RESUMO
This study hypothesized that SCFA, acetate impacts positively on hypothalamic pyroptosis and its related abnormalities in experimentally induced PCOS rat model, possibly through NrF2/HIF1-α modulation. Eight-week-old female Wister rats were divided into groups (n = 5), namely control, PCOS, acetate and PCOS + acetate groups. Induction of PCOS was performed by administering 1 mg/kg body weight of letrozole for 21 days. After PCOS confirmation, the animals were treated with 200 mg/kg of acetate for 6 weeks. Rats with PCOS were characterized with insulin resistance, leptin resistance, increased plasma testosterone as well as degenerated ovarian follicles. There was also a significant increase in hypothalamic triglyceride level, triglyceride-glucose index, inflammatory biomarkers (SDF-1 and NF-kB) and caspase-6 as well as plasma LH and triglyceride. A decrease was observed in plasma adiponectin, GnRH, FSH, and hypothalamic GABA with severe inflammasome expression in PCOS rats. These were accompanied by decreased level of NrF2/HIF1-α, and the alterations were reversed when treated with acetate. Collectively, the present results suggest the therapeutic impact of acetate on hypothalamic pyroptosis and its related comorbidity in PCOS, a beneficial effect that is accompanied by modulation of NrF2/HIF1-α.
Assuntos
Hipotálamo , Subunidade alfa do Fator 1 Induzível por Hipóxia , Síndrome do Ovário Policístico , Piroptose , Ratos Wistar , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/patologia , Feminino , Animais , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/patologia , Piroptose/efeitos dos fármacos , Ratos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Resistência à Insulina , Fator 2 Relacionado a NF-E2/metabolismo , Modelos Animais de Doenças , Letrozol/farmacologia , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Hormônio Luteinizante/sangue , Hormônio Foliculoestimulante/sangue , Adiponectina/metabolismo , Adiponectina/sangue , Testosterona/sangue , Leptina/sangue , Leptina/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
There has been an alarming trend toward earlier puberty in girls, suggesting the influence of an environmental factor(s). As the reactivation of the reproductive axis during puberty is thought to be mediated by the hypothalamic neuropeptides kisspeptin and gonadotropin-releasing hormone (GnRH), we asked whether an environmental compound might activate the kisspeptin (KISS1R) or GnRH receptor (GnRHR). We used GnRHR or KISS1R-expressing HEK293 cells to screen the Tox21 10K compound library, a compendium of pharmaceuticals and environmental compounds, for GnRHR and KISS1R activation. Agonists were identified using Ca2+ flux and phosphorylated extracellularly regulated kinase (p-ERK) detection assays. Follow-up studies included measurement of genes known to be upregulated upon receptor activation using relevant murine or human cell lines and molecular docking simulation. Musk ambrette was identified as a KISS1R agonist, and treatment with musk ambrette led to increased expression of Gnrh1 in murine and human hypothalamic cells and expansion of GnRH neuronal area in developing zebrafish larvae. Molecular docking demonstrated that musk ambrette interacts with the His309, Gln122, and Gln123 residues of the KISS1R. A group of cholinergic agonists with structures similar to methacholine was identified as GnRHR agonists. When applied to murine gonadotrope cells, these agonists upregulated Fos, Jun, and/or Egr1. Molecular docking revealed a potential interaction between GnRHR and 5 agonists, with Asn305 constituting the most conservative GnRHR binding site. In summary, using a Tox21 10K compound library screen combined with cellular, molecular, and structural biology techniques, we have identified novel environmental agents that may activate the human KISS1R or GnRHR.
Assuntos
Receptores de Kisspeptina-1 , Receptores LHRH , Humanos , Feminino , Animais , Receptores de Kisspeptina-1/metabolismo , Receptores de Kisspeptina-1/genética , Receptores LHRH/metabolismo , Receptores LHRH/genética , Camundongos , Células HEK293 , Peixe-Zebra , Hormônio Liberador de Gonadotropina/metabolismo , Puberdade/efeitos dos fármacos , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Simulação de Acoplamento Molecular , Maturidade Sexual/efeitos dos fármacos , Maturidade Sexual/fisiologia , Kisspeptinas/metabolismo , Kisspeptinas/genética , Poluentes Ambientais/toxicidade , Poluentes Ambientais/farmacologiaRESUMO
BACKGROUND: The lateral hypothalamus (LHA) is an evolutionarily conserved structure that regulates basic functions of an organism, particularly wakefulness. To clarify the function of LHAGABA neurons and their projections on regulating general anesthesia is crucial for understanding the excitatory and inhibitory effects of anesthetics on the brain. The aim of the present study is to investigate whether LHAGABA neurons play either an inhibitory or a facilitatory role in sevoflurane-induced anesthetic arousal regulation. METHODS: We used fiber photometry and immunofluorescence staining to monitor changes in neuronal activity during sevoflurane anesthesia. Opto-/chemogenetic modulations were employed to study the effect of neurocircuit modulations during the anesthesia. Anterograde tracing was used to identify a GABAergic projection from the LHA to a periaqueductal gray (PAG) subregion. RESULTS: c-Fos staining showed that LHAGABA activity was inhibited by induction of sevoflurane anesthesia. Anterograde tracing revealed that LHAGABA neurons project to multiple arousal-associated brain areas, with the lateral periaqueductal gray (LPAG) being one of the dense projection areas. Optogenetic experiments showed that activation of LHAGABA neurons and their downstream target LPAG reduced the burst suppression ratio (BSR) during continuous sevoflurane anesthesia. Chemogenetic experiments showed that activation of LHAGABA and its projection to LPAG neurons prolonged the anesthetic induction time and promoted wakefulness. CONCLUSIONS: In summary, we show that an inhibitory projection from LHAGABA to LPAGGABA neurons promotes arousal from sevoflurane-induced loss of consciousness, suggesting a complex control of wakefulness through intimate interactions between long-range connections.
