressing neurons of the nucleus tractus solitarius (NTS; CalcrNTS cells) contribute to the long-term control of food intake and body weight. Here, we show that Prlh-expressing NTS (PrlhNTS) neurons represent a subset of CalcrNTS cells and that Prlh expression in these cells restrains body weight gain in the face of high fat diet challenge in mice. To understand the relationship of PrlhNTS cells to hypothalamic feeding circuits, we determined the ability of PrlhNTS-mediated signals to overcome enforced activation of AgRP neurons. We found that PrlhNTS neuron activation and Prlh overexpression in PrlhNTS cells abrogates AgRP neuron-driven hyperphagia and ameliorates the obesity of mice deficient in melanocortin signaling or leptin. Thus, enhancing Prlh-mediated neurotransmission from the NTS dampens hypothalamically-driven hyperphagia and obesity, demonstrating that NTS-mediated signals can override the effects of orexigenic hypothalamic signals on long-term energy balance.


Assuntos
Obesidade/metabolismo , Hormônio Liberador de Prolactina/metabolismo , Núcleo Solitário/metabolismo , Animais , Apetite , Dieta , Ingestão de Alimentos , Metabolismo Energético , Feminino , Humanos , Hipotálamo/metabolismo , Leptina/metabolismo , Masculino , Melanocortinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Obesidade/genética , Obesidade/fisiopatologia , Obesidade/psicologia , Hormônio Liberador de Prolactina/genética , Receptores da Calcitonina/genética , Receptores da Calcitonina/metabolismo
16.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445614

RESUMO

The anorexigenic neuropeptide prolactin-releasing peptide (PrRP) is involved in the regulation of food intake and energy expenditure. Lipidization of PrRP stabilizes the peptide, facilitates central effect after peripheral administration and increases its affinity for its receptor, GPR10, and for the neuropeptide FF (NPFF) receptor NPFF-R2. The two most potent palmitoylated analogs with anorectic effects in mice, palm11-PrRP31 and palm-PrRP31, were studied in vitro to determine their agonist/antagonist properties and mechanism of action on GPR10, NPFF-R2 and other potential off-target receptors related to energy homeostasis. Palmitoylation of both PrRP31 analogs increased the binding properties of PrRP31 to anorexigenic receptors GPR10 and NPFF-R2 and resulted in a high affinity for another NPFF receptor, NPFF-R1. Moreover, in CHO-K1 cells expressing GPR10, NPFF-R2 or NPFF-R1, palm11-PrRP and palm-PrRP significantly increased the phosphorylation of extracellular signal-regulated kinase (ERK), protein kinase B (Akt) and cAMP-responsive element-binding protein (CREB). Palm11-PrRP31, unlike palm-PrRP31, did not activate either c-Jun N-terminal kinase (JNK), p38, c-Jun, c-Fos or CREB pathways in cells expressing NPFF-1R. Palm-PrRP31 also has higher binding affinities for off-target receptors, namely, the ghrelin, opioid (KOR, MOR, DOR and OPR-L1) and neuropeptide Y (Y1, Y2 and Y5) receptors. Palm11-PrRP31 exhibited fewer off-target activities; therefore, it has a higher potential to be used as an anti-obesity drug with anorectic effects.


Assuntos
Cálcio/metabolismo , Lipoilação , Hormônio Liberador de Prolactina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Técnicas In Vitro , Hormônio Liberador de Prolactina/química , Hormônio Liberador de Prolactina/genética , Receptores Acoplados a Proteínas G/genética , Receptores de Neuropeptídeos/genética
17.
Physiol Behav ; 239: 113511, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34181929

