The Localization of R-Spondin1 and R-Spondin 3 Peptides in Rat Hypothalamus: An Immunohistochemical Study / Localización de los Péptidos R-Spondin1 y R-Spondin3 en el Hipotálamo de Rata: Un Estudio Inmunohistoquímico

SUMMARY: The R-spondin protein family is a group of proteins that enhance Wnt/b-catenin signaling and have pleiotropic functions in stem cell growth and development. In the literature reviews, there is no histomorphological study showing the localization and distribution of R-spondins in different hypothalamic nuclei. For this reason, the purpose of this study was to determine the localization, distribution characteristics, and densities in the hypothalamic nuclei of neurons expressing Rspo1 and Rspo3 proteins. The free-floating brain sections of the male rats who were not exposed to any treatment were stained with the indirect immunoperoxidase method using the relevant antibodies. As a result of the immunohistochemical studies, it was determined that neurons expressing the Rspo1 protein were found in large numbers in the supraoptic nucleus (SON), the suprachiasmatic nucleus (SCh), anterior paraventricular nucleus, periventricular hypothalamic nucleus (PeV), anterior hypothalamic area, magnocellular preoptic nucleus (MCPO) and the lateral hypothalamic area (LH) from the hypothalamic nuclei, while they were localized in fewer numbers in the arcuate nucleus (ARC). Rspo3 protein expression was found in neurons localized in the hypothalamic nuclei SON, paraventricular nucleus (PVN), PeV, ARC, ventromedial nucleus (VMH), LH, anterior parvicellular nucleus, and zona inserta (ZI). In addition, neurons synthesizing both peptides were found in the cortex and hippocampus regions (H). Rspo1 and 3 proteins are expressed in hypothalamic energy homeostatic areas, thus these proteins may be involved in the regulation of food intake.

La familia de proteínas R-espondina es un grupo de proteínas que mejoran la señalización de Wnt/b-catenina y tienen funciones pleiotrópicas en el crecimiento y desarrollo de las células madre. En las revisiones de la literatura no existen estudios histomorfológicos que muestren la localización y distribución de las R-espondinas en diferentes núcleos hipotalámicos. Por esta razón, el propósito de este estudio fue determinar la localización, características de distribución y densidades en los núcleos hipotalámicos de neuronas que expresan las proteínas Rspo1 y Rspo3. Secciones de cerebro flotantes de ratas macho que no fueron expuestas a ningún tratamiento se tiñeron con el método de inmunoperoxidasa indirecta utilizando los anticuerpos pertinentes. Como resultado de los estudios inmunohistoquímicos, se determinó que las neuronas que expresan la proteína Rspo1 se encontraron en gran número en el núcleo supraóptico (SON), el núcleo supraquiasmático (SCh), el núcleo paraventricular anterior, el núcleo hipotalámico periventricular (PeV), el núcleo hipotalámico anterior área, núcleo preóptico magnocelular (MCPO) y el área hipotalámica lateral (LH) de los núcleos hipotalámicos, mientras que se localizaron en menor número en el núcleo arqueado (ARC). La expresión de la proteína Rspo3 se encontró en neuronas localizadas en los núcleos hipotalámicos SON, núcleo paraventricular (PVN), PeV, ARC, núcleo ventromedial (VMH), LH, núcleo parvicelular anterior y zona inserta (ZI). Además, se encontraron neuronas que sintetizan ambos péptidos en las regiones de la corteza y el hipocampo (H). Las proteínas Rspo1 y 3 se expresan en áreas homeostáticas de energía hipotalámicas, por lo que estas proteínas pueden estar involucradas en la regulación de la ingesta de alimentos.

Xiaoyao San, a Chinese herbal formula, ameliorates depression-like behavior in mice through the AdipoR1/AMPK/ACC pathway in hypothalamus / 中西医结合学报

OBJECTIVE@#Depression and metabolic disorders have overlapping psychosocial and pathophysiological causes. Current research is focused on the possible role of adiponectin in regulating common biological mechanisms. Xiaoyao San (XYS), a classic Chinese medicine compound, has been widely used in the treatment of depression and can alleviate metabolic disorders such as lipid or glucose metabolism disorders. However, the ability of XYS to ameliorate depression-like behavior as well as metabolic dysfunction in mice and the underlying mechanisms are unclear.@*METHODS@#An in vivo animal model of depression was established by chronic social defeat stress (CSDS). XYS and fluoxetine were administered by gavage to the drug intervention group. Depression-like behaviors were analyzed by the social interaction test, open field test, forced swim test, and elevated plus maze test. Glucose levels were measured using the oral glucose tolerance test. The involvement of certain molecules was validated by immunofluorescence, histopathology, and Western blotting. In vitro, hypothalamic primary neurons were exposed to high glucose to induce neuronal damage, and the neuroprotective effect of XYS was evaluated by cell counting kit-8 assay. Immunofluorescence and Western blotting were used to evaluate the influences of XYS on adiponectin receptor 1 (AdipoR1), adenosine 5'-monophosphate-activated protein kinase (AMPK), acetyl-coenzyme A carboxylase (ACC) and other related proteins.@*RESULTS@#XYS ameliorated CSDS-induced depression-like behaviors and glucose tolerance impairment in mice and increased the level of serum adiponectin. XYS also restored Nissl bodies in hypothalamic neurons in mice that exhibited depression-like behaviors and decreased the degree of neuronal morphological damage. In vivo and in vitro studies indicated that XYS increased the expression of AdipoR1 in hypothalamic neurons.@*CONCLUSION@#Adiponectin may be a key regulator linking depression and metabolic disorders; regulation of the hypothalamic AdipoR1/AMPK/ACC pathway plays an important role in treatment of depression by XYS.

