RESUMO
In normal hormonal conditions, increased neuronal activity in the ventromedial hypothalamus (VMH) induces lordosis whereas activation of the preoptic area (POA) exerts an opposite effect. In the present work, we explored the effect of bilateral infusion of different doses of the apelin-13 (0.37, 0.75, 1.5, and 15 µg) in both brain areas on the expression of lordosis behavior. Lordosis quotient and lordosis reflex score were performed at 30, 120, and 240 min. Weak lordosis was observed following the 0.37 µg dose of apelin-13 at 30 min in the VMH of EB-primed rats; however, the rest of the doses induced significant lordosis relative to the control group. At 120 min, all doses induced lordosis behavior, while at 240 min, the highest dose of 15 µg did not induce significant differences. Interestingly, only the 0.75 µg infusion of apelin in the POA induced significant lordosis at 120 and 240 min. These results indicate that apelin-13 acts preferably in HVM and slightly in POA to initiate lordosis behavior in estrogen-primed rats.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular , Lordose , Área Pré-Óptica , Animais , Estradiol/farmacologia , Estrogênios/farmacologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/patologia , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Lordose/induzido quimicamente , Área Pré-Óptica/efeitos dos fármacos , Área Pré-Óptica/patologia , Progesterona/farmacologia , Ratos , Comportamento Sexual Animal/efeitos dos fármacos , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacos , Núcleo Hipotalâmico Ventromedial/patologiaRESUMO
Chronic stress is one of the main risk factors of bone loss. While the neurons and neural circuits of the ventromedial hypothalamus (VMH) mediate bone loss induced by chronic stress, the detailed intrinsic mechanisms within the VMH nucleus still need to be explored. Astrocytes in brain regions play important roles in the regulation of metabolism and anxiety-like behavior through interactions with surrounding neurons. However, whether astrocytes in the VMH affect neuronal activity and therefore regulate chronic stress-induced anxiety and bone loss remain elusive. In this study, we found that VMH astrocytes were activated during chronic stress-induced anxiety and bone loss. Pharmacogenetic activation of the Gi and Gq pathways in VMH astrocytes reduced and increased the levels of anxiety and bone loss, respectively. Furthermore, activation of VMH astrocytes by optogenetics induced depolarization in neighboring steroidogenic factor-1 (SF-1) neurons, which was diminished by administration of N-methyl-D-aspartic acid (NMDA) receptor blocker but not by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker. These results suggest that there may be a functional "glial-neuron microcircuit" in VMH nuclei that mediates anxiety and bone loss induced by chronic stress. This study not only advances our understanding of glial cell function but also provides a potential intervention target for chronic stress-induced anxiety and bone loss therapy.
Assuntos
Transtornos de Ansiedade/fisiopatologia , Astrócitos/fisiologia , Reabsorção Óssea/fisiopatologia , Estresse Psicológico/complicações , Núcleo Hipotalâmico Ventromedial/patologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Densidade Óssea , Reabsorção Óssea/etiologia , Reabsorção Óssea/prevenção & controle , Doença Crônica , Clozapina/farmacologia , Clozapina/uso terapêutico , Teste de Labirinto em Cruz Elevado , Emoções , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/agonistas , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/fisiologia , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/fisiologia , Genes Reporter , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Teste de Campo Aberto , Optogenética , Proteínas Proto-Oncogênicas c-fos/biossíntese , Proteínas Proto-Oncogênicas c-fos/genética , Distribuição Aleatória , Receptores de N-Metil-D-Aspartato/fisiologia , Núcleo Hipotalâmico Ventromedial/fisiopatologiaRESUMO
Leptin signaling pathways, stemming primarily from the hypothalamus, are necessary for maintaining normal energy homeostasis and body weight. In both rodents and humans, dysregulation of leptin signaling leads to morbid obesity and diabetes. Since leptin resistance is considered a primary factor underlying obesity, understanding the regulation of leptin signaling could lead to therapeutic tools and provide insights into the causality of obesity. While leptin actions in some hypothalamic regions such as the arcuate nuclei have been characterized, less is known about leptin activity in the hypothalamic ventromedial nuclei (VMN). Recently, pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to reduce feeding behavior and alter metabolism when administered into the VMN in a pattern similar to that of leptin. In the current study, we examined whether leptin and PACAP actions in the VMN share overlapping pathways in the regulation of energy balance. Interestingly, PACAP administration into the VMN increased STAT3 phosphorylation and SOCS3 mRNA expression, both of which are hallmarks of leptin receptor activation. In addition, BDNF mRNA expression in the VMN was increased by both leptin and PACAP administration. Moreover, antagonizing PACAP receptors fully reversed the behavioral and cellular effects of leptin injections into the VMN. Electrophysiological studies further illustrated that leptin-induced effects on VMN neurons were blocked by antagonizing PACAP receptors. We conclude that leptin dependency on PACAP signaling in the VMN suggests a potential common signaling cascade, allowing a tonically and systemically secreted neuropeptide to be more precisely regulated by central neuropeptides.
