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1.
Nihon Yakurigaku Zasshi ; 154(4): 179-185, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597896

RESUMO

G-protein-coupled receptors (GPCRs), which constitute a highly diverse family of seven transmembrane receptors, respond to external signals and regulate a variety of cellular and physiological processes. GPCRs are encoded by about 800 different genes in human and they represent the largest family of drug targets in clinical trials, which accounts for about 30% of approved drugs acting on 108 unique GPCRs. Signaling through GPCRs can be optimized by enriching receptors, selective binding partners, and downstream effectors in discrete cellular environment. The primary cilium is a ubiquitous organelle that functions as a sensory antenna for surrounding physical and chemical stimuli. Primary cilium's compartment is as little as 1/10,000th of the total cell volume. Therefore, the ciliary membrane is highly enriched for specific signaling molecules, allowing the primary cilium to organize signaling in a highly ordered microenvironment. Recently, a set of non-olfactory GPCRs such as somatostatin receptor 3 and melanin-concentrating hormone receptor 1 (MCHR1) have been found to be selectively targeted to cilia on several mammalian cell types including neuronal cells both in vitro and in vivo approaches. Moreover, investigations into the pathophysiology have implicated GPCR ciliary signaling in a number of developmental and cellular pathways. Thus, cilia are now considered as an increasingly important connection for GPCR signaling. This review summarizes our current understanding of the signaling pathways though ciliary GPCR, especially feeding- and mood-related GPCR MCHR1, along with specific biological phenomenon as cilia length shortening.


Assuntos
Cílios/fisiologia , Receptores Acoplados a Proteínas-G/fisiologia , Receptores do Hormônio Hipofisário/fisiologia , Transdução de Sinais , Animais , Humanos
2.
Nat Commun ; 10(1): 2505, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175285

RESUMO

Brain signals that govern memory formation remain incompletely identified. The hypothalamus is implicated in memory disorders, but how its rapidly changing activity shapes memorization is unknown. During encounters with objects, hypothalamic melanin-concentrating hormone (MCH) neurons emit brief signals that reflect object novelty. Here we show that targeted optogenetic silencing of these signals, performed selectively during the initial object encounters (i.e. memory acquisition), prevents future recognition of the objects. We identify an upstream inhibitory microcircuit from hypothalamic GAD65 neurons to MCH neurons, which constrains the memory-promoting MCH cell bursts. Finally, we demonstrate that silencing the GAD65 cells during object memory acquisition improves future object recognition through MCH-receptor-dependent pathways. These results provide causal evidence that object-associated signals in genetically distinct but interconnected hypothalamic neurons differentially control whether the brain forms object memories. This gating of memory formation by hypothalamic activity establishes appropriate behavioral responses to novel and familiar objects.


Assuntos
Glutamato Descarboxilase/metabolismo , Hormônios Hipotalâmicos/metabolismo , Hipotálamo/fisiologia , Melaninas/metabolismo , Memória/fisiologia , Neurônios/metabolismo , Hormônios Hipofisários/metabolismo , Receptores do Hormônio Hipofisário/metabolismo , Reconhecimento Psicológico/fisiologia , Animais , Hipotálamo/citologia , Hipotálamo/metabolismo , Memória/efeitos dos fármacos , Camundongos , Inibição Neural/fisiologia , Vias Neurais , Optogenética , Piperidinas/farmacologia , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Reconhecimento Psicológico/efeitos dos fármacos
3.
Gen Comp Endocrinol ; 281: 91-104, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31121165

RESUMO

Two structurally related peptides, arginine vasotocin (AVT) and mesotocin (MT), are reported to regulate many physiological processes, such as anti-diuresis and oviposition in birds, and their actions are likely mediated by four AVT/MT receptors (AVPR1A, AVPR1B, MTR and AVPR2b), which are orthologous/paralogous to human AVPR1A, AVPR1B, OXTR and AVPR2 respectively. However, our knowledge regarding the functions of these avian AVT/MT receptors has been limited. Here, we examined the functionality and expression of these receptors in chickens and investigated the roles of AVT in the anterior pituitary. Our results showed that 1) AVPR1A, AVPR1B and AVPR2b could be preferentially activated by AVT, monitored by cell-based luciferase reporter assays and/or Western blot, indicating that they are AVT-specific receptors (AVPR1A; AVPR1B) or AVT-preferring receptor (AVPR2b) functionally coupled to intracellular calcium, MAPK/ERK and cAMP/PKA signaling pathways. In contrast, MTR could be activated by AVT and MT with similar potencies, indicating that MTR is a receptor common for both peptides; 2) Using qPCR, differential expression of the four receptors was found in chicken tissues including the oviduct and anterior pituitary. In particular, only AVPR1A is abundantly expressed in the uterus, suggesting its involvement in mediating AVT-induced oviposition. 3) In cultured chick pituitary cells, AVT could stimulate ACTH and PRL expression and secretion, an action likely mediated by AVPR1B and/or AVPR1A abundantly expressed in anterior pituitary. Collectively, our data helps to elucidate the roles of AVT/MT in birds, such as the 'oxytocic action' of AVT, which induces uterine muscle contraction during oviposition.