The hypothalamus for whole-body physiology: from metabolism to aging

Obesity and aging are two important epidemic factors for metabolic syndrome and many other health issues, which contribute to devastating diseases such as cardiovascular diseases, stroke and cancers. The brain plays a central role in controlling metabolic physiology in that it integrates information from other metabolic organs, sends regulatory projections and orchestrates the whole-body function. Emerging studies suggest that brain dysfunction in sensing various internal cues or processing external cues may have profound effects on metabolic and other physiological functions. This review highlights brain dysfunction linked to genetic mutations, sex, brain inflammation, microbiota, stress as causes for whole-body pathophysiology, arguing brain dysfunction as a root cause for the epidemic of aging and obesity-related disorders. We also speculate key issues that need to be addressed on how to reveal relevant brain dysfunction that underlines the development of these disorders and diseases in order to develop new treatment strategies against these health problems.

Hypothalamic transcriptional expression of the kisspeptin system and sex steroid receptors differs among polycystic ovary syndrome rat models with different endocrine phenotypes

OBJECTIVES: Polycystic ovary syndrome is a heterogeneous endocrine disorder that affects reproductive-age women. The mechanisms underlying the endocrine heterogeneity and neuroendocrinology of polycystic ovary syndrome are still unclear. In this study, we investigated the expression of the kisspeptin system and gonadotropin-releasing hormone pulse regulators in the hypothalamus as well as factors related to luteinizing hormone secretion in the pituitary of polycystic ovary syndrome rat models induced by testosterone or estradiol. METHODS: A single injection of testosterone propionate (1.25 mg) (n=10) or estradiol benzoate (0.5 mg) (n=10) was administered to female rats at 2 days of age to induce experimental polycystic ovary syndrome. Controls were injected with a vehicle (n=10). Animals were euthanized at 90-94 days of age, and the hypothalamus and pituitary gland were used for gene expression analysis. RESULTS: Rats exposed to testosterone exhibited increased transcriptional expression of the androgen receptor and estrogen receptor-β and reduced expression of kisspeptin in the hypothalamus. However, rats exposed to estradiol did not show any significant changes in hormone levels relative to controls but exhibited hypothalamic downregulation of kisspeptin, tachykinin 3 and estrogen receptor-α genes and upregulation of the gene that encodes the kisspeptin receptor. CONCLUSIONS: Testosterone- and estradiol-exposed rats with different endocrine phenotypes showed differential transcriptional expression of members of the kisspeptin system and sex steroid receptors in the hypothalamus. These differences might account for the different endocrine phenotypes found in testosterone- and estradiol-induced polycystic ovary syndrome rats.

Interactions between prolactin and kisspeptin to control reproduction

ABSTRACT Prolactin is best known for its effects of stimulating mammary gland development and lactogenesis. However, prolactin is a pleiotropic hormone that is able to affect several physiological functions, including fertility. Prolactin receptors (PRLRs) are widely expressed in several tissues, including several brain regions and reproductive tract organs. Upon activation, PRLRs may exert prolactin’s functions through several signaling pathways, although the recruitment of the signal transducer and activator of transcription 5 causes most of the known effects of prolactin. Pathological hyperprolactinemia is mainly due to the presence of a prolactinoma or pharmacological effects induced by drugs that interact with the dopamine system. Notably, hyperprolactinemia is a frequent cause of reproductive dysfunction and may lead to infertility in males and females. Recently, several studies have indicated that prolactin may modulate the reproductive axis by acting on specific populations of hypothalamic neurons that express the Kiss1 gene. The Kiss1 gene encodes neuropeptides known as kisspeptins, which are powerful activators of gonadotropin-releasing hormone neurons. In the present review, we will summarize the current knowledge about prolactin’s actions on reproduction. Among other aspects, we will discuss whether the interaction between prolactin and the Kiss1-expressing neurons can affect reproduction and how kisspeptins may become a novel therapeutic approach to treat prolactin-induced infertility.

