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Thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH2) is an intercellular signal produced mainly by neurons. Among the multiple pharmacological effects of TRH, that on food intake is not well understood. We review studies demonstrating that peripheral injection of TRH generally produces a transient anorexic effect, discuss the pathways that might initiate this effect, and explain its short half-life. In addition, central administration of TRH can produce anorexic or orexigenic effects, depending on the site of injection, that are likely due to interaction with TRH receptor 1. Anorexic effects are most notable when TRH is injected into the hypothalamus and the nucleus accumbens, while the orexigenic effect has only been detected by injection into the brain stem. Functional evidence points to TRH neurons that are prime candidate vectors for TRH action on food intake. These include the caudal raphe nuclei projecting to the dorsal motor nucleus of the vagus, and possibly TRH neurons from the tuberal lateral hypothalamus projecting to the tuberomammillary nuclei. For other TRH neurons, the anatomical or physiological context and impact of TRH in each synaptic domain are still poorly understood. The manipulation of TRH expression in well-defined neuron types will facilitate the discovery of its role in food intake control in each anatomical scene.
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Neonatal oxygen deficiency in rats may disturb growth and long-term metabolic homeostasis. In order to facilitate metabolic evaluation, the subjects are usually housed individually. However, social isolation associated with individually housed conditions alters animal behavior, which may influence the experimental results. This study investigated the effects of social isolation on neonatal anoxia-induced changes in growth and energy metabolism. Male and female Wistar rats were exposed, on postnatal day 2 (P2), to either 25-min of anoxia or control treatment. From P27 onward, part of the subjects of each group was isolated in standard cages, and the remaining subjects were housed in groups. At P34 or P95, the subjects were fasted for 18 h, refeed for 1 h, and then perfused 30 min later. Glycemia, leptin, insulin, and morphology of the pancreas were evaluated at both ages. For subjects perfused at P95, body weight and food intake were recorded up to P90, and the brain was collected for Fos and NeuN immunohistochemistry. Results showed that male rats exposed to neonatal anoxia and social isolation exhibited increased body weight gain despite the lack of changes in food intake. In addition, social isolation (1) decreased post-fasting weight loss and post-fasting food intake and (2) increased glycemia, insulin, and leptin levels of male and female rats exposed to anoxia and control treatments, both at P35 and P95. Furthermore, although at P35, anoxia increased insulin levels of males, it decreased the area of the ß-positive cells in the pancreas of females. At P95, anoxia increased post-prandial weight loss of males, post-fasting food intake, insulin, and leptin, and decreased Fos expression in the arcuate nucleus (ARC) of males and females. Hyperphagia was associated with possible resistance to leptin and insulin, suspected by the high circulating levels of these hormones and poor neuronal activation of ARC. This study demonstrated that continuous social isolation from weaning modifies, in a differentiated way, the long-term energy metabolism and growth of male and female Wistar rats exposed to neonatal anoxia or even control treatments. Therefore, social isolation should be considered as a factor that negatively influences experimental results and the outcomes of the neonatal injury. These results should also be taken into account in clinical procedures, since the used model simulates the preterm babies' conditions and some therapeutic approaches require isolation.
Assuntos
Animais Recém-Nascidos , Peso Corporal , Ingestão de Alimentos , Metabolismo Energético , Hipóxia , Ratos Wistar , Isolamento Social , Animais , Isolamento Social/psicologia , Masculino , Feminino , Ratos , Metabolismo Energético/fisiologia , Ingestão de Alimentos/fisiologia , Hipóxia/metabolismo , Peso Corporal/fisiologia , Leptina/sangue , Leptina/metabolismo , Glicemia/metabolismo , Insulina/sangue , Insulina/metabolismo , Desmame , Fatores EtáriosRESUMO
Short sleep is linked to disturbances in glucose metabolism and may induce a prediabetic condition. The biological clock in the suprachiasmatic nucleus (SCN) regulates the glucose rhythm in the circulation and the sleep-wake cycle. SCN vasopressin neurons (SCNVP) control daily glycemia by regulating the entrance of glucose into the arcuate nucleus (ARC). Thus, we hypothesized that sleep delay may influence SCN neuronal activity. We, therefore, investigated the role of SCNVP when sleep is disrupted by forced locomotor activity. After 2 h of sleep delay, rats exhibited decreased SCNVP neuronal activity, a decrease in the glucose transporter GLUT1 expression in tanycytes lining the third ventricle, lowered glucose entrance into the ARC, and developed hyperglycemia. The association between reduced SCNVP neuronal activity and hyperglycemia in sleep-delayed rats was evidenced by injecting intracerebroventricular vasopressin; this increased GLUT1 immunoreactivity in tanycytes, thus promoting normoglycemia. Following sleep recovery, glucose levels decreased, whereas SCNVP neuronal activity increased. These results imply that sleep-delay-induced changes in SCNVP activity lead to glycemic impairment, inferring that disruption of biological clock function might represent a critical step in developing type 2 diabetes.