Assuntos
Comportamento Animal/fisiologia , Regulação da Temperatura Corporal/fisiologia , Ingestão de Alimentos/fisiologia , Leptina/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Transdução de Sinais/fisiologia , Núcleo Hipotalâmico Ventromedial/patologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/metabolismoRESUMO
Previous studies showed that restraint water-immersion stress (RWIS) increases the expression of Fos protein in the ventromedial hypothalamic nucleus (VMH), indicating the VMH involving in the stress-induced gastric mucosal injury (SGMI). The present study was designed to investigate its possible neuro-regulatory mechanisms in rats receiving either VMH lesions or sham surgery. The model for SGMI was developed by restraint and water (21 ± 1 °C) immersion for 2 h. Gastric mucosal injury index, gastric motility, gastric acid secretion and Fos expression in the hypothalamus and brainstem were examined on the 15th postoperative day in RWIS rats. Gastric mucosal injury in VMH-lesioned rats was obviously aggravated compared to the control. Gastric acidity under RWIS was obviously higher in VMH-lesioned rats than that in sham rats. Meantime, the VMH-lesioned rats exhibited marked increases in the amplitude of gastric motility in the VMH lesions group after RWIS. In VMH-lesioned rats, Fos expression significantly increased in the dorsal motor nucleus of the vagus (DMV), the nucleus of the solitary tract (NTS), the area postrema (AP), the paraventricular nucleus (PVN) and the supraoptic nucleus (SON) in response to RWIS. These results indicate that VMH lesions can aggravate the stress-induced gastric mucosal injury through the VMH-dorsal vagal complex (DVC)-vagal nerve pathway.
Assuntos
Mucosa Gástrica/lesões , Mucosa Gástrica/patologia , Estresse Psicológico/complicações , Núcleo Hipotalâmico Ventromedial/patologia , Animais , Peso Corporal , Ácido Gástrico/metabolismo , Imersão , Masculino , Neurônios/patologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Wistar , Restrição Física , Núcleo Hipotalâmico Ventromedial/metabolismo , ÁguaRESUMO
BACKGROUND AND OBJECTIVE: The most important alkaloid of opium family, morphine, may show unfavorable effect on the reproductive organs. This research investigated the effect of microinjection of morphine into the rat's ventromedial hypothalamus (VMH) on cystic genesis in the ovary and the health of neurons of VMH. MATERIALS AND METHODS: Female rats (Wistar, weighing 200-250 g) kept under standard conditions were cannulated under anesthesia by Stoelting stereotaxic instrument at the coordinates anterior-posterior: -1.92, ventral: 9, lateral: 0.5. After being recovered, they were microinjected single morphine (0.1-0.4 µg/rat, once intra-VMH) and/or naloxone hydrochloride (0.1-0.4 µg/rat, once intra-VMH) using a 5-µL Hamilton syringe with the polyethylene tubing. The control group solely given physiological saline (1 µL/rat, intra-VMH). Three days after the experiment, both ovary and brain samples were collected from the control and the experimental groups, and they were studied histopathologically. The brain samples were checked out with the aid of the cresyl violet, and the ovaries were stained by the hematoxylin and eosin. The samples were also biometrically examined to compare the ovaries' cystic formations. Also, the number of healthy or injured neurons in the nuclei was compared. RESULTS: The ovaries of morphine-treated rats showed polycystic characteristics in comparison with the control samples. In addition, the brain slices of the morphine-treated rats illustrated a significant decrease in intact neurons. Both mal effects were resolved in the presence of naloxone. CONCLUSION: These results may show that the morphine induces anovulatory infertility probably by hypothalamus-pituitary-ovary axis dysfunction.