Gabapentin Differentially Modulate c-Fos Expression in Hypothalamus and Spinal Trigeminal Nucleus in Surgical Molar Extraction

Abstract The study on the efficacy of oral analgesics reported that no single class of drug is effective in post-surgical dental pain. Pain following removal of third molar is most commonly used and widely accepted acute pain model for assessing the analgesic effect of drugs in humans. Reports demonstrated that analgesic efficacy in the human dental model is highly predictive. The high incidence of false-negative findings in analgesic investigations hinders the process of molecular discovery. Molecular mechanism of post-surgical pain is not known. More importantly, the animal model for postoperative dental pain is not well established. In an attempt to discover an effective post-surgical dental pain blocker with acceptable side effects, it is essential to elucidate the molecular mechanism of post-operative dental pain. The present study investigated mandibular molars extraction in rat as an animal model for the post-operative dental pain in central nervous system. Using c-Fos immunohistochemistry, we demonstrated that pre administration of GBP (150 mg/kg. i.p) significantly (p< 0.01) neutralized the surgical molar extraction induced c-Fos expression bilaterally in rat hypothalamus. Present results indicate that pain after surgical molar extraction might follow novel neural pathways therefore difficult to treat with existing anti-nociceptive drugs.

Resumo O estudo da eficácia relativa dos analgésicos orais relatou que nenhuma classe única de fármaco é eficaz na dor pós-cirúrgica dental. A dor após a remoção do terceiro molar é o modelo de dor aguda mais comumente usado e amplamente aceito para avaliar o efeito analgésico de drogas em seres humanos. Os relatos demonstraram que a eficácia analgésica no modelo dental humano é altamente preditiva. A alta incidência de achados falso-negativos em investigações analgésicas dificulta o processo de descoberta molecular. O mecanismo molecular da dor pós-cirúrgica não é conhecido. Mais importante ainda, o modelo animal para a dor pós-operatória não está bem estabelecido. Numa tentativa de descobrir um bloqueador de dor dental pós-cirúrgico eficaz com efeitos secundários aceitáveis, é essencial elucidar o mecanismo molecular da dor pós-operatória dental. Neste estudo investigamos a extração de molares inferiores de ratos como modelo animal para a dor pós-operatória no sistema nervoso central. Utilizando análise imunohistoquímica de c-Fos, demonstrou-se que a administração prévia de GBP (150 mg/kg i.p) significativamente (p<0,01) neutralizou a expressão c-Fos induzida por extração molar cirúrgica bilateralmente no hipotálamo de rato. Os resultados indicam que a dor após a extração molar cirúrgica pode seguir novas vias neurais, portanto, difícil tratar com as drogas anti-nociceptivas existentes.

Obesidade e o hipotálamo / Obesity and the hypothalamus

A obesidade é hoje um grande problema de saúde pública. Este artigo revisa o papel do hipotálamo na obesidade, em especial a dos neurônios NPY/AGRP, POMC/ CART, da área lateral e dos núcleos paraventricular e ventromedial do hipotálamo, e as conexões com a via corticolímbica (AU)

Obesity is currently a major public health problem. This article reviews the role of the hypothalamus in obesity, with special reference to the NPY/AGRP and POMC/ CART neurons, located in the lateral hypothalamic area and in the paraventricular and ventromedial nuclei. We also review these neurons' connections to the corticallimbic pathway (AU)

Disfunção hipotalâmica na obesidade / Hypothalamic dysfunction in obesity

A obesidade, definida como o acúmulo excessivo ou anormal de gordura que pode causar dano à saúde do indivíduo, é considerada atualmente um dos principais problemas de saúde pública. Resulta de um desequilíbrio entre a ingestão alimentar e o gasto corporal de energia. O controle do balanço energético de animais e seres humanos é realizado pelo sistema nervoso central (SNC) por meio de conexões neuroendócrinas, em que hormônios periféricos circulantes, como a leptina e a insulina, sinalizam neurônios especializados do hipotálamo sobre os estoques de gordura do organismo e induzem respostas apropriadas para a manutenção da estabilidade desses estoques. A maioria dos casos de obesidade se associa a um quadro de resistência central à ação da leptina e da insulina. Em animais de experimentação, a dieta hiperlipídica é capaz de induzir um processo inflamatório no hipotálamo, que interfere com as vias intracelulares de sinalização por esses hormônios, resultando em hiperfagia, diminuição do gasto de energia e, por fim, obesidade. Evidências recentes obtidas por intermédio de estudos de neuroimagem e avaliação de marcadores inflamatórios no líquido cefalorraquidiano de indivíduos obesos sugerem que alterações semelhantes podem estar presentes também em seres humanos. Nesta revisão, apresentamos sumariamente os mecanismos envolvidos com a perda do controle homeostático do balanço energético em modelos animais de obesidade e as evidências atuais de disfunção hipotalâmica em humanos obesos.