Assuntos
Anestésicos Inalatórios , Nível de Alerta , Neurônios GABAérgicos , Vias Neurais , Substância Cinzenta Periaquedutal , Sevoflurano , Animais , Sevoflurano/farmacologia , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância Cinzenta Periaquedutal/metabolismo , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/fisiologia , Camundongos , Anestésicos Inalatórios/farmacologia , Masculino , Nível de Alerta/efeitos dos fármacos , Nível de Alerta/fisiologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Camundongos Endogâmicos C57BL , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/fisiologia , Camundongos Transgênicos , Optogenética , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismoRESUMO
Kynurenic acid (KYNA), a tryptophan metabolite, is believed to exert neuromodulatory and neuroprotective effects in the brain. This study aimed to examine KYNA's capacity to modify gene expression and the activity of cellular antioxidant enzymes in specific structures of the sheep brain. Anestrous sheep were infused intracerebroventricularly with two KYNA doses-lower (4 × 5 µg/60 µL/30 min, KYNA20) and higher (4 × 25 µg/60 µL/30 min, KYNA100)-at 30 min intervals. The abundance of superoxide dismutase 2 (SOD2), catalase (CAT), and glutathione peroxidase 1 (GPx1) mRNA, as well as enzyme activities, were determined in the medial-basal hypothalamus (MBH), the preoptic (POA) area of the hypothalamus, and in the hippocampal CA1 field. Both doses of KYNA caused a decrease (p < 0.01) in the expression of SOD2 and CAT mRNA in all structures examined compared to the control group (except for CAT in the POA at the KYNA100 dose). Furthermore, lower levels of SOD2 mRNA (p < 0.05) and CAT mRNA (p < 0.01) were found in the MBH and POA and in the POA and CA, respectively, in sheep administered with the KYNA20 dose. Different stimulatory effects on GPx1 mRNA expression were observed for both doses (p < 0.05-p < 0.01). KYNA exerted stimulatory but dose-dependent effects on SOD2, CAT, and GPx1 activities (p < 0.05-p < 0.001) in all brain tissues examined. The results indicate that KYNA may influence the level of oxidative stress in individual brain structures in sheep by modulating the expression of genes and the activity of at least SOD2, CAT, and GPx1. The present findings also expand the general knowledge about the potential neuroprotective properties of KYNA in the central nervous system.
Assuntos
Antioxidantes , Catalase , Glutationa Peroxidase GPX1 , Glutationa Peroxidase , Hipocampo , Hipotálamo , Ácido Cinurênico , Superóxido Dismutase , Animais , Ovinos , Ácido Cinurênico/metabolismo , Ácido Cinurênico/farmacologia , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Catalase/metabolismo , Catalase/genética , Superóxido Dismutase/metabolismo , Superóxido Dismutase/genética , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Glutationa Peroxidase/metabolismo , Glutationa Peroxidase/genética , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Regulação da Expressão Gênica/efeitos dos fármacos , FemininoRESUMO
Middle-aged obesity and aging anorexia with muscle loss (sarcopenia) of old people present public health burden. These alterations may appear both in humans and rodents suggesting the role for regulatory alterations. Previously, we demonstrated that biphasic changes in the weight-reducing (catabolic) effects of neuropeptides of the hypothalamus-adipose tissue axis (e.g. leptin) may contribute to both trends. With regard to the anabolic effects of the hypothalamic neuropeptide Y (NPY) inhibited by leptin, we hypothesized non-linear age-related changes with shifts in the opposite directions. We investigated the orexigenic and hypometabolic effects of intracerebroventricularly administered NPY (hyperphagia induced by NPY injection or changes in food intake, body weight, heart rate, body temperature, locomotor activity during a 7-day NPY infusion), the immunoreactivity and gene expression of NPY in the hypothalamic arcuate nucleus of male Wistar rats of five age groups from young to old. The orexigenic/hypometabolic efficacy and the immunoreactivity of NPY increased in middle-aged animals preceding the peak of adiposity observed in aging rats, then decreased preceding anorexia and weight loss in old rats. These shifts may contribute to the development of both age-related obesity and aging anorexia, sarcopenia, and should be considered in future drug development targeting the NPY system.