Assuntos
Oviposição/fisiologia , Hipófise/metabolismo , Prolactina/metabolismo , Receptores do Hormônio Hipofisário/metabolismo , Receptores de Vasopressinas/metabolismo , Transdução de Sinais , Vasotocina/metabolismo , Sequência de Aminoácidos , Animais , Células Cultivadas , Galinhas/metabolismo , Patos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Modelos Biológicos , Pró-Opiomelanocortina/farmacologia , Prolactina/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Distribuição Tecidual , Vasotocina/química
4.
Neuropharmacology ; 139: 238-256, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29981758

RESUMO

The rat nucleus incertus (NI) contains GABA/peptide-projection neurons responsive to orexin (hypocretin)/orexin receptor-2 (OX2) signalling. Melanin-concentrating hormone (MCH) and orexin neurons often innervate and influence common target areas. Therefore, we assessed the relationship between these hypothalamic peptidergic systems and rat NI, by investigating the presence of an MCH innervation and MCH receptor-1 (MCH1) expression, and neurophysiological and behavioural effects of MCH c.f. orexin-A (OXA), within the NI. We identified lateral hypothalamus (LH), perifornical and sub-zona incerta MCH neurons that innervate NI, and characterised the rostrocaudal distribution of MCH-containing fibres in NI. Single-cell RT-PCR detected MCH1 and OX2 mRNA in NI, and multiplex, fluorescent in situ hybridisation revealed distinct co-expression patterns of MCH1 and OX2 mRNA in NI neurons expressing vesicular GABA transporter (vGAT) mRNA. Patch-clamp recordings revealed 34% of NI neurons tested were hyperpolarised by MCH (1 µM), representing a distinct population from OXA-sensitive NI neurons (35%). Intra-NI OXA infusion (600 pmol) in satiated rats during the light/inactive phase produced increased locomotor activity and food (standard chow) intake, whereas intra-NI MCH infusion (600 pmol) produced only a trend for decreased locomotor activity and no effect on food intake. Furthermore, in satiated or pre-fasted rats tested during the dark/active phase, intra-NI infusion of MCH did not alter the elevated locomotor activity or higher food intake observed. However, quantification of neuropeptide-immunostaining revealed differential diurnal fluctuations in orexin and MCH trafficking to NI. Our findings identify MCH and orexin inputs onto divergent NI populations which may differentially influence arousal and motivated behaviours.


Assuntos
Neurônios/citologia , Neurônios/metabolismo , Receptores de Orexina/metabolismo , Núcleos da Rafe/citologia , Núcleos da Rafe/metabolismo , Receptores do Hormônio Hipofisário/metabolismo , Animais , Nível de Alerta/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/fisiologia , Ingestão de Alimentos/efeitos dos fármacos , Região Hipotalâmica Lateral/citologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Hormônios Hipotalâmicos/metabolismo , Masculino , Melaninas/metabolismo , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Neurônios/efeitos dos fármacos , Orexinas/metabolismo , Hormônios Hipofisários/metabolismo , RNA Mensageiro/metabolismo , Núcleos da Rafe/efeitos dos fármacos , Ratos Sprague-Dawley , Ratos Wistar , Técnicas de Cultura de Tecidos , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismo , Ácido gama-Aminobutírico/metabolismo
5.
Reprod Sci ; 25(8): 1218-1223, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29141508

RESUMO

OBJECTIVE: To test whether recombinant anti-Müllerian hormone (AMH) can inhibit ovarian cortex function by modulating the expression of other hormone receptors. MATERIALS AND METHODS: Pilot experimental study with ovarian cortex obtained from 5 patients. Immediately after explant, the ovarian cortex specimens were divided into 5 equal fragments. One fragment was flash-frozen (uncultured) and 4 were incubated for 48 hours at 37°C in a pH-adjusted gamete buffer medium with increasing AMH concentrations of 0, 5, 25, and 50 ng/mL. After incubation, all specimens were rinsed and flash-frozen for polymerase chain reaction (PCR) executed in triplicates. We utilized real-time reverse transcription-polymerase chain reaction (RT-PCR) to determine messenger RNA (mRNA) levels of AMH and its receptor Anti-Müllerian Hormone-Receptor 2 (AMH-R2), follicle stimulating hormone receptor (FSH-R), luteinizing hormone receptor (LH-R), inhibin B, and insulin-like growth factor 1 receptor 1 (IGF1-R1) in ovarian cortex tissue. In addition, we performed Ki-67 immunostaining to evaluate cell proliferation in the treatment groups. RESULTS: Absence of recombinant human AMH (rAMH) caused upregulation of all markers. Exposure to increasing rAMH concentrations caused tissue AMH expression downregulation ( P = .024), while AMH-R2 ( P = .005), FSH-R ( P = .009), LH-R ( P = .003), and inhibin B ( P = .001) mRNA expression followed a bell-shaped response with an increased expression at low dose, followed by a decreased expression at higher doses. Expression of IGF1-R1 was independent ( P = .039) of rAMH exposure. The Ki-67 immunostaining showed an increased cell proliferation in the media control compared to the uncultured and the tissue cultured with rAMH. CONCLUSIONS: Culture with increasing rAMH concentrations caused downregulation of its own, as well as other hormone receptors, and a decreased ovarian cortex cell proliferation. These results help understanding the inhibitory effects of AMH on follicular development.