Obesity, defined as abnormal or excessive fat accumulation that may impair life quality, is one of the major public health problems worldwide. It results from an imbalance between food intake and energy expenditure. The control of energy balance in animals and humans is performed by the central nervous system (CNS) by means of neuroendocrine connections, in which circulating peripheral hormones, such as leptin and insulin, provide signals to specialized neurons of the hypothalamus reflecting body fat stores, and induce appropriate responses to maintain the stability of these stores. The majority of obesity cases are associated with central resistance to both leptin and insulin actions. In experimental animals, high-fat diets can induce an inflammatory process in the hypothalamus, which impairs leptin and insulin intracellular signaling pathways, and results in hyperphagia, decreased energy expenditure and, ultimately, obesity. Recent evidence obtained from neuroimaging studies and assessment of inflammatory markers in the cerebrospinal fluid of obese subjects suggests that similar alterations may be also present in humans. In this review, we briefly present the mechanisms involved with the loss of homeostatic control of energy balance in animal models of obesity, and the current evidence of hypothalamic dysfunction in obese humans.

Desnutrição perinatal e o controle hipotalâmico do comportamento alimentar e do metabolismo do músculo esquelético / Perinatal undernutrition and hypothalamic control of food intake and energy metabolism in the skeletal muscle

A deficiência de nutrientes durante os períodos críticos do desenvolvimento tem sido associada com maior risco para desenvolver obesidade e diabetes Mellitus na vida adulta. Um dos mecanismos propostos refere-se à regulação do comportamento alimentar e às alterações do metabolismo energético do músculo esquelético. Recentemente, tem sido proposta a existência de uma comunicação entre o hipotálamo e o músculo esquelético a partir de sinais autonômicos que podem explicar as repercussões da desnutrição perinatal. Assim, esta revisão tem como objetivo discutir as repercussões da desnutrição perinatal sobre o comportamento alimentar e o metabolismo energético muscular e a comunicação existente entre o hipotálamo e o músculo via sinais adrenérgicos. Foram utilizadas as bases de dados MedLine/PubMed, Lilacs e Bireme, com publicações entre 2000 e 2011. Os termos de indexação utilizados foram: feeding behavior, energy metabolism, protein malnutrition, developmental plasticity, skeletal muscle e autonomic nervous system. Concluiu-se que a desnutrição perinatal pode atuar no controle hipotalâmico do comportamento alimentar e no metabolismo energético muscular, e a comunicação hipotálamo-músculo pode favorecer o desenvolvimento de obesidade e comorbidades durante o desenvolvimento.

Undernutrition during the critical period of development has been associated with susceptibility to obesity and diabetes Mellitus in adulthood. One of the underlying mechanisms can be related with the relationship between the food intake and the metabolism of skeletal muscle. A communication between the hypothalamus and skeletal muscle has been recently proposed, which can explain the repercussion of perinatal undernutrition. Thus, this review aims mainly to discuss the repercussions of perinatal undernutrition on food intake and skeletal muscle metabolism by adrenergic signals. Articles published from 2000 to 2011 were searched in the Medline/Pubmed, Lilacs and Bireme databases using the following keywords: feeding behavior, energy metabolism, protein malnutrition, developmental plasticity, skeletal muscle and autonomic nervous system. In conclusion, perinatal undernutrition can alter the hypothalamic control of food intake and skeletal muscle metabolism. Additionally, communication between the hypothalamus and skeletal muscle can promote the development of obesity and associated diseases.

Serotonina e controle hipotalâmico da fome: uma revisão / Serotonin and hypothalamic control of hunger: a review

Este trabalho revisa a participação do sistema serotonérgico no controle da ingestão de alimentos e saciedade. É de grande interesse compreender a relevância desse sistema para o controle fisiológico do balanço energético e da obesidade. Mais de 35 anos de pesquisas sugerem que a serotonina (5-HT) desempenha um importante papel na saciedade. Assim, o sistema serotonérgico tem sido um alvo viável para o controle de peso. A 5-HT apresenta controle sobre a fome e a saciedade através de diversos receptores, com diferentes funções. O receptor 5-HT2C parece ser o mais importante na relação entre ingestão alimentar e balanço energético. Nesta revisão serão discutidos os mecanismos do sistema serotonérgico envolvidos no controle da ingestão de alimentos e saciedade.