RESUMO

Competing motivational drives coordinate behaviors essential for survival. For example, interoceptive feedback from the body during a state of negative energy balance serves to suppress anxiety-like behaviors and promote exploratory behaviors in rats. Results from past research suggest that this shift in motivated behavior is linked to reduced activation of specific neural populations within the caudal nucleus of the solitary tract (cNTS). However, the potential impact of metabolic state and the potential role of cNTS neurons on conditioned avoidance behaviors has not been examined. The present study investigated these questions in male and female rats, using a task in which rats learn to avoid a context (i.e., a darkened chamber) after it is paired with a single mild footshock. When rats later were tested for passive avoidance of the shock-paired chamber, male rats tested in an overnight food-deprived state and female rats (regardless of feeding status) displayed significantly less avoidance compared to male rats that were fed ad libitum prior to testing. Based on prior evidence that prolactin-releasing peptide (PrRP)-positive noradrenergic neurons and glucagon-like peptide 1 (GLP1)-positive neurons within the cNTS are particularly sensitive to metabolic state, we examined whether these neural populations are activated in conditioned rats after re-exposure to the shock-paired chamber, and whether neural activation is modulated by metabolic state. Compared to the control condition, chamber re-exposure activated PrRP+ noradrenergic neurons and also activated neurons within the anterior ventrolateral bed nucleus of the stria terminalis (vlBNST), which receives dense input from PrRP+ terminals, in both male and female rats when fed ad libitum. In parallel with sex differences in passive avoidance behavior, PrRP+ neurons were less activated in female vs. male rats after chamber exposure. GLP1+ neurons were not activated in either sex. In both sexes, overnight food deprivation before chamber re-exposure reduced activation of PrRP+ neurons, and also reduced vlBNST activation. Our results support the view that PrRP+ noradrenergic neurons and their inputs to the vlBNST contribute to the expression of passive avoidance memory, and that this contribution is modulated by metabolic state.


Assuntos
Neurônios Adrenérgicos , Núcleos Septais , Animais , Feminino , Masculino , Hormônio Liberador de Prolactina/metabolismo , Ratos , Ratos Sprague-Dawley , Núcleo Solitário/metabolismo
18.
Physiol Res ; 70(4): 579-590, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34062082

RESUMO

Prolactin-releasing peptide (PrRP) has been proposed to mediate the central satiating effects of cholecystokinin (CCK) through the vagal CCK1 receptor. PrRP acts as an endogenous ligand of G protein-coupled receptor 10 (GPR10), which is expressed at the highest levels in brain areas related to food intake regulation, e.g., the paraventricular hypothalamic nucleus (PVN) and nucleus of the solitary tract (NTS). The NTS and PVN are also significantly activated after peripheral CCK administration. The aim of this study was to determine whether the endogenous PrRP neuronal system in the brain is involved in the central anorexigenic effect of the peripherally administered CCK agonist JMV236 or the CCK1 antagonist devazepide and whether the CCK system is involved in the central anorexigenic effect of the peripherally applied lipidized PrRP analog palm-PrRP31 in fasted lean mice. The effect of devazepide and JMV236 on the anorexigenic effects of palm-PrRP31 as well as devazepide combined with JMV236 and palm-PrRP31 on food intake and Fos cell activation in the PVN and caudal NTS was examined. Our results suggest that the anorexigenic effect of JMV236 is accompanied by activation of PrRP neurons of the NTS in a CCK1 receptor-dependent manner. Moreover, while the anorexigenic effect of palm-PrRP31 was not affected by JMV236, it was partially attenuated by devazepide in fasted mice. The present findings indicate that the exogenously influenced CCK system may be involved in the central anorexigenic effect of peripherally applied palm-PrRP31, which possibly indicates some interaction between the CCK and PrRP neuronal systems.