Assuntos
Hormônio Antimülleriano/metabolismo , Ovário/metabolismo , Receptores de Peptídeos/metabolismo , Receptores do Hormônio Hipofisário/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Adulto , Hormônio Antimülleriano/administração & dosagem , Feminino , Regulação da Expressão Gênica , Humanos , Inibinas/metabolismo , Ovário/efeitos dos fármacos , Projetos Piloto , Pré-Menopausa , RNA Mensageiro/metabolismo , Receptor IGF Tipo 1/metabolismo , Receptores do FSH/metabolismo , Receptores do LH/metabolismo , Receptores de Somatomedina/metabolismo , Proteínas Recombinantes
6.
Obes Res Clin Pract ; 12(2): 158-166, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29066024

RESUMO

BACKGROUND: Prader Willi Syndrome (PWS) is a syndromic form of obesity caused by a chromosomal aberration on chromosome 15q11.2-q13. Patients with a comparable phenotype to PWS not carrying the 15q11.2-q13 defect are classified as Prader Willi like (PWL). In literature, PWL patients do frequently harbor deletions at 6q16, which led to the identification of the single-minded 1 (SIM1) gene as a possible cause for the presence of obesity in these patients. However, our previous work in a PWL cohort showed a rather limited involvement of SIM1 in the obesity phenotype. In this paper, we investigated the causal role of the melanin-concentrating hormone receptor 2 (MCHR2) gene in PWL patients, as most of the reported 6q16 deletions also encompass this gene and it is suggested to be active in the control of feeding behavior and energy metabolism. METHODS: Copy number variation analysis of the MCHR2 genomic region followed by mutation analysis of MCHR2 was performed in a PWL cohort. RESULTS: Genome-wide microarray analysis of 109 patients with PWL did not show any gene harboring deletions on chromosome 6q16. Mutation analysis in 92 patients with PWL demonstrated three MCHR2 variants: p.T47A (c.139A>G), p.A76A (c.228T>C) and c.*16A>G. We identified a significantly higher prevalence of the c.228T>C C allele in our PWL cohort compared to previously published results and controls of the ExAC Database. CONCLUSION: Overall, our results are in line with some previously performed studies suggesting that MCHR2 is not a major contributor to human obesity and the PWL phenotype.


Assuntos
Variações do Número de Cópias de DNA/genética , Obesidade/genética , Síndrome de Prader-Willi/genética , Receptores Acoplados a Proteínas-G/genética , Receptores do Hormônio Hipofisário/genética , Análise de Sequência de DNA , Adolescente , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Criança , Análise Mutacional de DNA , Metabolismo Energético/genética , Comportamento Alimentar/fisiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise em Microsséries , Obesidade/etiologia , Fenótipo , Síndrome de Prader-Willi/complicações
7.
Gen Comp Endocrinol ; 264: 138-150, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28647318

RESUMO

To evaluate the association of the melanotropic peptides and their receptors for morphological color change, we investigated the effects of changes in background color, between white and black, on xanthophore density in the scales and expression levels of genes for hormonal peptides and corresponding receptors (MCH-R2, MC1R, and MC5R) in goldfish (Carassius auratus). The xanthophore density in both dorsal and ventral scales increased after transfer from a white to black background. However, xanthophore density in dorsal scales increased after transfer from a black to white background, and that of ventral scales decreased after transfer from a black to black background, which served as the control. In the white-reared fish, melanin-concentrating hormone (mch) mRNA content in the brain was higher than that in black-reared fish, whereas proopiomelanocortin a (pomc-a) mRNA content in the pituitary was lower than that in the black-reared fish. Agouti-signaling protein (asp) mRNA was detected in the ventral skin but not in the dorsal skin. No difference was observed in the asp mRNA content between fish reared in white or black background, suggesting that ASP might not be associated with background color adaptation. In situ hybridization revealed that both mc1r and mc5r were expressed in the xanthophores in scales. The mRNA content of mc1r in scales did not always follow the background color change, whereas those of mc5r decreased in the white background and increased in the black background, suggesting that mc5r might be a major factor reinforcing the function of MSH in morphological color changes. White backgrounds increased mch mRNA content in the brain, but decreased mch-r2 mRNA content in the scales. These altered expression levels of melanotropin receptors might affect reactivity to melanotropins through long-term adaptation to background color.