This paper reviews involvement of the serotonergic system in the control of food intake and satiety. It is of great interest to understand the relevance of this system for physiological control of energy balance and obesity. Over 35 years of research suggest that serotonin (5-HT) plays an important role in satiety. Thus, the serotonergic system has been a viable target for weight control. The 5-HT has control over hunger and satiety through different receptors with distinct functions. The 5-HT2C receptor may be more important in the relationship between food intake and energy balance. This review will discuss the mechanisms of the serotonergic system involved in the control of food intake and satiety.

The PI3K signaling pathway mediates the biological effects of leptin / A via de sinalização intracelular da PI3K medeia os efeitos biológicos da leptina

The activation of the leptin receptor recruits several intracellular signaling pathways, including the phosphatidylinositol 3-kinase (PI3K) pathway. While some of the leptin-induced signaling pathways, such as the JAK2/STAT3 pathway, induce cellular responses primarily through changes in gene expression, the PI3K pathway affects cellular properties more rapidly, through post-translational changes such as protein phosphorylation. Accordingly, several studies have shown that the PI3K pathway is required for the acute effects of leptin, such as a leptin-induced decrease in food intake. Leptin signaling through PI3K also affects the electrophysiological properties of neurons, including changes in their membrane potential and firing rates. In this review, we summarize the recent advances in our understanding of the role played by the PI3K signaling pathway in controlling food intake and energy balance. In particular, we focus on the importance of the PI3K signaling pathway as a mediator of the effects of leptin on hypothalamic neurons.

A ativação do receptor de leptina recruta diversas vias de sinalização intracelular, entre elas a via da fosfatidilinositol 3-quinase (PI3K). Enquanto algumas dessas vias, como a sinalização pelo JAK2/STAT3, induzem respostas celulares por meio de mudanças na transcrição gênica, a via da PI3K altera propriedades celulares de forma rápida, via fosforilação de proteínas. Em concordância, estudos mostraram que a via da PI3K é necessária para que a leptina induza seus efeitos agudos, como redução da ingestão alimentar, após administração de leptina. A ativação da PI3K pela leptina também afeta as propriedades fisiológicas de neurônios, incluindo mudanças no potencial de membrana e no potencial de ação. Nesta revisão, resumimos os recentes avanços na compreen-são do papel desempenhado pela via de sinalização da PI3K no controle da ingestão alimentar e do balanço energético. Discutimos, principalmente, como a via da PI3K é importante para mediar os efeitos da leptina sobre os neurônios hipotalâmicos.

Programação do processo fome-saciedade de animais desnutridos no início da lactação: papel do NPY/AgRP e POMC / Programming hunger-satiety process of malnourished animals in early lactation: role of NPY/AgRP and POMC

A modulação do processo fome-saciedade é um fator determinante para o crescimento normal dos sistemas metabólicos. Tem sido demonstrado que variações nutricionais nos períodos pré e pós-natal induzem modificações nas projeções e/ou contatos dos circuitos neuronais hipotalâmicos, gerando uma "reprogramação" deste sistema que envolve mecanismos de interação da ação primária de hormônios como leptina em neurônios orexigênico (NPY/AgRP) anorexigênicos (POMC) no núcleo arqueado, para regular o comportamento alimentar. O objetivo deste trabalho foi estudar a programação do processo fome-saciedade no núcleo arqueado hipotalâmico, em curto e longo prazos, em animais que foram desnutridos no início da lactação. Para isso, utilizamos ratos Wister desnutridos nos primeiros 10 dias de lactação com a utilização de dieta materna com 0% de proteína e que foram submetidos a novo período de desnutrição protéica na fase adulta (60 dias de idade) por 3 dias. Para o estudo do processo fome-saciedade, as variáveis avaliadas foram peso corporal, razão peso corporal / consumo alimentar, conteúdos de receptores de leptina (Ob-Rb) e de neuropeptídeos hipotalâmicos (NPY/AgRP e POMC). Observamos que ao final de 10 dias de desnutrição na lactação, os animais desnutridos apresentaram menor peso corporal (FD - fêmea desnutrida, 50% e MD - macho desnutrido, 53%) e aumento dos conteúdos de Ob-Rb (FD: 121,67% e MD: 132,73%), NPY/AgRP (FD: 32,31% e MD: 115,62%) e POMC (FD: 71,2% e MD: 26,58%). Aos 60 dias de vida, os animais desnutridos apresentaram maior razão peso corporal / consumo alimentar e não evidenciamos diferença nos conteúdos de Ob-Rb, NPY/AgRP e POMC (p<-0,05). Aos 63 dias de vida, fêmeas (FDD) e machos desnutridos (MDD), após um segundo episódio de desnutrição, apresentaram redução de peso corporal (FDD: 12,4% e MDD: 10,75%) e consumo alimentar (FDD: 57,5% e MDD: 39,88%). O conteúdo dos neuropeptídeos orexigênicos (NPY/AgRP)...