Assuntos
Envelhecimento , Ingestão de Alimentos , Hipotálamo , Neuropeptídeo Y , Ratos Wistar , Animais , Neuropeptídeo Y/metabolismo , Masculino , Ratos , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Obesidade/metabolismo , Núcleo Arqueado do Hipotálamo/metabolismo , Núcleo Arqueado do Hipotálamo/efeitos dos fármacosRESUMO
Perimenopausal depression is a subtype of depression and is prevalent among perimenopausal women, which has brought a heavy burden to family and society. The pathogenesis of perimenopausal depression is still unclear, which affects the prevention and treatment of perimenopausal depression to a certain extent. Quercetin is a flavonoid compound, and has estrogenic activity and pharmacological effects such as antioxidant, anti-inflammatory, and neuroprotective effects. This study investigated whether quercetin improved perimenopausal depression-like behaviors and potential mechanism. The results demonstrated that quercetin could alleviate the depression-like behaviors in perimenopausal depression rat model, inhibit astrocyte activation, improve ferroptosis-associated mitochondrial damage (such as mitochondrial pyknosis and mitochondrial cristae reduction) in hypothalamus, increase the expressions of histone 3 lysine 9 acetylation (acetyl-H3K9), ferroptosis-associated protein including glutathione peroxidase 4 (GPX4) and Xc- antiporter (SLC7A11), and reduce the expressions of endoplasmic reticulum stress-related proteins including inositol-requiring enzyme 1 (IRE1α), phosphorylated IRE1α (p-IRE1α), X-box binding protein 1 (XBP1) and glucose-regulated protein 78 (GRP78) in hypothalamus of perimenopausal depression rat model. Furtherly, in vitro study indicated that quercetin could restore histone acetylase (HAT)/histone deacetylase (HDAC) homeostasis through binding to estrogen receptors and increase the expression of acetyl-H3K9, inhibiting ferroptosis through IRE1α/XBP1 pathway in astrocytes of hypothalamus. Our findings demonstrated that acetyl-H3K9 is a crucial target in development of perimenopausal depression, and quercetin exhibited antidepressant effects through modulating acetyl-H3K9 mediated ferroptosis in perimenopausal depression. Quercetin might be the prevention and adjuvant treatment strategy of perimenopausal depression.
Assuntos
Depressão , Modelos Animais de Doenças , Ferroptose , Histonas , Hipotálamo , Perimenopausa , Quercetina , Ratos Sprague-Dawley , Animais , Quercetina/farmacologia , Ferroptose/efeitos dos fármacos , Feminino , Ratos , Perimenopausa/efeitos dos fármacos , Perimenopausa/psicologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Histonas/metabolismo , Comportamento Animal/efeitos dos fármacos , Acetilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
The hypothalamus receives serotonergic projections from the raphe nucleus in a sex-specific manner. During systemic inflammation, hypothalamic levels of serotonin (5-hydroxytryptamine [5-HT]) decrease in male rats. The present study evaluated the involvement of endothelin-1 (ET-1) in the febrile response, hypolocomotion, and changes in hypothalamic 5-HT levels during systemic inflammation in male and female rats. An intraperitoneal injection of lipopolysaccharide (LPS) induced a febrile response and hypolocomotion in both male and female rats. However, although LPS reduced hypothalamic levels of 5-HT and its metabolite 5-hydroxyindol acetic acid (5-HIAA) in male rats, it increased these levels in female rats. An intracerebroventricular injection of the endothelin-B receptor antagonist BQ788 significantly reduced LPS-induced fever and hypolocomotion and changes in hypothalamic 5-HT and 5-HIAA levels in both male and female rats. The i.c.v. administration of ET-1 induced a significant fever and hypolocomotion, but reduced the hypothalamic levels of 5-HT and 5-HIAA in both males and females. These results suggest an important sexual dimorphism during systemic inflammation regarding the release of 5-HT in the hypothalamus. Moreover, ET-1 arises as an important mediator involved in the changes in hypothalamic 5-HT levels in both male and female rats.
Assuntos
Endotelina-1 , Hipotálamo , Inflamação , Piperidinas , Ratos Wistar , Serotonina , Caracteres Sexuais , Animais , Masculino , Feminino , Endotelina-1/metabolismo , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Ratos , Inflamação/metabolismo , Inflamação/induzido quimicamente , Serotonina/metabolismo , Piperidinas/farmacologia , Lipopolissacarídeos/toxicidade , Oligopeptídeos/farmacologia , Ácido Hidroxi-Indolacético/metabolismo , Antagonistas dos Receptores de Endotelina/farmacologia , Febre/metabolismo , Febre/induzido quimicamenteRESUMO
Insomnia is one of the most common sleep disorders, affecting 10-15% of the global population. Because classical remedies used to treat insomnia have various side effects, new therapeutics for insomnia are attracting attention. In the present study, we found that N2-Ethyl-N4-(furan-2-ylmethyl) quinazoline-2,4-diamine (AR-001) has adenosine A1 receptor agonistic activity and exhibits hypnotic efficacy by decreasing sleep onset latency and increasing total sleep time in a pentobarbital-induced sleep model. This hypnotic effect of AR-001 was significantly inhibited by the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). As a result of immunohistochemistry, AR-001 was shown to increase neural activity in the sleep-promoting region, ventrolateral preoptic nucleus (VLPO), and decrease neural activity in the wake-promoting region, basal forebrain (BF), and lateral hypothalamus (LH), and that these effects of AR-001 were significantly inhibited by DPCPX treatment. In addition, AR-001 increased adenosine A1 receptor mRNA levels in the hypothalamus. In conclusion, this study suggests that AR-001 has a hypnotic effect, at least partially, through adenosine A1 receptor and may have therapeutic potential for insomnia.