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Diabetes Mellitus Tipo 2 , Hiperglicemia , Ratos , Animais , Transportador de Glucose Tipo 1/metabolismo , Ritmo Circadiano/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Núcleo Supraquiasmático/fisiologia , Sono , Glucose/metabolismo , Hiperglicemia/metabolismo , Vasopressinas/metabolismoRESUMO
Luteinizing hormone (LH) secretion during the ovarian cycle is governed by fluctuations in circulating estradiol (E2) that oppositely regulate kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC) of the hypothalamus. However, how these effects are orchestrated to achieve fertility is unknown. Here, we have tested the hypothesis that AVPV and ARC neurons have different sensitivities to E2 to coordinate changes in LH secretion. Cycling and ovariectomized rats with low and high E2 levels were used. As an index of E2 responsiveness, progesterone receptor (PR) was expressed only in the AVPV of rats with high E2, showing the preovulatory LH surge. On the other hand, kisspeptin neurons in the ARC responded to low E2 levels sufficient to suppress LH release. Notably, the Esr1/Esr2 ratio of gene expression was higher in the ARC than AVPV, regardless of E2 levels. Accordingly, the selective pharmacological activation of estrogen receptor α (ERα) required lower doses to induce PR in the ARC. The activation of ERß, in turn, amplified E2-induced PR expression in the AVPV and the LH surge. Thus, ARC and AVPV neurons are differently responsive to E2. Lower E2 levels activate ERα in the ARC, whereas ERß potentiates the E2 positive feedback in the AVPV, which appears related to the differential Esr1/Esr2 ratio in these 2 brain areas. Our findings provide evidence that the distinct expression of ER isoforms in the AVPV and ARC plays a key role in the control of periodic secretion of LH required for fertility in females.
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Estradiol , Kisspeptinas , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Estradiol/metabolismo , Estradiol/farmacologia , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Feminino , Hipotálamo/metabolismo , Kisspeptinas/metabolismo , Hormônio Luteinizante/metabolismo , Isoformas de Proteínas/metabolismo , Ratos , Receptores de Estrogênio/metabolismoRESUMO
Ghrelin is a stomach-derived peptide hormone that acts via the growth hormone secretagogue receptor (GHSR) and displays a plethora of neuroendocrine, metabolic, autonomic and behavioral actions. It has been proposed that some actions of ghrelin are exerted via the vagus nerve, which provides a bidirectional communication between the central nervous system and peripheral systems. The vagus nerve comprises sensory fibers, which originate from neurons of the nodose and jugular ganglia, and motor fibers, which originate from neurons of the medulla. Many anatomical studies have mapped GHSR expression in vagal sensory or motor neurons. Also, numerous functional studies investigated the role of the vagus nerve mediating specific actions of ghrelin. Here, we critically review the topic and discuss the available evidence supporting, or not, a role for the vagus nerve mediating some specific actions of ghrelin. We conclude that studies using rats have provided the most congruent evidence indicating that the vagus nerve mediates some actions of ghrelin on the digestive and cardiovascular systems, whereas studies in mice resulted in conflicting observations. Even considering exclusively studies performed in rats, the putative role of the vagus nerve in mediating the orexigenic and growth hormone (GH) secretagogue properties of ghrelin remains debated. In humans, studies are still insufficient to draw definitive conclusions regarding the role of the vagus nerve mediating most of the actions of ghrelin. Thus, the extent to which the vagus nerve mediates ghrelin actions, particularly in humans, is still uncertain and likely one of the most intriguing unsolved aspects of the field.