Assuntos
Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Ovário/efeitos dos fármacos , Ovário/patologia , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacos , Núcleo Hipotalâmico Ventromedial/patologia , Animais , Feminino , Ciclo Menstrual , Naloxona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Neurônios/efeitos dos fármacos , Neurônios/patologia , Síndrome do Ovário Policístico/induzido quimicamente , Ratos WistarAssuntos
Ilhotas Pancreáticas/metabolismo , Receptor A1 de Adenosina/metabolismo , Núcleo Hipotalâmico Ventromedial/cirurgia , Animais , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica/métodos , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Receptor A1 de Adenosina/genética , Núcleo Hipotalâmico Ventromedial/metabolismo , Núcleo Hipotalâmico Ventromedial/patologiaRESUMO
Estrogen-receptor alpha (ERα) neurons in the ventrolateral region of the ventromedial hypothalamus (VMHVL) control an array of sex-specific responses to maximize reproductive success. In females, these VMHVL neurons are believed to coordinate metabolism and reproduction. However, it remains unknown whether specific neuronal populations control distinct components of this physiological repertoire. Here, we identify a subset of ERα VMHVL neurons that promotes hormone-dependent female locomotion. Activating Nkx2-1-expressing VMHVL neurons via pharmacogenetics elicits a female-specific burst of spontaneous movement, which requires ERα and Tac1 signaling. Disrupting the development of Nkx2-1(+) VMHVL neurons results in female-specific obesity, inactivity, and loss of VMHVL neurons coexpressing ERα and Tac1. Unexpectedly, two responses controlled by ERα(+) neurons, fertility and brown adipose tissue thermogenesis, are unaffected. We conclude that a dedicated subset of VMHVL neurons marked by ERα, NKX2-1, and Tac1 regulates estrogen-dependent fluctuations in physical activity and constitutes one of several neuroendocrine modules that drive sex-specific responses.
Assuntos
Receptor alfa de Estrogênio/metabolismo , Locomoção/genética , Proteínas Nucleares/biossíntese , Obesidade/metabolismo , Taquicininas/genética , Fatores de Transcrição/biossíntese , Animais , Receptor alfa de Estrogênio/genética , Estrogênios/metabolismo , Feminino , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Proteínas Nucleares/genética , Obesidade/genética , Obesidade/fisiopatologia , Caracteres Sexuais , Taquicininas/metabolismo , Fator Nuclear 1 de Tireoide , Fatores de Transcrição/genética , Núcleo Hipotalâmico Ventromedial/metabolismo , Núcleo Hipotalâmico Ventromedial/patologiaRESUMO
To determine the relationship between the right and left sides of the ventrolateral ventromedial hypothalamic nucleus (vlVMN) in regulating the expression of oestrogen receptor (ER)α, the unilateral vlVMN was lesioned and the number of ERα-immunoreactive cells and the ERα mRNA level in the intact side of the vlVMN and arcuate nucleus (ARC) were measured in ovariectomised rats. Twenty-four hours after lesioning, brain samples were collected for analysis of ERα expression by immunohistochemistry and the real-time reverse transcriptase-polymerase chain reaction. The number of ERα-immunoreactive cells in the intact side of the vlVMN but not the ARC in the unilateral lesioned group was significantly higher than that in the control or sham-lesioned group. Expression levels of ERα mRNA in the intact side of the vlVMN but not the ARC in unilateral lesioned rats were significantly higher than those in the sham-lesioned group. Of transcript variants with alternative 5'-untranslated regions (0S, 0N, 0, 0T and E1), the ERα 0 transcript level was significantly increased. These results indicate that unilateral damage of vlVMN induces an increase in ERα in the intact side by increasing ERα transcription in a promoter-specific manner. The findings also suggest the existence of new neuroendocrine control system between the right and left sides for the expression of ERα in the vlVMN.
Assuntos
Receptor alfa de Estrogênio/metabolismo , Ovariectomia , Núcleo Hipotalâmico Ventromedial/metabolismo , Animais , Sequência de Bases , Primers do DNA , Feminino , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Núcleo Hipotalâmico Ventromedial/patologiaRESUMO
Infantile neuronal ceroid lipofuscinosis (INCL) is a fatal neurodegenerative disorder caused by a deficiency of palmitoyl-protein thioesterase-1 (PPT1). We have previously shown that children with INCL have increased risk of hypothermia during anesthesia and that PPT1-deficiency in mice is associated with disruption of adaptive energy metabolism, downregulation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), and mitochondrial dysfunction. Here we hypothesized that Ppt1-knockout mice, a well-studied model of INCL that shows many of the neurologic manifestations of the disease, would recapitulate the thermoregulation impairment observed in children with INCL. We also hypothesized that when exposed to cold, Ppt1-knockout mice would be unable to maintain body temperature as in mice thermogenesis requires upregulation of Pgc-1α and uncoupling protein 1 (Ucp-1) in brown adipose tissue. We found that the Ppt1-KO mice had lower basal body temperature as they aged and developed hypothermia during cold exposure. Surprisingly, this inability to maintain body temperature during cold exposure in Ppt1-KO mice was associated with an adequate upregulation of Pgc-1α and Ucp-1 but with lower levels of sympathetic neurotransmitters in brown adipose tissue. In addition, during baseline conditions, brown adipose tissue of Ppt1-KO mice had less vacuolization (lipid droplets) compared to wild-type animals. After cold stress, wild-type animals had significant decreases whereas Ppt1-KO had insignificant changes in lipid droplets compared with baseline measurements, thus suggesting that Ppt1-KO had less lipolysis in response to cold stress. These results uncover a previously unknown phenotype associated with PPT1 deficiency, that of altered thermoregulation, which is associated with impaired lipolysis and neurotransmitter release to brown adipose tissue during cold exposure. These findings suggest that INCL should be added to the list of neurodegenerative diseases that are linked to alterations in peripheral metabolic processes. In addition, extrapolating these findings clinically, impaired thermoregulation and hypothermia are potential risks in patients with INCL.