Assuntos
Agonistas do Receptor A1 de Adenosina , Hipnóticos e Sedativos , Receptor A1 de Adenosina , Sono , Animais , Receptor A1 de Adenosina/metabolismo , Receptor A1 de Adenosina/genética , Masculino , Hipnóticos e Sedativos/farmacologia , Sono/efeitos dos fármacos , Agonistas do Receptor A1 de Adenosina/farmacologia , Quinazolinas/farmacologia , Ratos Sprague-Dawley , Ratos , Camundongos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Furanos/farmacologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Xantinas/farmacologia , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Antagonistas do Receptor A1 de Adenosina/farmacologia , Pentobarbital/farmacologiaRESUMO
Previous studies have suggested that the effects of androgens on body weight (BW) and appetite are affected by the estrogen milieu in females; however, the mechanism underlying these effects remains unclear. We hypothesized that androgens may affect endogenous oxytocin (OT), which is a hypothalamic anorectic factor, and that these effects of androgens may be altered by the estrogen milieu in females. To investigate this hypothesis, in the present study, we examined the effects of testosterone on peripheral and central OT levels in ovariectomized female rats that did or did not receive estradiol supplementation. Ovariectomized female rats were randomly divided into non-estradiol-supplemented or estradiol-supplemented groups, and half of the rats in each group were concurrently supplemented with testosterone (i.e., rats were divided into four groups, n = 7 per each group). We also measured peripheral and central OT receptor (OTR) gene expression levels. As a result, we found that testosterone increased serum and hypothalamic OT levels and OT receptor mRNA levels in non-estradiol-supplemented rats, whereas it had no effects on these factors in estradiol-supplemented rats. In addition, testosterone reduced food intake, BW gain, and fat weight in non-estradiol-supplemented rats, whereas it did not have any effects on BW, appetite, or fat weight in estradiol-supplemented rats. These findings indicate that the effects of androgens on OT may be affected by the estrogen milieu, and elevated OT levels may be related to the blunting of appetite and prevention of obesity under estrogen-deficient conditions.
Assuntos
Estradiol , Hipotálamo , Ovariectomia , Ocitocina , Receptores de Ocitocina , Testosterona , Animais , Ocitocina/sangue , Ocitocina/farmacologia , Feminino , Testosterona/sangue , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Estradiol/sangue , Estradiol/farmacologia , Ratos , Receptores de Ocitocina/metabolismo , Receptores de Ocitocina/genética , Estrogênios/sangue , Estrogênios/farmacologia , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Ratos Sprague-Dawley , Apetite/efeitos dos fármacos , RNA Mensageiro/metabolismoRESUMO
(1) Background: We examined the effect of the acute administration of olive oil (EVOO), linseed oil (GLO), soybean oil (SO), and palm oil (PO) on gastric motility and appetite in rats. (2) Methods: We assessed food intake, gastric retention (GR), and gene expression in all groups. (3) Results: Both EVOO and GLO were found to enhance the rate of stomach retention, leading to a decrease in hunger. On the other hand, the reduction in food intake caused by SO was accompanied by delayed effects on stomach retention. PO caused an alteration in the mRNA expression of NPY, POMC, and CART. Although PO increased stomach retention after 180 min, it did not affect food intake. It was subsequently verified that the absence of an autonomic reaction did not nullify the influence of EVOO in reducing food consumption. Moreover, in the absence of parasympathetic responses, animals that received PO exhibited a significant decrease in food consumption, probably mediated by lower NPY expression. (4) Conclusions: This study discovered that different oils induce various effects on parameters related to food consumption. Specifically, EVOO reduces food consumption primarily through its impact on the gastrointestinal tract, making it a recommended adjunct for weight loss. Conversely, the intake of PO limits food consumption in the absence of an autonomic reaction, but it is not advised due to its contribution to the development of cardiometabolic disorders.
Assuntos
Regulação do Apetite , Hipotálamo , Neuropeptídeo Y , Azeite de Oliva , Óleo de Palmeira , Óleo de Soja , Nervo Vago , Animais , Nervo Vago/efeitos dos fármacos , Nervo Vago/fisiologia , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Masculino , Azeite de Oliva/farmacologia , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , Óleo de Palmeira/farmacologia , Regulação do Apetite/efeitos dos fármacos , Óleo de Soja/administração & dosagem , Óleo de Soja/farmacologia , Ratos Wistar , Óleo de Semente do Linho/farmacologia , Ratos , Ingestão de Alimentos/efeitos dos fármacos , Óleos de Plantas/farmacologia , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Motilidade Gastrointestinal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , RNA Mensageiro/metabolismo , RNA Mensageiro/genéticaRESUMO
Excessive stress can exceed the adjustment ability of body and cause injury and dysfunction, while elucidation of the mechanism and prevention measures of stress-related injury are still insufficient. The present study was to observe the effect of glucocorticoid (GC) on stress-induced hypothalamic nerve injury and elucidate the potential mechanism. The present study intended to establish a chronic restraint stress rat model for follow-up study. Open field test and elevated plus maze test were used to observe behavioral changes of stress rats; Enzyme-linked immunosorbent assay (ELISA) was used to detect changes in the levels of hypothalamus-pituitary-adrenal (HPA) axis-related hormones and inflammatory factors in hypothalamus; toluidine blue staining was used to observe pathological changes of hypothalamus. The results showed that stress rats showed obvious anxiety-like behaviors, the levels of HPA axis-related hormones and inflammatory factors showed abnormal fluctuations, and morphological results showed significant nerve injury in hypothalamus. Low-dose GC treatment significantly improved behavioral changes, alleviated hypothalamic nerve injury, and restored hypothalamic levels of inflammatory factors, serum levels of GC, corticotropin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH) and GC level in adrenal cortex of stressed rats, while GC receptor (GR) inhibitor, CRH receptor inhibitor, and adrenalectomy reversed the ameliorative effects of low-dose GC. Our study clarified that low-dose GC can restore stress coping ability by reshaping the homeostasis of the HPA axis, thus alleviating behavioral abnormalities and hypothalamic nerve injury in stressed rats.