Assuntos
Regulação da Expressão Gênica , Carpa Dourada/genética , Hormônios Estimuladores de Melanócitos/genética , Pigmentação/genética , Receptores do Hormônio Hipofisário/genética , Escamas de Animais/metabolismo , Animais , Encéfalo/metabolismo , Cor , Carpa Dourada/metabolismo , Hormônios Hipotalâmicos/genética , Hormônios Hipotalâmicos/metabolismo , Melaninas/genética , Melaninas/metabolismo , Hormônios Estimuladores de Melanócitos/metabolismo , Hormônios Hipofisários/genética , Hormônios Hipofisários/metabolismo , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores do Hormônio Hipofisário/metabolismo , Pele/metabolismo
8.
Gen Comp Endocrinol ; 253: 44-52, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28842217

RESUMO

Primary cilia are specialized microtubule-based organelles. Their importance is highlighted by the gamut of ciliary diseases associated with various syndromes including diabetes and obesity. Primary cilia serve as signaling hubs through selective interactions with ion channels and conventional G-protein-coupled receptors (GPCRs). Melanin-concentrating hormone (MCH) receptor 1 (MCHR1), a key regulator of feeding, is selectively expressed in neuronal primary cilia in distinct regions of the mouse brain. We previously found that MCH acts on ciliary MCHR1 and induces cilia shortening through a Gi/o-dependent Akt pathway with no cell cycle progression. Many factors can participate in cilia length control. However, the mechanisms for how these molecules are relocated and coordinated to activate cilia shortening are poorly understood. In the present study, we investigated the role of cytoskeletal dynamics in regulating MCH-induced cilia shortening using clonal MCHR1-expressing hTERT-RPE1 cells. Pharmacological and biochemical approaches showed that cilia shortening mediated by MCH was associated with increased soluble cytosolic tubulin without changing the total tubulin amount. Enhanced F-actin fiber intensity was also observed in MCH-treated cells. The actions of various pharmacological agents revealed that coordinated actin machinery, especially actin polymerization, was required for MCHR1-mediated cilia shortening. A recent report indicated the existence of actin-regulated machinery for cilia shortening through GPCR agonist-dependent ectosome release. However, our live-cell imaging experiments showed that MCH progressively elicited cilia shortening without exclusion of fluorescence-positive material from the tip. Short cilia phenotypes have been associated with various metabolic disorders. Thus, the present findings may contribute toward better understanding of how the cytoskeleton is involved in the GPCR ligand-triggered cilia shortening with cell mechanical properties that underlies clinical manifestations such as obesity.


Assuntos
Cílios/metabolismo , Citoesqueleto/metabolismo , Receptores do Hormônio Hipofisário/metabolismo , Animais , Corpo Celular/metabolismo , Linhagem Celular , Micropartículas Derivadas de Células/metabolismo , Cílios/efeitos dos fármacos , Citosol/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Humanos , Hormônios Hipotalâmicos/farmacologia , Ligantes , Melaninas/farmacologia , Camundongos , Microtúbulos/metabolismo , Modelos Biológicos , Hormônios Hipofisários/farmacologia , Polimerização , Solubilidade , Tubulina (Proteína)/metabolismo
9.
CPT Pharmacometrics Syst Pharmacol ; 6(7): 458-468, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28556607

RESUMO

In this study, we present the translational modeling used in the discovery of AZD1979, a melanin-concentrating hormone receptor 1 (MCHr1) antagonist aimed for treatment of obesity. The model quantitatively connects the relevant biomarkers and thereby closes the scaling path from rodent to man, as well as from dose to effect level. The complexity of individual modeling steps depends on the quality and quantity of data as well as the prior information; from semimechanistic body-composition models to standard linear regression. Key predictions are obtained by standard forward simulation (e.g., predicting effect from exposure), as well as non-parametric input estimation (e.g., predicting energy intake from longitudinal body-weight data), across species. The work illustrates how modeling integrates data from several species, fills critical gaps between biomarkers, and supports experimental design and human dose-prediction. We believe this approach can be of general interest for translation in the obesity field, and might inspire translational reasoning more broadly.