Assuntos
Tecido Adiposo Marrom/anormalidades , Tecido Adiposo Marrom/fisiopatologia , Regulação da Temperatura Corporal/fisiologia , Lipofuscinoses Ceroides Neuronais/enzimologia , Lipofuscinoses Ceroides Neuronais/fisiopatologia , Tioléster Hidrolases/deficiência , Trifosfato de Adenosina/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Animais , Temperatura Baixa , Modelos Animais de Doenças , Feminino , Temperatura Alta , Canais Iônicos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Mitocondriais/metabolismo , NAD/metabolismo , Lipofuscinoses Ceroides Neuronais/patologia , Neurotransmissores/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores Adrenérgicos beta/metabolismo , Tioléster Hidrolases/metabolismo , Proteína Desacopladora 1 , Núcleo Hipotalâmico Ventromedial/metabolismo , Núcleo Hipotalâmico Ventromedial/patologia , Núcleo Hipotalâmico Ventromedial/fisiopatologiaRESUMO
Hypothalamic obesity (HO) is a major and unsolved problem in patients with medial hypothalamic lesions and is associated with hyperinsulinemia and hyperleptinemia. The purpose of this study was to create a rodent model that mimics metabolic changes in HO for use in therapeutic testing. Female Sprague-Dawley rats were used to test the individual and combined effects of two types of medial hypothalamic lesions: arcuate nucleus (ARC) lesions by injection of monosodium glutamate at neonatal age, and ventromedial nucleus (VMN) lesions by passing an anodal current through an electrode placed in the VMN at age 80 days. Adiposity in ARC-lesioned animals was associated with decreased food intake and stunted growth, while VMN lesions were associated with hyperphagia but not reduced growth. The greatest weight gain (weight at age 200 days 712 +/- 65 vs. 451 +/- 19 g in controls), hyperphagia (food intake 10 days following surgery 33 +/- 0.8 vs. 18.5 +/- 0.7 g/day in sham-treated rats), hyperinsulinemia and hyperleptinemia occurred in rats that received both ARC and VMN lesions. Thus, the combined medial hypothalamic lesions result in an obesity phenotype similar to that of patients that suffer from HO and are consequently more suitable for testing potential therapeutics for this disorder than lesions of single hypothalamic nuclei.
Assuntos
Doenças Hipotalâmicas/complicações , Animais , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Hiperinsulinismo/etiologia , Hiperfagia/etiologia , Hiperfagia/fisiopatologia , Doenças Hipotalâmicas/etiologia , Doenças Hipotalâmicas/patologia , Insulina/sangue , Leptina/sangue , Obesidade , Ratos , Ratos Sprague-Dawley , Glutamato de Sódio/farmacologia , Núcleo Hipotalâmico Ventromedial/lesões , Núcleo Hipotalâmico Ventromedial/patologia , Aumento de PesoRESUMO
Patients with craniopharyngioma (CP), a tumor located in the pituitary and/or hypothalamus, are susceptible to developing obesity and many metabolic complications. The study aim was to create a rodent model that mimics the complex neuroanatomical and metabolic disturbances commonly seen in obese CP patients. We compared the metabolic phenotype of animals with three distinct types of hypothalamic lesions: 1) destruction of the arcuate nucleus (ARC) induced by monosodium glutamate (MSG), 2) electrolytic lesion of the adjacent ventromedial nucleus (VMN) alone, 3) both the VMN and dorsomedial nucleus (DMN), or a 4) combined medial hypothalamic lesion (CMHL) affecting the VMN, DMN, and the ARC. Only the CMHL model exhibited all key features observed in patients with hypothalamic obesity induced by CP. These features included excessive weight gain due to increased adiposity, increased food intake, and pronounced hyperinsulinemia and hyperleptinemia. Similar to characteristics of patients with CP, CMHL animals exhibited reduced plasma levels of alpha-melanocyte stimulating hormone and reduced ambulatory activity compared with weight-matched controls. Therefore, the CMHL model best mimics the complex metabolic abnormalities observed in obese CP patients compared with lesions to other hypothalamic areas and provides a foundation for future pharmacological approaches to treat obesity in children with hypothalamic damage.