Assuntos
Depressores do Apetite/administração & dosagem , Colecistocinina/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Hormônio Liberador de Prolactina/análogos & derivados , Núcleo Solitário/efeitos dos fármacos , Animais , Quimiocinas CC/efeitos dos fármacos , Quimiocinas CC/metabolismo , Devazepida/administração & dosagem , Jejum , Antagonistas de Hormônios/administração & dosagem , Injeções Intraperitoneais , Injeções Subcutâneas , Masculino , Camundongos Endogâmicos C57BL , Núcleo Hipotalâmico Paraventricular/metabolismo , Fragmentos de Peptídeos/administração & dosagem , Hormônio Liberador de Prolactina/administração & dosagem , Proteínas Proto-Oncogênicas c-fos/metabolismo , Transdução de Sinais , Sincalida/administração & dosagem , Sincalida/análogos & derivados , Núcleo Solitário/metabolismo
19.
Int J Mol Sci ; 22(9)2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33923285

RESUMO

Prolactin-releasing Peptide (PrRP) is a neuropeptide whose receptor is GPR10. Recently, the regulatory role of PrRP in the neuroendocrine field has attracted increasing attention. However, the influence of PrRP on macrophages, the critical housekeeper in the neuroendocrine field, has not yet been fully elucidated. Here, we investigated the effect of PrRP on the transcriptome of mouse bone marrow-derived macrophages (BMDMs) with RNA sequencing, bioinformatics, and molecular simulation. BMDMs were exposed to PrRP (18 h) and were subjected to RNA sequencing. Differentially expressed genes (DEGs) were acquired, followed by GO, KEGG, and PPI analysis. Eight qPCR-validated DEGs were chosen as hub genes. Next, the three-dimensional structures of the proteins encoded by these hub genes were modeled by Rosetta and Modeller, followed by molecular dynamics simulation by the Gromacs program. Finally, the binding modes between PrRP and hub proteins were investigated with the Rosetta program. PrRP showed no noticeable effect on the morphology of macrophages. A total of 410 DEGs were acquired, and PrRP regulated multiple BMDM-mediated functional pathways. Besides, the possible docking modes between PrRP and hub proteins were investigated. Moreover, GPR10 was expressed on the cell membrane of BMDMs, which increased after PrRP exposure. Collectively, PrRP significantly changed the transcriptome profile of BMDMs, implying that PrRP may be involved in various physiological activities mastered by macrophages.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Macrófagos/metabolismo , Hormônio Liberador de Prolactina/farmacologia , Transcriptoma/efeitos dos fármacos , Animais , Biologia Computacional , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
20.
Gene ; 774: 145427, 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33450349

RESUMO

G-protein-coupled receptor GPR10 is expressed in brain areas regulating energy metabolism. In this study, the effects of GPR10 gene deficiency on energy homeostasis in mice of both sexes fed either standard chow or a high-fat diet (HFD) were studied, with a focus on neuronal activation of PrRP neurons, and adipose tissue and liver metabolism. GPR10 deficiency in males upregulated the phasic and tonic activity of PrRP neurons in the nucleus of the solitary tract. GPR10 knockout (KO) males on a standard diet displayed a higher body weight than their wild-type (WT) littermates due to an increase in adipose tissue mass; however, HFD feeding did not cause weight differences between genotypes. Expression of lipogenesis genes was suppressed in the subcutaneous adipose tissue of GPR10 KO males. In contrast, GPR10 KO females did not differ in body weight from their WT controls, but showed elevated expression of lipid metabolism genes in the liver and subcutaneous adipose tissue compared to WT controls. An attenuated non-esterified fatty acids change after glucose load compared to WT controls suggested a defect in insulin-mediated suppression of lipolysis in GPR10 KO females. Indirect calorimetry did not reveal any differences in energy expenditure among groups. In conclusion, deletion of GPR10 gene resulted in changes in lipid metabolism in mice of both sexes, however in different extent. An increase in adipose tissue mass observed in only GPR10 KO males may have been prevented in GPR10 KO females owing to a compensatory increase in the expression of metabolic genes.


Assuntos
Homeostase/genética , Resistência à Insulina/genética , Metabolismo dos Lipídeos/genética , Receptores Acoplados a Proteínas G/genética , Animais , Metabolismo Energético/genética , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Hormônio Liberador de Prolactina/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...