Assuntos
Hormônio Adrenocorticotrópico , Glucocorticoides , Homeostase , Sistema Hipotálamo-Hipofisário , Hipotálamo , Sistema Hipófise-Suprarrenal , Ratos Sprague-Dawley , Estresse Psicológico , Animais , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Masculino , Ratos , Glucocorticoides/farmacologia , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Hormônio Adrenocorticotrópico/sangue , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Hormônio Liberador da Corticotropina/farmacologia , Modelos Animais de Doenças , Comportamento Animal/efeitos dos fármacosRESUMO
Konjac glucomannan (KGM), high-viscosity dietary fiber, is utilized in weight management. Previous investigations on the appetite-suppressing effects of KGM have centered on intestinal responses to nutrients and gastric emptying rates, with less focus on downstream hypothalamic neurons of satiety hormones. In our studies, the molecular mechanisms through which KGM and its degradation products influence energy homeostasis via the adipocyte-hypothalamic axis have been examined. It was found that high-viscosity KGM more effectively stimulates enteroendocrine cells to release glucagon-like peptide-1 (GLP-1) and reduces ghrelin production, thereby activating hypothalamic neurons and moderating short-term satiety. Conversely, low-viscosity DKGM has been shown to exhibit stronger anti-inflammatory properties in the hypothalamus, enhancing hormone sensitivity and lowering the satiety threshold. Notably, both KGM and DKGM significantly reduced leptin signaling and fatty acid signaling in adipose tissue and activated brown adipose tissue thermogenesis to suppress pro-opiomelanocortin (POMC) expression and activate agouti-related protein (AgRP) expression, thereby reducing food intake and increasing energy expenditure. Additionally, high-viscosity KGM has been found to activate the adipocyte-hypothalamus axis more effectively than DKGM, thereby promoting greater daily energy expenditure. These findings provide novel insights into the adipocyte-hypothalamic axis for KGM to suppress appetite and reduce weight.
Assuntos
Adipócitos , Regulação do Apetite , Dieta Hiperlipídica , Metabolismo Energético , Hipotálamo , Camundongos Endogâmicos C57BL , Animais , Camundongos , Metabolismo Energético/efeitos dos fármacos , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Masculino , Regulação do Apetite/efeitos dos fármacos , Adipócitos/metabolismo , Adipócitos/efeitos dos fármacos , Humanos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Grelina/metabolismo , Leptina/metabolismo , Proteína Relacionada com Agouti/metabolismo , Proteína Relacionada com Agouti/genética , Termogênese/efeitos dos fármacos , Pró-Opiomelanocortina/metabolismo , Pró-Opiomelanocortina/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , Obesidade/dietoterapia , MananasRESUMO
BACKGROUND: Male reproductive functions are regulated in the hypothalamic-pituitary-gonadal (HPG) axis. Any problem in this axis would lead to the deterioration of reproductive functions. The present study aimed to investigate the effects of intracerebroventricular (icv) Spexin (SPX) infusion on the HPG axis in detail. METHODS: 40 Wistar albino rats were divided into four groups: control, sham, SPX 30 nmol and SPX 100 nmol (n=10). 30 nmol/1⯵l/hour SPX was administered icv to the rats in the SPX 30 nmol group for 7 days, while rats in the SPX 100 nmol group were administered 100 nmol/1⯵l/hour SPX. On the 7th day, the rats were decapitated, blood and tissue samples were collected. Serum LH, FSH and testosterone levels were determined with the ELISA method, GnRH mRNA expression level was determined in hypothalamus with the RT-PCR method. Seminiferous tubule diameter and epithelial thickness were determined with the hematoxylin-eosin staining method. RESULTS: SPX infusion was increased GnRH mRNA expression in the hypothalamus tissue independent of the dose (p<0.05). Serum LH, FSH and testosterone levels in the SPX groups were increased when compared to the control and sham groups independent of the dose (p <0.05). Histological analysis revealed that SPX infusion did not lead to any changes in seminiferous epithelial thickness, while the tubule diameter increased in the SPX groups (p<0.05). CONCLUSION: The study findings demonstrated that icv SPX infusion stimulated the HPG axis and increased the secretion of male reproductive hormones.