Assuntos
Fármacos Antiobesidade/administração & dosagem , Azetidinas/administração & dosagem , Modelos Biológicos , Obesidade/tratamento farmacológico , Oxidiazóis/administração & dosagem , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Pesquisa Médica Translacional , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Azetidinas/farmacocinética , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Biomarcadores/metabolismo , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Descoberta de Drogas , Ingestão de Energia/efeitos dos fármacos , Feminino , Humanos , Masculino , Camundongos , Obesidade/metabolismo , Oxidiazóis/farmacocinética , Oxidiazóis/farmacologia , Oxidiazóis/uso terapêutico , Ratos , Receptores do Hormônio Hipofisário/metabolismo , Projetos de Pesquisa
10.
Gene ; 615: 57-67, 2017 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-28300612

RESUMO

Melanin-concentrating hormone (MCH) is a neuropeptide expressed in the brain and exerts its actions through interaction with the two known G protein-coupled receptors, namely melanin-concentrating hormone receptor 1 and 2 (MCHR1 and MCHR2) in mammals. However, the information regarding the expression and functionality of MCH and MCHR(s) remains largely unknown in birds. In this study, using RT-PCR and RACE PCR, we amplified and cloned a MCHR1-like receptor, which is named cMCHR4 according to its evolutionary origin, and a MCHR2 from chicken brain. The cloned cMCHR4 was predicted to encode a receptor of 367 amino acids, which shares high amino acid identities with MCHR4 of ducks (90%), western painted turtles (85%), and coelacanths (77%), and a comparatively low identity to human MCHR1 (58%) and MCHR2 (38%), whereas chicken MCHR2 encodes a putative C-terminally truncated receptor and is likely a pseudogene. Using cell-based luciferase reporter assays or Western blot, we further demonstrated that chicken (and duck) MCHR4 could be potently activated by chicken MCH1-19, and its activation can elevate calcium concentration and activate MAPK/ERK and cAMP/PKA signaling pathways, indicating an important role of MCHR4 in mediating MCH actions in birds. Quantitative real-time PCR revealed that both cMCH and cMCHR4 mRNA are expressed in various brain regions including the hypothalamus, and cMCH expression in the hypothalamus of 3-week-old chicks could be induced by 36-h fasting, indicating that cMCH expression is correlated with energy balance. Taken together, characterization of chicken MCH and MCHR4 will aid to uncover the conserved roles of MCH across vertebrates.


Assuntos
Galinhas/genética , Hormônios Hipotalâmicos/genética , Hipotálamo/metabolismo , Melaninas/genética , Hormônios Hipofisários/genética , Receptores do Hormônio Hipofisário/genética , Animais , Clonagem Molecular , Patos/genética , Jejum , Regulação da Expressão Gênica , Células HEK293 , Humanos , Hormônios Hipotalâmicos/metabolismo , Melaninas/metabolismo , Hormônios Hipofisários/metabolismo , Receptores do Hormônio Hipofisário/metabolismo , Regulação para Cima
11.
Exp Dermatol ; 26(6): 536-541, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27306922

RESUMO

Alopecia areata (AA) is a common hair loss disorder of autoimmune aetiology, which often results in pronounced psychological distress. Understanding of the pathophysiology of AA is increasing, due in part to recent genetic findings implicating common variants at several genetic loci. To date, no study has investigated the contribution of copy number variants (CNVs) to AA, a prominent class of genomic variants involved in other autoimmune disorders. Here, we report a genomewide- and a candidate gene-focused CNV analysis performed in a cohort of 585 patients with AA and 1340 controls of Central European origin. A nominally significant association with AA was found for CNVs in the following five chromosomal regions: 4q35.2, 6q16.3, 9p23, 16p12.1 and 20p12.1. The most promising finding was a 342.5-kb associated region in 6q16.3 (duplications in 4/585 patients; 0/1340 controls). The duplications spanned the genes MCHR2 and MCHR2-AS1, implicated in melanin-concentrating hormone (MCH) signalling. These genes have not been implicated in previous studies of AA pathogenesis. However, previous research has shown that MCHR2 affects the scale colour of barfin flounder fish via the induction of melanin aggregation. AA preferentially affects pigmented hairs, and the hair of patients with AA frequently shows a change in colour when it regrows following an acute episode of AA. This might indicate a relationship between AA, pigmentation and MCH signalling. In conclusion, the present results provide suggestive evidence for the involvement of duplications in MCHR2 in AA pathogenesis.


Assuntos
Alopecia em Áreas/genética , Variações do Número de Cópias de DNA , Estudo de Associação Genômica Ampla , Receptores Acoplados a Proteínas-G/genética , Receptores do Hormônio Hipofisário/genética , Adulto , Bélgica , Mapeamento Cromossômico , Estudos de Coortes , Europa (Continente) , Feminino , Genótipo , Alemanha , Humanos , Hormônios Hipotalâmicos/metabolismo , Masculino , Melaninas/metabolismo , Países Baixos , Pigmentação , Hormônios Hipofisários/metabolismo , Polimorfismo de Nucleotídeo Único , Transdução de Sinais
12.
Eur J Pharmacol ; 796: 45-53, 2017 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-27986627