Assuntos
Craniofaringioma/complicações , Modelos Animais de Doenças , Neoplasias Hipotalâmicas/complicações , Obesidade/etiologia , Neoplasias Hipofisárias/complicações , Animais , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/patologia , Peso Corporal , Criança , Craniofaringioma/patologia , Núcleo Hipotalâmico Dorsomedial/metabolismo , Núcleo Hipotalâmico Dorsomedial/patologia , Ingestão de Alimentos , Metabolismo Energético , Feminino , Homeostase , Humanos , Neoplasias Hipotalâmicas/patologia , Hipotálamo/anatomia & histologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Hipotálamo/patologia , Masculino , Neoplasias Hipofisárias/patologia , Gravidez , Ratos , Ratos Sprague-Dawley , Glutamato de Sódio/efeitos adversos , Núcleo Hipotalâmico Ventromedial/metabolismo , Núcleo Hipotalâmico Ventromedial/patologiaRESUMO
Physiological conditions of low leptin levels like those observed during negative energy balance are usually characterized by the suppression of luteinizing hormone (LH) secretion and fertility. Leptin administration restores LH levels and reproductive function. Leptin action on LH secretion is thought to be mediated by the brain. However, the neuronal population that mediates this effect is still undefined. The hypothalamic ventral premammillary nucleus (PMV) neurons express a dense concentration of leptin receptors and project to brain areas related to reproductive control. Therefore, we hypothesized that the PMV is well located to mediate leptin action on LH secretion. To test our hypothesis, we performed bilateral excitotoxic lesions of the PMV in adult female rats. PMV-lesioned animals displayed a clear disruption of the estrous cycle, remaining in anestrus for 15-20 d. After apparent recovery of cyclicity, animals perfused in the afternoon of proestrus showed decreased Fos immunoreactivity in the anteroventral periventricular nucleus and in gonadotropin releasing hormone neurons. PMV-lesioned animals also displayed decreased estrogen and LH secretion on proestrus. Lesions caused no changes in mean food intake and body weight up to 7 weeks after surgery. We further tested the ability of leptin to induce LH secretion in PMV-lesioned fasted animals. We found that complete lesions of the PMV precluded leptin stimulation of LH secretion on fasting. Our findings demonstrate that the PMV is a key site linking changing levels of leptin and coordinated control of reproduction.
Assuntos
Jejum/metabolismo , Leptina/metabolismo , Hormônio Luteinizante/metabolismo , Núcleo Hipotalâmico Ventromedial/metabolismo , Animais , Jejum/sangue , Feminino , Leptina/sangue , Hormônio Luteinizante/antagonistas & inibidores , Hormônio Luteinizante/sangue , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Reprodução/fisiologia , Núcleo Hipotalâmico Ventromedial/patologiaRESUMO
Estrogens act within the ventromedial nucleus of the hypothalamus (VMN) to facilitate lordosis behavior. Estradiol treatment in vivo induces alpha(1b)-adrenoreceptor mRNA and increases the density of alpha(1B)-adrenoreceptor binding in the hypothalamus. Activation of hypothalamic alpha(1)-adrenoceptors also facilitates estrogen-dependent lordosis. To investigate the cellular mechanisms of adrenergic effects on VMN neurons, whole-cell patch-clamp recordings were carried out on hypothalamic slices from control and estradiol-treated female rats. In control slices, bath application of the alpha(1)-agonist phenylephrine (PHE; 10 microM) depolarized 10 of 25 neurons (40%), hyperpolarized three neurons (12%), and had no effect on 12 neurons (48%). The depolarization was associated with decreased membrane conductance, and this current had a reversal potential close to the K(+) equilibrium potential. The alpha(1b)-receptor antagonist chloroethylclonidine (10 microM) blocked the depolarization produced by PHE in all cells. From estradiol-treated rats, significantly more neurons in slices depolarized (71%) and fewer neurons showed no response (17%) to PHE. PHE-induced depolarizations were significantly attenuated with 4-aminopyridine (5 mM) but unaffected by tetraethylammonium chloride (20 mM) or blockers of Na(+) and Ca(2+) channels. These data indicate that alpha(1)-adrenoceptors depolarize VMN neurons by reducing membrane conductance for K(+). Estradiol amplifies alpha(1b)-adrenergic signaling by increasing the proportion of VMN neurons that respond to stimulation of alpha(1b)-adrenergic receptors, which is expected in turn to promote lordosis.