The modulation of the hunger-satiety process is a determining factor for the normal growth of the metabolic systems. It has been demonstrated that nutritional variations during pre- and postnatal lead to modifications in projetions and/or contacts of hypothalamic neuronal circuits generating a "reprogramation" of this system, which involves mechanisms of interation of primary action of hormone as leptin in NPY/AgRP and POMC neurons in the arcuate nucleus, to regulate eating behavior. Our aim was to study the programation in the hunger-satiety process in the arcuate nucleus, in the short and long terms, in animals that were malnourished during the early lactation period. In the present study we used Wistar rats that were malnourished during the first 10 days of lactation (0% protein maternal diet) and that were submitted to new a period of malnutrition at adulthood (60 days-old) for 3 days. To study the hunger-satiety process, the variables evaluated were: body weight, body weight/food intake ratio, hypothalamic content of the leptin receptor (Ob-Rb) and the orexigenic NPY/AgRP and anorexigenic POMC neuropeptides. We observed at the end of 10 days of malnutrition during lactation, that the malnourished animals had lower body weight (MF - malnourished female, 50% and MM - malnourished male, 53%) and higher content of Ob-Rb (MF: 121,67% and MM: 132,73%), NPY/AgRP (MF: 32,31% e MM: 115,62%) and POMC (MF: 71,2% e MM: 26,58%). At 60 days, the malnourished animals had higher body weight/food intake ratio and showed no change in the Ob-Rb, NPY/AgRP and POMC content (p<-0,05). At 63 days of life, malnourished female and male after a second episode of malnutrition, had lower body weight (MMF: 12,4% and MMM: 10,75%) and food intake (MMF: 57,5% and MMM: 39,88%). The content of neuropeptides (NPY/AgRP) was significantly lower (MMF: 22,6% and MMM: 26,58%), while the content of Ob-Rb (MMF: 92,27% and MMM: 28%) and POMC neuropeptide (MMF: 22,34% and MMM:27,27%)...

Leptina: aspectos sobre o balanço energético, exercício físico e amenorréia do esforço / Leptin: aspects on energetic balance, physical exercise and athletic amenorhea

O presente manuscrito teve por objetivo realizar uma revisão bibliográfica acerca do papel da leptina no balanço energético, no exercício físico e na incidência da amenorréia do esforço. A leptina é um hormônio secretado pelo tecido adiposo, reconhecido principalmente por sua ação adipostática sobre o sistema nervoso central. Esse hormônio sinaliza o hipotálamo a respeito das reservas energéticas, modulando o funcionamento dos eixos hormonais que envolvam o hipotálamo e a hipófise. A leptina tem ainda ações periféricas importantes, incluindo seu papel sobre o tecido ovariano. Os mecanismos de sinalização intracelular desse hormônio foram identificados no hipotálamo, porém em tecidos periféricos há necessidade de maiores investigações. Existe certo consenso de que quando o exercício e a ingestão alimentar são capazes de promover um balanço energético negativo, as concentrações plasmáticas de leptina diminuem, alterando conseqüentemente: a liberação hipotalâmica de GnRH (fator hipotalâmico de liberação de gonadotrofinas); a liberação hipofisária de LH (hormônio luteinizante) e FSH (hormônio folículo-estimulante). Como resultado, há menor liberação de estrógenos ovarianos. Esse processo pode iniciar a chamada amenorréia hipotalâmica funcional, com repercussões na saúde da mulher. Nessa perspectiva, a avaliação do gasto energético e a elaboração de um plano alimentar adequado em atletas são fundamentais.

The aim of this manuscript was to review the knowledge about leptin, detailing its relationship with energetic intake and physical activity. Leptin is an adipocyte hormone, recognized mainly for its putative role in control of energy expenditure, food intake, body weight and reproductive function. Leptin has still important peripheral actions, including its role on the ovarian tissue. The intracellular signaling mechanisms are recognized in hypothalamus, but in peripheral tissue are not fully understood. The exercise, when practiced by women, if not appropriately planned according to food intake, can modify the leptin release. When energy imbalances induced by exercise and/or deficient food ingestion occurs, low leptin levels are observed, leading to a reduction in GnRH (gonadotropin-release hormone), in LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in pituitary, and consequently a minor release of ovarian estrogens. This process is named hypothalamic amenorrhea, and has repercussions in the woman's health. In this perspective, it is important to emphasize the need to evaluate the energy expenditure from exercise and to formulate adequate alimentary plans to these individuals.