Assuntos
Hormônio Foliculoestimulante , Hormônio Liberador de Gonadotropina , Sistema Hipotálamo-Hipofisário , Hormônio Luteinizante , Hormônios Peptídicos , Ratos Wistar , Testículo , Testosterona , Animais , Masculino , Ratos , Testículo/efeitos dos fármacos , Testículo/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Testosterona/sangue , Hormônio Luteinizante/sangue , Hormônios Peptídicos/administração & dosagem , Hormônios Peptídicos/metabolismo , Hormônio Foliculoestimulante/sangue , Hormônio Liberador de Gonadotropina/metabolismo , Injeções Intraventriculares , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Infusões Intraventriculares , RNA Mensageiro/metabolismoRESUMO
Relatively low levels of antioxidant enzymes coupled with high oxygen metabolism result in the formation of numerous oxidative DNA damages in the tissues of the central nervous system. Recently, kynurenic acid (KYNA), knowns for its neuroprotective properties, has gained increasing attention in this context. Therefore, our hypothesis assumed that increased KYNA levels in the brain would positively influence mRNA expression of selected enzymes of the base excision repair pathway as well as enhance their efficiency in excising damaged nucleobases in specific areas of the sheep brain. The study was conducted on adult anestrous sheep (n = 18), in which two different doses of KYNA (20 and 100 µg/day) were infused into the third brain ventricle for three days. Molecular and biochemical analysis included the hypothalamus (preoptic and mediol-basal areas), hippocampus (CA3 field) and amygdala (central amygdaloid nucleus), dissected from the brain of sheep euthanized immediately after the last infusion. The results revealed a significant increase P < 0.001) in the relative mRNA abundance of N-methylpurine DNA glycosylase (MPG) following administration of both dose of KYNA across all examined tissues. The transcription of thymine-DNA glycosylase (TDG) increased significantly (P < 0.001) in all tissues in response to the lower KYNA dose compared to the control group. Moreover, 8-oxoguanine (8-oxoG) DNA glycosylase (OGG1) mRNA levels were also higher in both animal groups (P < 0.001). In addition, in the hypothalamus, hippocampus and amygdala, AP endonuclease 1 (APE1) mRNA expression increased under both doses of KYNA. Moreover, the both dose of KYNA significantly stimulated the efficiency of 8-oxoG excision in hypothalamus and amygdala (P < 0.05-0.001). The lower and higher doses of KYNA significantly influenced the effectiveness of εA and εC in all structures (P < 0.01-0.001). In conclusion, the favorable effect of KYNA in the brain may include the protection of genetic material in nerve and glial cells by stimulating the expression and efficiency of BER pathway enzymes.
Assuntos
Encéfalo , DNA Glicosilases , Reparo do DNA , Ácido Cinurênico , Animais , Reparo do DNA/efeitos dos fármacos , Ovinos , Ácido Cinurênico/metabolismo , DNA Glicosilases/metabolismo , DNA Glicosilases/genética , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Dano ao DNA/efeitos dos fármacos , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Feminino , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Reparo por ExcisãoRESUMO
Regulation of physiological homeostasis, including energy balance, is thought to be modified by low levels of adult neurogenesis in the hypothalamus. Hormones such as oestradiol can influence both embryonic and adult hypothalamic neurogenic programs, demonstrating a sensitivity of hypothalamic neural progenitor cells to endogenous hormones. Previously we showed that gestational exposure to environmental levels of the xenoestrogen bisphenol A (BPA) changed neural progenitor cell behaviors in the embryo; however, we did not examine if these changes were permanent to affect adult neurogenesis. Here we investigated whether adult neuro- and/or gliogenesis were altered in mice prenatally exposed to BPA and placed on a high-fat diet challenge. Gestationally exposed adult female mice on a standard diet gained less weight than non-BPA controls, whereas gestationally exposed BPA females on a high-fat diet gained more weight than controls. Males exposed to gestational BPA showed no differences in weight gain relative to control males. Concomitantly, adult neurogenesis was increased in the VMH, DMH, and PVN of adult female mice exposed to BPA on standard diet, suggesting that disrupted adult neurogenesis might perturb normal energy balance regulation in females. These results add to growing evidence that low-dose BPA exposure in utero causes changes to adult hypothalamic function.