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Most of the studies on neurochemical mapping, connectivity, and physiology in the hypothalamic region were carried out in rats and under the columnar morphologic paradigm. According to the columnar model, the entire hypothalamic region lies ventrally within the diencephalon, which includes preoptic, anterior, tuberal, and mamillary anteroposterior regions, and sometimes identifying dorsal, intermediate, and ventral hypothalamic partitions. This model is weak in providing little or no experimentally corroborated causal explanation of such subdivisions. In contrast, the modern prosomeric model uses different axial assumptions based on the parallel courses of the brain floor, alar-basal boundary, and brain roof (all causally explained). This model also postulates that the hypothalamus and telencephalon jointly form the secondary prosencephalon, separately from and rostral to the diencephalon proper. The hypothalamus is divided into two neuromeric (transverse) parts called peduncular and terminal hypothalamus (PHy and THy). The classic anteroposterior (AP) divisions of the columnar hypothalamus are rather seen as dorsoventral subdivisions of the hypothalamic alar and basal plates. In this study, we offered a prosomeric immunohistochemical mapping in the rat of hypothalamic cells expressing tyrosine hydroxylase (TH), which is the enzyme that catalyzes the conversion of L-tyrosine to levodopa (L-DOPA) and a precursor of dopamine. This mapping was also combined with markers for diverse hypothalamic nuclei [agouti-related peptide (Agrp), arginine vasopressin (Avp), cocaine and amphetamine-regulated transcript (Cart), corticotropin releasing Hormone (Crh), melanin concentrating hormone (Mch), neuropeptide Y (Npy), oxytocin/neurophysin I (Oxt), proopiomelanocortin (Pomc), somatostatin (Sst), tyrosine hidroxilase (Th), and thyrotropin releasing hormone (Trh)]. TH-positive cells are particularly abundant within the periventricular stratum of the paraventricular and subparaventricular alar domains. In the tuberal region, most labeled cells are found in the acroterminal arcuate nucleus and in the terminal periventricular stratum. The dorsal retrotuberal region (PHy) contains the A13 cell group of TH-positive cells. In addition, some TH cells appear in the perimamillary and retromamillary regions. The prosomeric model proved useful for determining the precise location of TH-positive cells relative to possible origins of morphogenetic signals, thus aiding potential causal explanation of position-related specification of this hypothalamic cell type.
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Glycemia is maintained within very narrow boundaries with less than 5% variation at a given time of the day. However, over the circadian cycle, glycemia changes with almost 50% difference. How the suprachiasmatic nucleus, the biological clock, maintains these day-night variations with such tiny disparities remains obscure. We show that via vasopressin release at the beginning of the sleep phase, the suprachiasmatic nucleus increases the glucose transporter GLUT1 in tanycytes. Hereby GLUT1 promotes glucose entrance into the arcuate nucleus, thereby lowering peripheral glycemia. Conversely, blocking vasopressin activity or the GLUT1 transporter at the daily trough of glycemia increases circulating glucose levels usually seen at the peak of the rhythm. Thus, biological clock-controlled mechanisms promoting glucose entry into the arcuate nucleus explain why peripheral blood glucose is low before sleep onset.
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Núcleo Arqueado do Hipotálamo , Glucose , Glicemia , Ritmo Circadiano , Transportador de Glucose Tipo 1 , Núcleo Supraquiasmático , VasopressinasRESUMO
The intermittent fasting (IF) might have benefits on metabolism and food intake. Twelve-week old C57BL/6 J mice were fed a control diet (C, 10% kcal fat), a high-fat diet (HF, 50% kcal fat) or a high-fructose diet (HFru, 50% kcal fructose) for 8 weeks, then half of the animals in each group underwent IF (24 h fed, 24 h fasting) for an additional 4 weeks. Although food intake on the fed day remained the same for all groups, all fasting groups showed a reduction in body mass compared to their counterparts. IF reduced total cholesterol, triacylglycerol, fasting glucose, fasting insulin resistance index, and plasma leptin, but increased plasma adiponectin. IF reduced Leptin gene expression in the HF-IF group, but increased proinflammatory markers in the hypothalamus, also in the C-IF group. Both groups HFru-IF and C-IF, showed alterations in the leptin signaling pathway (Leptin, OBRb, and SOCS3), mainly in the HFru-IF group, suggesting leptin resistance. NPY and POMC neuropeptides labeled the neurons of the hypothalamus by immunofluorescence, corroborating qualitatively other quantitative findings of the study. In conclusion, current results are convincing in demonstrating the IF effect on central regulation of food intake control, as shown by NPY and POMC neuropeptide expressions, resulting in a lower weight gain. Besides, IF improves glycemia, lipid metabolism, and consequently insulin and leptin resistance. However, there is increased expression of inflammatory markers in mouse hypothalamus challenged by the HF and HFru diets, which in the long term may induce adverse effects.