Assuntos
Estradiol/farmacologia , Hipotálamo/patologia , Norepinefrina/farmacologia , Fenilefrina/farmacologia , Núcleo Hipotalâmico Ventromedial/patologia , 4-Aminopiridina/química , Animais , Eletrofisiologia/métodos , Estrogênios/metabolismo , Feminino , Neurônios/metabolismo , Técnicas de Patch-Clamp , Canais de Potássio/química , Ratos , Tetraetilamônio/químicaRESUMO
Orexins are endogenous neuropeptides that potently facilitate appetite and food consumption. In the present study, we examined orexin immunoreactivity and prepro-orexin mRNA expression in the lateral hypothalamus by immunohistochemistry and competitive reverse transcription-polymerase chain reaction (RT-PCR) methods in different models of hyperphagia in rats. Hyperphagia was induced by lesions of either the ventromedial hypothalamus (VMHL) or the paraventricular nucleus (PVNL), and we also compared lactating rats to nonlactating controls. Both VMHL and PVNL increased food intake and body weight compared to shams. On day 7 post lesion, serum leptin and insulin concentrations exhibited 3.2- and 2.8-fold increases in VMHL rats, and nonsignificant 1.8- and 1.8-fold increases in PVNL rats; there were significant decreases (48% and 33%) in lactating rats on day 12 postpartum compared to controls, respectively. Serum glucose concentrations were not significantly changed compared to controls in these rats. Quantification by image analysis suggests that VMHL significantly decreased the number and mean staining intensity of orexin-A immunoreactive neurones compared to those in the sham-lesioned group; while PVNL did not change orexin-A immunoreactivity. Competitive RT-PCR analysis showed that VMHL significantly decreased the prepro-orexin mRNA expression compared to those in the sham-lesioned group, and PVNL did not change it. Lactating rats on days 11-12 of lactation had significantly greater number and mean staining intensity of orexin-A immunoreactive neurones, prepro-orexin mRNA expression food intake and body weight than nonlactating postpartum rats. Thus, changes in orexin-A immunoreactivity and prepro-orexin mRNA expression were not consistent between the hyperphagia models. These results suggest that the hyperphagia from VMHL or PVNL and lactating rats differ in their involvement of orexin-A, and the change in circulating leptin and insulin concentrations may be involved in the change of orexin-A immunoreactivity in these rats.
Assuntos
Proteínas de Transporte/análise , Hiperfagia/fisiopatologia , Peptídeos e Proteínas de Sinalização Intracelular , Lactação/fisiologia , Neuropeptídeos/análise , Neuropeptídeos/genética , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Precursores de Proteínas/genética , Núcleo Hipotalâmico Ventromedial/fisiopatologia , Animais , Glicemia , Peso Corporal , Proteínas de Transporte/imunologia , Ingestão de Alimentos , Expressão Gênica , Insulina/sangue , Leptina/sangue , Masculino , Neurônios/química , Neuropeptídeos/imunologia , Orexinas , Núcleo Hipotalâmico Paraventricular/patologia , RNA Mensageiro/análise , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Núcleo Hipotalâmico Ventromedial/patologiaRESUMO
Glucosensing neurons in the ventromedial hypothalamic nucleus (VMN) were studied using visually guided slice-patch recording techniques in brain slices from 14- to 21-day-old male Sprague-Dawley rats. Whole-cell current-clamp recordings were made as extracellular glucose levels were increased (from 2.5 to 5 or 10 mmol/l) or decreased (from 2.5 to 0.1 mmol/l). Using these physiological conditions to define glucosensing neurons, two subtypes of VMN glucosensing neurons were directly responsive to alterations in extracellular glucose levels. Another three subtypes were not directly glucose-sensing themselves, but rather were presynaptically modulated by changes in extracellular glucose. Of the VMN neurons, 14% were directly inhibited by decreases in extracellular glucose (glucose-excited [GE]), and 3% were directly excited by decreases in extracellular glucose (glucose-inhibited [GI]). An additional 14% were presynaptically excited by decreased glucose (PED neurons). The other two subtypes of glucosensing neurons were either presynaptically inhibited (PIR; 11%) or excited (PER; 8%) when extracellular glucose was raised to > 2.5 mmol/l. GE neurons sensed