RESUMO

Melanin-concentrating hormone (MCH), a cyclic neuropeptide expressed predominantly in the lateral hypothalamus, plays an important role in the control of feeding behavior and energy homeostasis. Mice lacking MCH or MCH1 receptor are resistant to diet-induced obesity (DIO) and MCH1 receptor antagonists show potent anti-obesity effects in preclinical studies, indicating that MCH1 receptor is a promising target for anti-obesity drugs. Moreover, recent studies have suggested the potential of MCH1 receptor antagonists for treatment of non-alcoholic fatty liver disease (NAFLD). In the present study, we show the anti-obesity and anti-hepatosteatosis effect of our novel MCH1 receptor antagonist, Compound A. Repeated oral administration of Compound A resulted in dose-dependent body weight reduction and had an anorectic effect in DIO mice. The body weight lowering effect of Compound A was more potent than that of pair-feeding. Compound A also reduced lipid content and the expression level of lipogenesis-, inflammation-, and fibrosis-related genes in the liver of DIO mice. Conversely, intracerebroventricular infusion of MCH caused induction of hepatic steatosis as well as increase in body weight in high-fat diet-fed wild type mice, but not MCH1 receptor knockout mice. The pair-feeding study revealed the MCH-MCH1 receptor system affects hepatic steatosis through a mechanism that is independent of body weight change. Metabolome analysis demonstrated that Compound A upregulated lipid metabolism-related molecules, such as acylcarnitines and cardiolipins, in the liver. These findings suggest that our novel MCH1 receptor antagonist, Compound A, exerts its beneficial therapeutic effect on NAFLD and obesity through a central MCH-MCH1 receptor pathway.


Assuntos
Fármacos Antiobesidade/farmacologia , Dieta Hiperlipídica/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Animais , Fármacos Antiobesidade/uso terapêutico , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Técnicas de Inativação de Genes , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Ratos , Receptores do Hormônio Hipofisário/deficiência , Receptores do Hormônio Hipofisário/genética
13.
Exp Dermatol ; 26(6): 542-543, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27673728

RESUMO

Alopecia areata (AA) is a common hair loss disorder characterized by discrete, well demarcated areas of non-scarring terminal hair alopecia, with the calculated lifetime risk of ~2%. In past decades, linkage and GWA studies have implicated dozens of susceptibility genes/loci that are linked to the development of AA. Fischer et al performed a genome-wide CNV analysis of 585 AA patients and 1,340 controls in a European population. This is the first genome-wide study of CNV to be performed in AA samples, and the association finding in the MCHR2 gene region further underscores the potential role of pigmentation in AA development.


Assuntos
Alopecia em Áreas , Receptores do Hormônio Hipofisário , Estudos de Coortes , Variações do Número de Cópias de DNA , Estudo de Associação Genômica Ampla , Humanos , Pigmentação , Receptores Acoplados a Proteínas-G
14.
Neuropeptides ; 64: 123-130, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27614713

RESUMO

Hypothalamic alpha-melanocyte-stimulating hormone (α-MSH) is a key catabolic mediator of energy homeostasis. Its anorexigenic and hypermetabolic effects show characteristic age-related alterations that may be part of the mechanism of middle-aged obesity and geriatric anorexia/cachexia seen in humans and other mammals. We aimed to investigate the role of α-MSH in mitochondrial energy metabolism during the course of aging in a rodent model. To determine the role of α-MSH in mitochondrial energy metabolism in muscle, we administered intracerebroventricular (ICV) infusions of α-MSH for 7-days to different age-groups of male Wistar rats. The activities of oxidative phosphorylation complexes I to V and citrate synthase were determined and compared to those of age-matched controls. We also quantified mitochondrial DNA (mtDNA) copy number and measured the expression of the master regulators of mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and peroxisome proliferator-activated receptor gamma (PPARγ). The peptide reduced weight gain in juvenile rats to one fifth of that of controls and increased the weight loss in older animals by about five fold. Mitochondrial DNA copy number inversely correlated with changes in body weight in controls, but not in α-MSH-treated animals. The strong increase in body weight in young rats was associated with a low mtDNA copy number and high PPARγ mRNA levels in controls. Expression of PGC-1α and PPARγ declined with age, whereas OXPHOS and citrate synthase enzyme activities were unchanged. In contrast, α-MSH treatment suppressed OXPHOS enzyme and citrate synthase activity. In conclusion, our results showed age-related differences in the metabolic effects of α-MSH. In addition, administration of α-MSH suppressed citrate synthase and OXPHOS activities independent of age. These findings suggest that α-MSH exposure may inhibit mitochondrial biogenesis.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Músculo Esquelético/metabolismo , alfa-MSH/metabolismo , Envelhecimento , Animais , Hipotálamo/metabolismo , Masculino , PPAR gama/metabolismo , Ratos Wistar , Receptores do Hormônio Hipofisário/efeitos dos fármacos , Receptores do Hormônio Hipofisário/metabolismo , Fatores de Transcrição/metabolismo
15.
Sci Rep ; 6: 28969, 2016 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-27373344