Assuntos
Compostos Benzidrílicos , Metabolismo Energético , Homeostase , Hipotálamo , Neurogênese , Fenóis , Efeitos Tardios da Exposição Pré-Natal , Animais , Compostos Benzidrílicos/toxicidade , Feminino , Fenóis/toxicidade , Neurogênese/efeitos dos fármacos , Gravidez , Camundongos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Homeostase/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Masculino , Dieta Hiperlipídica/efeitos adversosRESUMO
This study aimed to explore the regulating effect of Gegen Decoction(GGD) on the hypothalamic-pituitary-ovarian axis(HPOA) dysfunction in the mouse model of primary dysmenorrhea(PD). The mouse model of PD with periodic characteristics was established by administration of estradiol benzoate and oxytocin. Mice were randomized into control, model, GGD, and ibuprofen groups. The writhing response, hypothalamus index, pituitary index, ovary index, and uterus index were observed and determined. The serum levels of prostaglandin F_(2α)(PGF_(2α)), gonadotropin-releasing hormone(GnRH), follicle-stimulating hormone(FSH), luteinizing hormone(LH), and estrogen(E_2) levels were measured by ELISA kits. Western blot and qPCR were employed to determine the protein and mRNA levels, respectively, of gonadotropin-releasing hormone receptor(GnRH-R) in the pituitary tissue, follicle-stimulating hormone receptor(FSHR) and luteinizing hormone receptor(LHR) in the ovarian tissue, and estrogen receptor(ER) in the uterine tissue. The results showed that the writhing response, serum levels of PGF_(2α), GnRH, FSH, LH, and E_2, ovarian and uterine indexes, the protein and mRNA levels of GnRH-R in the pituitary tissue, FSHR and LHR in the ovarian tissue, and ER in the uterine tissue were significantly increased in the model group compared with those in the control group. GGD inhibited the writhing response, reduced the serum levels of PGF_(2α), GnRH, FSH, LH, and E_2, decreased the ovarian and uterine indexes, and down-regulated the protein and mRNA levels of GnRH-R in the pituitary tissue, FSHR and LHR in the ovarian tissue, and ER in the uterine tissue. The data suggested that GGD can regulate the HPOA and inhibit E_2 generation in the mice experiencing recurrent PD by down-regulating the expression of proteins and genes related to HPOA axis, thus exerting the therapeutic effect on PD.
Assuntos
Medicamentos de Ervas Chinesas , Dismenorreia , Ovário , Animais , Feminino , Camundongos , Ovário/efeitos dos fármacos , Ovário/metabolismo , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacologia , Dismenorreia/tratamento farmacológico , Dismenorreia/metabolismo , Dismenorreia/genética , Dismenorreia/fisiopatologia , Hormônio Luteinizante/sangue , Hormônio Foliculoestimulante/sangue , Hipófise/metabolismo , Hipófise/efeitos dos fármacos , Humanos , Receptores do FSH/genética , Receptores do FSH/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Hormônio Liberador de Gonadotropina/genética , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Receptores LHRH/genética , Receptores LHRH/metabolismo , Receptores do LH/genética , Receptores do LH/metabolismoRESUMO
Chlorpyrifos (CPF) is a widely used pesticide inducing adverse neurodevelopmental and reproductive effects. However, knowledge of the underlying mechanisms is limited, particularly in the hypothalamus. We investigated the mode of action of CPF at human relevant concentrations (1 nM-100 nM) in immortalized mouse hypothalamic GnRH neurons (GT1-7), an elective model for studying disruption of the hypothalamus-pituitary-gonads (HPG) axis. We firstly examined cell vitality, proliferation, and apoptosis/necrosis. At not-cytotoxic concentrations, we evaluated neuron functionality, gene expression, Transmission Electron Microscopy (TEM) and proteomics profiles, validating results by immunofluorescence and western blotting (WB). CPF decreased cell vitality with a dose-response but did not affect cell proliferation. At 100 nM, CPF inhibited gene expression and secretion of GnRH; in addition, CPF reduced the immunoreactivity of the neuronal marker Map2 in a dose-dependent manner. The gene expression of Estrogen Receptor α and ß (Erα, Erß), Androgen Receptor (Ar), aromatase and oxytocin receptor was induced by CPF with different trends. Functional analysis of differentially expressed proteins identified Autophagy, mTOR signaling and Neutrophil extracellular traps (NETs) formation as significant pathways affected at all concentrations. This finding was phenotypically supported by the TEM analysis, showing marked autophagy and damage of mitochondria, as well as by protein analysis demonstrating a dose-dependent decrease of mTOR and its direct target pUlk1 (Ser 757). The bioinformatics network analysis identified a core module of interacting proteins, including Erα, Ar, mTOR and Sirt1, whose down-regulation was confirmed by WB analysis. Overall, our results demonstrate that CPF is an inhibitor of the mTOR pathway leading to autophagy in GnRH neurons; a possible involvement of the Erα/Ar signaling is also suggested. The evidence for adverse effects of CPF in the hypothalamus in the nanomolar range, as occurs in human exposure, increases concern on potential adverse outcomes induced by this pesticide on the HPG axis.
Assuntos
Autofagia , Clorpirifos , Hormônio Liberador de Gonadotropina , Neurônios , Transdução de Sinais , Serina-Treonina Quinases TOR , Autofagia/efeitos dos fármacos , Animais , Camundongos , Serina-Treonina Quinases TOR/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Clorpirifos/toxicidade , Transdução de Sinais/efeitos dos fármacos , Inseticidas/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Linhagem Celular , Apoptose/efeitos dos fármacosRESUMO
Substance use disorder is a major concern, with few therapeutic options. Heparan sulfate (HS) and chondroitin sulfate (CS) interact with a plethora of growth factors and their receptors and have profound effects on cellular signaling. Thus, targeting these dynamic interactions might represent a potential novel therapeutic modality. In the present study, we performed mass spectrometry-based glycomic and proteomic analysis to understand the effects of cocaine and methamphetamine (METH) on HS, CS, and the proteome of two brain regions critically involved in drug addiction: the lateral hypothalamus and the striatum. We observed that cocaine and METH significantly alter HS and CS abundances as well as sulfate contents and composition. In particular, repeated METH or cocaine treatments reduced CS 4-O-sulfation and increased CS 6-O-sulfation. Since C4S and C6S exercise differential effects on axon growth, regeneration, and plasticity, these changes likely contribute to drug-induced neural plasticity in these brain regions. Notably, we observed that restoring these alterations by increasing CS 4-0 levels in the lateral hypothalamus by adeno-associated virus delivery of an shRNA to arylsulfatase B (N-acetylgalactosamine-4-sulfatase) ameliorated anxiety and prevented the expression of preference for cocaine in a novelty induced conditioned place preference test during cocaine withdrawal. Finally, proteomics analyses revealed a number of aberrant proteins in METH- and cocaine-treated versus saline-treated mice, including myelin proteolipid protein, calcium/calmodulin-dependent protein kinase type II subunit alpha, synapsin-2, tenascin-R, calnexin, annexin A7, hepatoma-derived growth factor, neurocan, and CSPG5, and oxidative phosphorylation among the top perturbed pathway. Taken together, these data support the role of HS, CS, and associated proteins in stimulants abuse and suggest that manipulation of HSPGs can represent a novel therapeutic strategy.