decreased glucose via an ATP-sensitive K(+) (K(ATP)) channel. The inhibitory effect of increased glucose on PIR neurons appears to be mediated by a presynaptic gamma-aminobutyric acid-ergic glucosensing neuron that probably originates outside the VMN. Finally, all types of glucosensing neurons were both fewer in number and showed abnormal responses to glucose in a rodent model of diet-induced obesity and type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Glucose/metabolismo , Neurônios/fisiologia , Obesidade/fisiopatologia , Sinapses/fisiologia , Núcleo Hipotalâmico Ventromedial/fisiopatologia , Trifosfato de Adenosina/farmacologia , Animais , Contagem de Células , Diabetes Mellitus Tipo 2/patologia , Dieta , Glucose/farmacologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/patologia , Obesidade/etiologia , Obesidade/patologia , Técnicas de Patch-Clamp , Canais de Potássio/fisiologia , Ratos , Ratos Sprague-Dawley , Núcleo Hipotalâmico Ventromedial/patologia , Ácido gama-Aminobutírico/fisiologiaRESUMO
When the hypothalamic ventromedial nucleus and arcuate nucleus were destroyed in rats by treatment with monosodium glutamate in the neonatal stage, increase in the Lee index (body weight 1/3/body length) and in retroperitoneal fat as well as decreases in spontaneous motor activity, food consumption and growth hormone secretion function associated with hypothalamic low body length obesity (monosodium glutamate-treated obesity; MSG-OB) were observed as these rats grew. Treatment with sibutramine at 3 and 10 mg/kg p.o. once a day continuously for 14 days improved these parameters, and the degree of improvement was dose related. The plasma lipid values in MSG-OB rats, which were the same as those in normal rats, were decreased by consecutive administration of sibutramine. Levels of hypothalamic monoamines (MAs) such as norepinephrine, 5-HT (serotonin) and dopamine and their metabolites DOPAC, HVA and 5-HIAA were decreased in MSG-OB rats, and further decrease in them, though slight, was observed with consecutive daily administration of sibutramine, probably as a result of the feedback attributable to an increase in MA in synapses caused by inhibition of MA uptake by sibutramine. These results suggest that sibutramine can activate the MA nervous system by MA uptake inhibition in regions of the brain such as the lateral hypothalamic area and the paraventricular nucleus, which control food intake and sympathetic nerve activity, and the nigrostriatal area related to the extrapyramidal motor system, and thereby exhibit anti-obesity effects in the MSG-OB rat.
Assuntos
Depressores do Apetite/farmacologia , Núcleo Arqueado do Hipotálamo/fisiologia , Monoaminas Biogênicas/sangue , Ciclobutanos/farmacologia , Atividade Motora/fisiologia , Obesidade/tratamento farmacológico , Glutamato de Sódio/toxicidade , Núcleo Hipotalâmico Ventromedial/fisiologia , Ácido 3,4-Di-Hidroxifenilacético/sangue , Tecido Adiposo/anatomia & histologia , Tecido Adiposo/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/patologia , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Dopamina/sangue , Ingestão de Energia/efeitos dos fármacos , Feminino , Ácido Homovanílico/sangue , Ácido Hidroxi-Indolacético/sangue , Lipídeos/sangue , Atividade Motora/efeitos dos fármacos , Norepinefrina/sangue , Obesidade/sangue , Obesidade/fisiopatologia , Ratos , Serotonina/sangue , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacos , Núcleo Hipotalâmico Ventromedial/patologiaRESUMO
Leptin is crucially involved in the central nervous regulation of body weight. Neurons of the ventromedial hypothalamic nucleus (VMH) express leptin receptors and signal satiety with increase in their firing. Normally, leptin mainly activates VMH neurons. Rats grown up in small litters (SL) develop persistent hyperphagia and obesity throughout life. We studied single unit activity in hypothalamic brain slices of juvenile SL rats overweight due to early postnatal overfeeding (Mann-Whitney U-test, P < 0.001). VMH neurons of normal rats were mainly activated by leptin (Wilcoxon test, P < 0.05, n = 39), whereas neurons of overweight SL rats were mainly inhibited (Wt, P < 0.001, n = 33). This clearly altered response to leptin in neonatally overnourished rats might contribute to their persistent overweight throughout life.