RESUMO

In many vertebrate species visible melanin-based pigmentation patterns correlate with high stress- and disease-resistance, but proximate mechanisms for this trait association remain enigmatic. Here we show that a missense mutation in a classical pigmentation gene, melanocyte stimulating hormone receptor (MC1R), is strongly associated with distinct differences in steroidogenic melanocortin 2 receptor (MC2R) mRNA expression between high- (HR) and low-responsive (LR) rainbow trout (Oncorhynchus mykiss). We also show experimentally that cortisol implants increase the expression of agouti signaling protein (ASIP) mRNA in skin, likely explaining the association between HR-traits and reduced skin melanin patterning. Molecular dynamics simulations predict that melanocortin 2 receptor accessory protein (MRAP), needed for MC2R function, binds differently to the two MC1R variants. Considering that mRNA for MC2R and the MC1R variants are present in head kidney cells, we hypothesized that MC2R activity is modulated in part by different binding affinities of the MC1R variants for MRAP. Experiments in mammalian cells confirmed that trout MRAP interacts with the two trout MC1R variants and MC2R, but failed to detect regulation of MC2R signaling, possibly due to high constitutive MC1R activity.


Assuntos
Regulação da Expressão Gênica , Oncorhynchus mykiss/fisiologia , Proteínas Modificadoras da Atividade de Receptores/metabolismo , Receptor Tipo 2 de Melanocortina/biossíntese , Receptores do Hormônio Hipofisário/metabolismo , Estresse Fisiológico , Animais , Expressão Gênica , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutação de Sentido Incorreto , Ligação Proteica , RNA Mensageiro/biossíntese , Receptores do Hormônio Hipofisário/genética
16.
Dokl Biochem Biophys ; 467(1): 141-4, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27193719

RESUMO

We have studied the influence of α-melanocyte-stimulating hormone (α-MSH) on proliferation and early stages of differentiation of human induced pluripotent stem cells (iPSc). We have demonstrated that α-MSH receptor genes are expressed in undifferentiated iPSc. The expression levels of MCR1, MCR2, and MCR3 increased at the embryoid body (EB) formation stage. The formation of neural progenitors was accompanied by elevation of MCR2, MCR3, and MCR4 expression. α-MSH had no effect on EB generation and iPSc proliferation at concentrations ranging from 1 nM to 10 µM. At the same time, α-MSH increased the generation of neural rosettes in human iPSc cultures more than twice.


Assuntos
Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Células-Tronco Pluripotentes Induzidas/fisiologia , alfa-MSH/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Expressão Gênica/fisiologia , Humanos , Células-Tronco Neurais/fisiologia , Neurônios/fisiologia , Receptores do Hormônio Hipofisário/metabolismo , alfa-MSH/administração & dosagem
17.
Physiol Behav ; 163: 239-244, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27195455

RESUMO

The post-oral actions of glucose stimulate intake and condition flavor preferences in rodents. Hypothalamic melanin-concentrating hormone (MCH) neurons are implicated in sugar reward, and this study investigated their involvement in glucose preference conditioning in mice. In Exp. 1 MCH receptor 1 knockout (KO) and C57BL/6 wildtype (WT) mice learned to prefer 8% glucose over an initially more-preferred non-nutritive 0.1% sucralose+saccharin (S+S) solution. In contrast, the KO and WT mice preferred S+S to 8% fructose, which is consistent with this sugar's weak post-oral reinforcing action. In Exp. 2 KO and WT mice were trained to drink a flavored solution (CS+) paired with intragastric (IG) infusion of 16% glucose and a different flavored solution (CS-) paired with IG water. Both groups drank more CS+ than CS- in training and preferred the CS+ to CS- in a 2-bottle test. These results indicate that MCH receptor signaling is not required for flavor preferences conditioned by the post-oral actions of glucose. This contrasts with other findings implicating MCH signaling in other types of sugar reward processing.


Assuntos
Condicionamento Clássico/fisiologia , Preferências Alimentares/fisiologia , Glucose/administração & dosagem , Receptores do Hormônio Hipofisário/deficiência , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores do Hormônio Hipofisário/genética , Sacarina/administração & dosagem , Edulcorantes , Paladar/fisiologia
18.
Endocrinol Nutr ; 63(6): 274-84, 2016.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-27091627