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Adipocinas/metabolismo , Jejum/metabolismo , Frutose/metabolismo , Hipotálamo/metabolismo , Insulina/sangue , Neuropeptídeos/sangue , Adipocinas/genética , Adiponectina/sangue , Animais , Glicemia/metabolismo , Peso Corporal , Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/efeitos adversos , Gorduras na Dieta/metabolismo , Frutose/efeitos adversos , Humanos , Leptina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Triglicerídeos/metabolismoRESUMO
To study the pathological effects of continuous hyperprolactinemia on food intake mechanisms we used female mice that lack dopamine D2 receptors in lactotropes (lacDrd2KO). These mice had lifelong hyperprolactinemia, increased food intake, and gradual development of obesity from 5 to 10 months of age. Ongoing endogenous prolactin signaling in lacDrd2KO mice was evidenced by increased basal phosphorylation of STAT5b in hypothalamic areas related to food intake, such as the arcuate (ARN), dorsomedial (DMN), and ventromedial nuclei. In the ARN of young lacDrd2KO mice there were higher Prlr mRNA levels and in obese 10-month-old lacDrd2KO mice increased expression of the orexigenic genes Neuropeptide Y (Npy) and Agouti-related peptide, compared to controls. Furthermore, Npy expression was increased in the DMN, probably contributing to increased food intake and decreased expression of Uncoupling protein-1 in brown adipose tissue, both events favoring weight gain. Leptin resistance in obese lacD2RKO mice was evidenced by its failure to lower food intake and a dampened response of STAT3 phosphorylation, specifically in the mediobasal hypothalamus. Our results suggest that pathological chronically high prolactin levels, as found in psychiatric treatments or patients with prolactinomas, may impact on specific hypothalamic nuclei altering gene expression, leptin response, and food intake.
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Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Prolactina/farmacologia , Animais , Glicemia/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Imuno-Histoquímica , Insulina/sangue , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismoRESUMO
BACKGROUND: Neonatal anoxia may cause neurological injuries, behavioral alterations and changes in somatic growth. Somatic developmental changes suggest a possible effect of anoxia on energy metabolism and/or feeding behavior. Short-term effects of oxygen deficit on energy homeostasis have been described. In contrast, just a few studies report long-term effects. This study investigated the effects of neonatal anoxia on energy metabolism and somatic development at adulthood of males and females Wistar rats. METHOD: Male (m) and female (f) rats were exposed, on postnatal day 2 (P2), to either 25-min of Anoxia or Control treatment. At P34 part of the subjects of each group was fasted for 18 h, refeed for 1 h and then perfused 30 min later, at P35; the remaining subjects were submitted to these treatments at P94 and perfused at P95. Therefore, there were 8 groups: AmP35, AmP95, AfP35, AfP95, CmP35, CmP95, CfP35 and CfP95. For subjects perfused at P95, body weight and food intake were recorded up to P90. For subjects perfused at P35 and P95, glycemia, leptin and insulin were assessed after fasting and refeed. After perfusion the encephalon and pancreas were collected for Fos immunohistochemistry and Hematoxylin-Eosin stain analyses. RESULTS: Even though neonatal anoxia did not interfere with regular food intake, it reduced body weight gain along growing in both male and female subjects as compared to the corresponding controls. At P35 neonatal anoxia decreased post-prandial glycemia and increased insulin. While at P95 neonatal anoxia altered the pancreatic histomorphology and increased post-fasting weight loss, decreasing leptin, insulin and glycemia secretion, as well Fos immunoreactivity (IR) in ARC. CONCLUSION: Neonatal anoxia impairs long-term energy metabolism and somatic development in Wistar rats, with differences related to sex and age.