Assuntos
Animais Recém-Nascidos/fisiologia , Hiperfagia/fisiopatologia , Leptina/farmacologia , Neurônios/efeitos dos fármacos , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacos , Animais , Técnicas In Vitro , Inibição Neural , Ratos , Valores de Referência , Núcleo Hipotalâmico Ventromedial/patologiaRESUMO
The effect of growth-retarding, obesifying lesions in the ventromedial hypothalamic nucleus (VMN) on bone geometry and biomechanics was investigated in male weanling rats. The animals received bilateral, symmetrical, electrolytic lesions (VMNL rats) shortly after weanling (age 27 days); sham-operated rats served as controls (SCON). The rats were maintained for 42 postoperative days and then terminated. Body weight, nose-tail length, food intake, carcass water, and lean body mass were all significantly (p < 0.001) reduced in the VMNL group compared to SCON rats. Carcass fat, lipogenic efficiency (carcass fat % laid down/mean food intake) (both p < 0.001) and epididymal fat pad weight (p < 0.01) were significantly increased in VMNL versus SCON. Femur length, anteroposterior diameter (both p < 0.001), and mediolateral femur diameter (p < 0.01) were significantly reduced in VMNL versus SCON rats, but torque and angle of torque were comparable among the groups. VMNL rats femora also showed a significant greater maximum shear stress compared to the control animals. The reduced parameters in the VMNL rats are in good agreement with the previously demonstrated reduced plasma and pituitary growth hormone levels found in this hypothalamus preparation.
Assuntos
Osso e Ossos/patologia , Transtornos do Crescimento/patologia , Doenças Hipotalâmicas/complicações , Núcleo Hipotalâmico Ventromedial/patologia , Animais , Fenômenos Biomecânicos , Composição Corporal , Peso Corporal , Transtornos do Crescimento/complicações , Transtornos do Crescimento/etiologia , Masculino , Ratos , Ratos Sprague-Dawley , Estresse Mecânico , Núcleo Hipotalâmico Ventromedial/cirurgiaRESUMO
It is generally thought that typical atherosclerotic lesions do not develop in the rodent. The Goto-Kakizaki (GK) rat is a nonobese strain in which a spontaneous type of non-insulin-dependent diabetes mellitus develops without apparent macroangiopathy. In our previous study, making ventromedial hypothalamic (VMH) lesions in GK rats induced hyperphagia and a further deterioration in glucose metabolism. In the current study, male GK rats in which VMH lesions were made were examined for vascular changes, with special reference to atherosclerotic lesions. Marked hyperglycemia in GK rats with VMH lesions (hereafter referred to as VMH lesion rats) was revealed over an observation period (plasma glucose levels 16 weeks after the operation: VMH lesion GK rats, 19.3 +/- 2.0 mmol/L, vs sham-operated GK rats, 10.1 +/- 1.3 mmol/L; p < 0.0001). Light microscopic observation of the descending aorta in VMH lesion GK rats 16 weeks after the surgery revealed that the intimal thickening and the number of infiltrating cells into the intima were significantly increased as compared with sham-operated GK rats (17531 +/- 3747 microm2 vs 3072 +/- 1192 microm2, p < 0.0001; 15.6 +/- 3.1 per one transverse section vs 6.8 +/- 2.5 per one transverse section, p < 0.0005). Electron microscopic observations demonstrated an increased number of microvilli and lysosomes in endothelial cells, infiltration of macrophages and lymphocytes into the intima, and migration of medial smooth muscle cells into the intima that are considered to be early events in atherosclerosis. These morphologic changes could be induced by a deterioration in glucose metabolism. This rat may thus be useful for studying the process of the initiation of atherosclerosis in diabetes mellitus.
Assuntos
Aorta/patologia , Arteriosclerose/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Núcleo Hipotalâmico Ventromedial/fisiopatologia , Animais , Aorta/metabolismo , Arteriosclerose/fisiopatologia , Glicemia/análise , Pressão Sanguínea , Peso Corporal , Ingestão de Alimentos , Doenças Hipotalâmicas/patologia , Doenças Hipotalâmicas/fisiopatologia , Insulina/sangue , Lipídeos/sangue , Masculino , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Ratos Endogâmicos , Núcleo Hipotalâmico Ventromedial/patologiaRESUMO
Elevated hypothalamic neuropeptide Y (NPY) expression is found in several rodent genetic models of obesity, but any association in nongenetic models of obesity is unclear. Consequently, we have measured NPY mRNA levels in the ventromedial hypothalamus of a well-characterized model of obesity, the gold thioglucose (GTG)-injected mouse. Fourteen days after injection (early stage), animals were hyperphagic but not obese, hyperglycemic, or overtly hyperinsulinemic. Ten weeks after treatment (late stage), animals were obese, markedly hyperinsulinemic, and hyperglycemic. In both the early and late stages, NPY mRNA levels were reduced in the arcuate nucleus of GTG-injected animals. Although overnight fasting doubled NPY mRNA levels in control animals, there was no change at either stage in GTG-injected animals. NPY mRNA levels in the deep layers of the cerebral cortex and in the dentate gyrus were not affected by GTG treatment or overnight fasting. We conclude that GTG treatment reduces the expression of NPY mRNA in the arcuate nucleus and that, therefore, increased hypothalamic NPY expression is unlikely to be an important factor causing the obesity and other metabolic changes found in this model.