RESUMO

Pituitary adenomas are uncommon, difficult to diagnose tumors whose heterogeneity and low incidence complicate large-scale studies. The Molecular Registry of Pituitary Adenomas (REMAH) was promoted by the Andalusian Society of Endocrinology and Nutrition (SAEN) in 2008 as a cooperative clinical-basic multicenter strategy aimed at improving diagnosis and treatment of pituitary adenomas by combining clinical, pathological, and molecular information. In 2010, the Spanish Society of Endocrinology and Nutrition (SEEN) extended this project to national level and established 6 nodes with common protocols and methods for sample and clinical data collection, molecular analysis, and data recording in a common registry (www.remahnacional.com). The registry combines clinical data with molecular phenotyping of the resected pituitary adenoma using quantitative real-time PCR of expression of 26 genes: Pituitary hormones (GH-PRL-LH-FSH-PRL-ACTH-CGA), receptors (somatostatin, dopamine, GHRH, GnRH, CRH, arginine-vasopressin, ghrelin), other markers (Ki67, PTTG1), and control genes. Until 2015, molecular information has been collected from 704 adenomas, out of 1179 patients registered. This strategy allows for comparative and relational analysis between the molecular profile of the different types of adenoma and the clinical phenotype of patients, which may provide a better understanding of the condition and potentially help in treatment selection. The REMAH is therefore a unique multicenter, interdisciplinary network founded on a shared database that provides a far-reaching translational approach for management of pituitary adenomas, and paves the way for the conduct of combined clinical-basic innovative studies on large patient samples.


Assuntos
Adenoma/epidemiologia , Endocrinologia/organização & administração , Neoplasias Hipofisárias/epidemiologia , Medicina de Precisão/tendências , Sistema de Registros , Pesquisa Médica Translacional/tendências , Adenoma/química , Adenoma/genética , Adolescente , Adulto , Idoso , Criança , Bases de Dados Factuais , Endocrinologia/tendências , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Biologia Molecular , Proteínas de Neoplasias/análise , Proteínas de Neoplasias/genética , Hormônios Hipofisários/análise , Hormônios Hipofisários/genética , Neoplasias Hipofisárias/química , Neoplasias Hipofisárias/genética , RNA Neoplásico/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores do Hormônio Hipofisário/análise , Receptores do Hormônio Hipofisário/genética , Sociedades Médicas , Espanha/epidemiologia , Adulto Jovem
19.
Physiol Behav ; 153: 149-54, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26545301

RESUMO

Mesotocin (MT) and arginine-vasotocin (AVT) are posterior pituitary derived hormones in birds and are homologous to mammalian oxytocin (OT) and vasopressin (VP), respectively. We previously reported that intracerebroventricular (ICV) injection of both MT and AVT inhibit feeding and induce wing-flapping in chicks (Gallus gallus). Because both peptides cause similar effects suggests that they might act via common receptors. However, the specific receptors of MT and AVT which mediate their anorexigenic effect have not been clarified in chicks. Thus, the purpose of the present study was to identify the receptor subtypes involved in MT- and AVT-induced anorexia and behavioral patterns by using several agonists. ICV injection of vasopressin-1 receptor agonist (V1R) (homologous to chicken AVT receptor-2 and -4 [VT2R and VT4R, respectively]), significantly decreased food intake while agonists of vasopressin-2 receptor (V2R) and OT receptor (OTR) (homologues of chicken AVT receptor-1 and MT receptor respectively) had no effect. In addition, V1R agonist induced wing-flapping although this was not affected by V2R or OTR agonists. Since VT2R has not been found in the brain of chicks, the present study suggested that VT4R might be related to the anorexigenic effect and wing-flapping induced by MT and AVT in chicks.


Assuntos
Desamino Arginina Vasopressina/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Ocitocina/análogos & derivados , Receptores do Hormônio Hipofisário/agonistas , Receptores de Vasopressinas/agonistas , Animais , Galinhas , Desamino Arginina Vasopressina/administração & dosagem , Desamino Arginina Vasopressina/análogos & derivados , Injeções Intraventriculares , Masculino , Ocitocina/administração & dosagem , Ocitocina/agonistas , Ocitocina/farmacologia , Asas de Animais/efeitos dos fármacos , Asas de Animais/fisiologia
20.
Oncotarget ; 7(3): 3033-46, 2016 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-26701888

RESUMO

We recently reported that normal hematopoietic stem cells express functional pituitary sex hormone (SexH) receptors. Here we report for the first time that pituitary-secreted gonadotrophins stimulate migration, adhesion, and proliferation of several human myeloid and lymphoid leukemia cell lines. Similar effects were observed after stimulation of human leukemic cell lines by gonadal SexHs. This effect seems to be direct, as the SexH receptors expressed by leukemic cells responded to stimulation by phosphorylation of MAPKp42/44 and AKTser473. Furthermore, in parallel studies we confirmed that human primary patient-derived AML and CML blasts also express several functional SexH receptors. These results shed more light on the potential role of SexHs in leukemogenesis and, in addition, provide further evidence suggesting a developmental link between hematopoiesis and the germline.


Assuntos
Hormônio Foliculoestimulante/farmacologia , Gonadotropinas Hipofisárias/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mieloide Aguda/metabolismo , Hormônio Luteinizante/farmacologia , Receptores do Hormônio Hipofisário/metabolismo , Adesão Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Humanos , Células Jurkat , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Células Mieloides/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
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