Assuntos
Cocaína , Corpo Estriado , Glicômica , Metanfetamina , Camundongos Endogâmicos C57BL , Proteômica , Animais , Cocaína/farmacologia , Metanfetamina/farmacologia , Masculino , Corpo Estriado/metabolismo , Corpo Estriado/efeitos dos fármacos , Camundongos , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Heparitina Sulfato/metabolismo , Proteoma/metabolismoRESUMO
The short-chain fatty acids (SCFAs) acetate, propionate and butyrate, the major products of intestinal microbial fermentation of dietary fibres, are involved in fine-tuning brain functions via the gut-brain axis. However, the effects of SCFAs in the hypothalamic neuronal network regulating several autonomic-brain functions are still unknown. Using NMR spectroscopy, we detected a reduction in brain acetate concentrations in the hypothalamus of obese leptin knockout ob/ob mice compared to lean wild-type littermates. Therefore, we investigated the effect of acetate on orexin/hypocretin neurons (hereafter referred as OX or OX-A neurons), a subset of hypothalamic neurons regulating energy homeostasis, which we have characterized in previous studies to be over-activated by the lack of leptin and enhancement of endocannabinoid tone in the hypothalamus of ob/ob mice. We found that acetate reduces food-intake in concomitance with a reduction of orexin neuronal activity in ob/ob mice. This was demonstrated by evaluating food-intake behaviour and orexin-A/c-FOS immunoreactivity coupled with patch-clamp recordings in Hcrt-eGFP neurons, quantification of prepro-orexin mRNA, and immunolabeling of GPR-43, the main acetate receptor. Our data provide new insights into the mechanisms of the effects of chronic dietary supplementation with acetate, or complex carbohydrates, on energy intake and body weight, which may be partly mediated by inhibition of orexinergic neuron activity.
Assuntos
Acetatos , Eixo Encéfalo-Intestino , Metabolismo Energético , Homeostase , Neurônios , Orexinas , Animais , Orexinas/metabolismo , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Camundongos , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Acetatos/farmacologia , Acetatos/metabolismo , Eixo Encéfalo-Intestino/efeitos dos fármacos , Eixo Encéfalo-Intestino/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ácidos Graxos Voláteis/metabolismo , Ácidos Graxos Voláteis/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologiaRESUMO
Central administration of valine has been shown to cause hyperphagia in fish. Although mechanistic target of rapamycin (mTOR) is involved in this response, the contributions to feed intake of central and peripheral metabolite changes due to excess valine are unknown. Here, we investigated whether intracerebroventricular injection of valine modulates central and peripheral metabolite profiles and may provide insights into feeding response in fish. Juvenile rainbow trout (Oncorhynchus mykiss) were administered an intracerebroventricular injection of valine (10 µg·µL-1 at 1 µL·100·g-1 body wt), and the metabolite profile in plasma, hypothalamus, and rest of the brain (composing of telencephalon, optic tectum, cerebellum, and medulla oblongata) was carried out by liquid chromatography-mass spectrometry (LC/MS)-based metabolomics. Valine administration led to a spatially distinct metabolite profile at 1 h postinjection in the brain: enrichment of amino acid metabolism and energy production pathways in the rest of the brain but not in hypothalamus. This suggests a role for extrahypothalamic input in the regulation of feed intake. Also, there was enrichment of several amino acids, including tyrosine, proline, valine, phenylalanine, and methionine, in plasma in response to valine. Changes in liver transcript abundance and protein expression reflect an increased metabolic capacity, including energy production from glucose and fatty acids, and a lower protein kinase B (Akt) phosphorylation in the valine group. Altogether, valine intracerebroventricular administration affects central and peripheral metabolism in rainbow trout, and we propose a role for the altered metabolite profile in modulating the feeding response to this branched-chain amino acid.NEW & NOTEWORTHY Valine causes hyperphagia in fish when it is centrally administered; however, the exact mechanisms are far from clear. We tested how intracerebroventricular injection of valine in rainbow trout affected the brain and plasma metabolome. The metabolite changes in response to valine were more evident in the rest of the brain compared with the hypothalamus. Furthermore, we demonstrated for the first time that central valine administration affects peripheral metabolism in rainbow trout.