Effects of stress on catecholamine stores in central and peripheral tissues of long-term socially isolated rats

Both the peripheral sympatho-adrenomedullary and central catecholaminergic systems are activated by various psycho-social and physical stressors. Catecholamine stores in the hypothalamus, hippocampus, adrenal glands, and heart auricles of long-term socially isolated (21 days) and control 3-month-old male Wistar rats, as well as their response to immobilization of all 4 limbs and head fixed for 2 h and cold stress (4°C, 2 h), were studied. A simultaneous single isotope radioenzymatic assay based on the conversion of catecholamines to the corresponding O-methylated derivatives by catechol-O-methyl-transferase in the presence of S-adenosyl-l-(³H-methyl)-methionine was used. The O-methylated derivatives were oxidized to ³H-vanilline and the radioactivity measured. Social isolation produced depletion of hypothalamic norepinephrine (about 18 percent) and hippocampal dopamine (about 20 percent) stores and no changes in peripheral tissues. Immobilization decreased catecholamine stores (approximately 39 percent) in central and peripheral tissues of control animals. However, in socially isolated rats, these reductions were observed only in the hippocampus and peripheral tissues. Cold did not affect hypothalamic catecholamine stores but reduced hippocampal dopamine (about 20 percent) as well as norepinephrine stores in peripheral tissues both in control and socially isolated rats, while epinephrine levels were unchanged. Thus, immobilization was more efficient in reducing catecholamine stores in control and chronically isolated rats compared to cold stress. The differences in rearing conditions appear to influence the response of adult animals to additional stress. In addition, the influence of previous exposure to a stressor on catecholaminergic activity in the brainstem depends on both the particular catecholaminergic area studied and the properties of additional acute stress. Therefore, the sensitivity of the catecholaminergic system to habituation appears to be tissue-specific.

O controle hipotalâmico da fome e da termogênese: implicações no desenvolvimento da obesidade / The hypothalamic control of feeding and thermogenesis: implications on the development of obesity

O aumento da prevalência de obesidade em várias regiões do planeta vem se revelando como um dos mais importantes fenômenos clínico-epidemiológicos da atualidade. Fatores como a mudança do hábito alimentar e o estilo de vida sedentário, aliados a determinantes genéticos ainda pouco conhecidos, desempenham um papel relevante na patogênese desta doença. Nos últimos dez anos, desde o descobrimento do hormônio leptina, avanços consideráveis foram obtidos na caracterização dos mecanismos hipotalâmicos do controle da ingestão alimentar e da termogênese. Tais avanços têm revelado as particularidades de um sistema complexo e integrado, e têm oferecido novas perspectivas para abordagens terapêuticas farmacológicas específicas. Esta revisão apresenta os mais recentes avanços nesta área, tendo como foco a ação hipotalâmica da leptina e da insulina e explorando a hipótese de que a resistência à ação central destes hormônios possa ser o elo entre a obesidade e as outras condições clínicas nas quais a resistência à insulina desempenha um papel patogenético proeminente.

The worldwide increase in the prevalence of obesity is becoming one of the most important clinical-epidemiological phenomena of the present days. Environmental factors such as changes in life-style and feeding behavior associated with poorly characterized genetic determinants are though to play the most important roles in the pathogenesis of this disease. During the last ten years, since the discovery of leptin, great advances were obtained in the characterization of the hypothalamic mechanisms involved in the control of food intake and thermogenesis. Such advances are unveiling a complex and integrated system and are opening a wide perspective for the finding of novel therapeutic targets for the treatment of this harming condition. This review will present some of the most recent findings in this field. It will be focused on the actions of leptin and insulin in the hypothalamus and will explore the hypothesis that hypothalamic resistance to the action of these hormones may play a role in the development of obesity and may act as a molecular link between obesity, type 2 diabetes mellitus and other clinical conditions on which insulin resistance plays an important pathogenetic role.

Changes in orexin-A and neuropeptide Y expression in the hypothalamus of the fasted and high-fat diet fed rats

This study was aimed to investigate the changes of orexin-A (OXA) and neuropeptide Y (NPY) expression in the hypothalamus of the fasted and high-fat diet fed rats. For the experiments, the male Sprague-Dawley (SD) rats were used as the model of high-fat diet-induced obesity. The mean loss of body weight (MLBW) did not show the linear pattern during the fasting; from 24 h to 84 h of fastings, the MLBW was not significantly changed. The numbers of OXA-immunoreactive (IR) neurons were decreased at 84 h of fasting compared with those in other five fasting subgroups. The NPY immunoreactivities in the arcuate nucleus (ARC) and the suprachiasmatic nucleus (SCN) observed at 84 h of fasting were higher than that observed at 24 h of fasting. The number of OXA-IR neurons of the LHA (lateral hypothalamic area) in the high-fat (HF) diet fed group was more increased than that of the same area in the normal-fat (NF) diet fed group. The NPY immunoreactivities of the ARC and the SCN were higher in HF group than those observed in the same areas of NF group. Based on these results, it is noteworthy that the decrease of the body weight during the fast was not proportionate to the time-course, implicating a possible adaptation of the body for survival against starvation. The HF diet might activate the OXA and the NPY in the LHA to enhance food intake.

Hypothalamic digoxin and regulation of body mass index.

The hypothalamus produces digoxin, an endogenous membrane Na+-K+ ATPase inhibitor and regulator of neurotransmission. Digoxin being a steroidal glycoside, is synthesised by the isoprenoid pathway. In view of the reports of elevated digoxin levels in metabolic syndrome X with high body mass index, the isoprenoid pathway mediated biochemical cascade was assessed in individuals with high and low body mass index. It was also assessed in individuals with differing hemispheric dominance to find out the relationship between digoxin status, body mass index and hemispheric dominance. The isoprenoid pathway metabolites, tryptophan / tyrosine catabolic patterns and membrane composition were assessed. In individuals with high body mass index an upregulated isoprenoid pathway with increased HMG CoA reductase activity, serum digoxin and dolichol levels and low ubiquinone levels were observed. The RBC membrane Na+-K+ ATPase activity and serum magnesium levels were decreased. The tyrosine catabolites (dopamine, morphine, epinephrine and norepinephrine) were reduced and the tryptophan catabolites (serotonin, quinolinic acid, strychnine and nicotine) were increased. There was an increase in membrane cholesterol : phospholipid ratio and a reduction in membrane glycoconjugates in individuals with high body mass index. The reverse patterns were seen in individuals with low body mass index. The patterns in individuals with high body mass index and low body mass index correlated with right hemispheric dominance and left hemispheric dominance respectively. Hemispheric dominance and digoxin status regulates the differential metabolic pattern observed in individuals with high and low body mass index.

Hypothalamic digoxin and irritable bowel syndrome.

BACKGROUND: The hypothalamus produces an endogenous membrane Na+-K+ ATPase inhibitor digoxin that can modulate neurotransmitter transport and may play a role in hemispheric dominance. It can also modulate glycoconjugate synthesis and thus affect synaptic connectivity in the bowel wall. Digoxin could play a role in the genesis of irritable bowel syndrome (IBS). AIM: To study digoxin status in IBS and to correlate it with hemispheric dominance. METHODS: The isoprenoid pathway, tryptophan/tyrosine catabolic patterns and glycoconjugate metabolism were assessed in patients with IBS and in right hemispheric dominant/left hemispheric dominant/bihemispheric dominant individuals. RESULTS: The isoprenoid pathway was upregulated in IBS, with increased HMG CoA reductase activity (0.8 [0.07] vs 0.4 [0.06] in controls; p<0.01), serum digoxin (14.8 [1.0] vs 29.0 [1.2] ng/dL; p<0.01) and dolichol levels (63.8 [3.0] vs 120.3 [3.6] mg/dL; p<0.01). RBC membrane Na+-K+ ATPase activity (3.0 [0.2] vs 1.0 [0.1] microg/p/mg protein; p<0.01), serum magnesium (1.7 [0.1] vs 1.0 [0.1] mg/dL; p<0.01) and ubiquinone (86.4 [5.9] vs 39.8 [1.2] microg/dL; p<0.01) were reduced. There was increase in tryptophan catabolites and reduction in tyrosine catabolites. Serum total glycosaminoglycan and carbohydrate component of glycoproteins were increased in IBS. The activity of glycosaminoglycan degrading enzymes and glycohydrolases were increased. This pattern correlated with those obtained in right hemispheric chemical dominance. CONCLUSION: Hypothalamic digoxin and right hemispheric dominance could play a role in the genesis of irritable bowel syndrome.

Distribution of delta sleep-inducing peptide in the newborn and infant human hypothalamus: an immunohistochemical study

The distribution of delta sleep-inducing peptide immunoreactive cell bodies, fibers, and terminal-like structures was investigated in the normal human hypothalamus during the first postnatal year, using immunohistofluorescence and peroxidase anti-peroxidase techniques. Immunolabeled perikarya were relatively few and were mostly scattered through the anterior (preoptic) and mediobasal regions (infundibular nucleus) of the hypothalamus. DSIP-immunoreactive fibers and terminal-like fibers were observed throughout the entire rostrocaudal extent of the hypothalamus. They exhibit high densities in the preoptic region, the organum vasculosum of lamina terminalis, infundibular nucleus and median eminence. Moderate to low densities of DSIP-immunoreactive fibers were observed in the other hypothalamic structures, located in the anterior and mediobasal regions of hypothalamus, such as periventricular, paraventricular, suprachiasmatic, ventromedial, dorsomedial and parafornical nuclei. In the present study, the analysis of the immunohistochemical pattern of DSIP-immunoreactive neuronal elements in the human infant hypothalamus during the first postnatal year provided evidence of the presence of several differences. We have found qualitative age-related changes in the density of DSIP immunoreactivity in several hypothalamic structures such as the anterior region and the median eminence.