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1.
J Agric Food Chem ; 68(10): 3149-3162, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32062961

RESUMO

Moringa oleifera Lam. (MO), which is widely consumed as both food and herbal medicine in tropical and subtropical regions, has a wide spectrum of health benefits. Yet, whether the oil obtained from MO seeds could affect (improve) the sleep activity remains unclear. Herein, we used the locomotor activity, pentobarbital-induced sleeping, and pentetrazol-induced convulsions test to examine sedative-hypnotic effects (SHE) of MO oil (MOO) and explored the underlying mechanisms. Besides, the main components of MOO like oleic acid, ß-Sitosterol, and Stigmasterol were also evaluated. The results showed that they possessed good SHE. Except for oleic acid and Stigmasterol, they could significantly elevate γ-amino butyric acid (GABA) and reduce glutamic acid (Glu) levels in the hypothalamus of mice. Moreover, SHE was blocked by picrotoxin, flumazenil, and bicuculline, except for oleic acid, which could not be antagonized by picrotoxin. Molecular mechanisms showed that MOO and ß-Sitosterol significantly upregulated the amount of protein-level expression of Glu decarboxylase-65 (GAD65) and α1-subunit of GABAA receptors in the hypothalamus of mice, not affecting GAD67, γ2 subunits. These data indicated that MOO modulates sleep architectures via activation of the GABAA-ergic systems.


Assuntos
Hipnóticos e Sedativos/administração & dosagem , Moringa oleifera/química , Pentobarbital/administração & dosagem , Extratos Vegetais/administração & dosagem , Óleos Vegetais/administração & dosagem , Receptores de GABA-A/metabolismo , Sono/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Animais , Humanos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Receptores de GABA-A/genética , Sementes/química , Ácido gama-Aminobutírico/genética
2.
Gen Comp Endocrinol ; 285: 113250, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31445009

RESUMO

Seasonally breeding animals initiate gonadal recrudescence when mechanisms that suppress reproduction give way to mechanisms that stimulate it. However, knowledge of mechanistic changes in hormonal regulation during this transition is limited. Further, most studies of reproductive timing have focused on males, despite the critical role of females in determining breeding phenology. Closely related populations that live in the same environment but differ in reproductive timing provide an opportunity to examine differences in mechanisms during the transition from the pre-reproductive to reproductive state. We studied closely related migrant and resident populations of dark-eyed juncos (Junco hyemalis) that reside in the same environment in spring but differ in breeding phenology. Residents initiate breeding earlier than migrants, which do not breed until after they have migrated. To directly study differences in the hypothalamic mechanisms of reproduction, we captured 16 migrant and 13 resident females from the field on March 25-April 11. We quantified expression of mRNA transcripts and show that resident females had higher abundance of gonadotropin-releasing hormone transcripts than migrant females, indicating greater reproductive development in resident than migrant females living in the same environment. We also found higher transcript abundance of estrogen receptor and androgen receptor in migrant than resident females, suggesting that negative feedback may delay reproductive development in migrant females until after they migrate. These differences in hypothalamic mechanisms may help to explain differences in reproductive timing in populations that differ in migratory strategy.


Assuntos
Migração Animal/fisiologia , Sistemas Neurossecretores/metabolismo , Estações do Ano , Aves Canoras/fisiologia , Simpatria/fisiologia , Animais , Feminino , Hormônio Liberador de Gonadotropina/genética , Hormônio Liberador de Gonadotropina/metabolismo , Hipotálamo/metabolismo , Modelos Lineares , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
3.
Gen Comp Endocrinol ; 285: 113264, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31469997

RESUMO

Thyroid hormone (TH) is involved in regulating the reproduction of vertebrates. Its physiological action in the target tissues is due to the conversion of TH by iodothyronine deiodinases. In this study, we aimed to clone and characterize type 2 (sdDio2) and type 3 (sdDio3) of the sapphire devil Chrysiptera cyanea, a tropical damselfish that undergoes active reproduction under long-day conditions, and to study the involvement of THs in the ovarian development of this species. When the cDNAs of sdDio2 and sdDio3 were partially cloned, they had deduced amino acid sequences of lengths 271 and 267, respectively, both of which were characterized by one selenocysteine residue. Real-time quantitative PCR (qPCR) revealed that both genes are highly expressed in the whole brain, and sdDio2 and sdDio3 are highly transcribed in the liver and ovary, respectively. In situ hybridization analyses showed positive signals of sdDio2 and sdDio3 transcripts in the hypothalamic area of the brain. Little change in mRNA abundance of sdDio2 and sdDio3 in the brain was observed during the vitellogenic phases. It is assumed that simultaneous activation and inactivation of THs occur in this area because oral administration of triiodothyronine (T3), but not of thyroxine (T4), upregulated mRNA abundance of both genes in the brain. The transcript levels of sdDio2 in the liver and sdDio3 in the ovary increased as vitellogenesis progressed, suggesting that, through the metabolism of THs, sdDio2 and sdDio3 play a role in vitellogenin synthesis in the liver and yolk accumulation/E2 synthesis in the ovary. Taken together, these results suggest that iodothyronine deiodinases act as a driver for vitellogenesis in tropical damselfish by conversion of THs in certain peripheral tissues.


Assuntos
Perfilação da Expressão Gênica , Iodeto Peroxidase/genética , Perciformes/genética , Clima Tropical , Vitelogênese/genética , Animais , Feminino , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Iodeto Peroxidase/metabolismo , Ovário/efeitos dos fármacos , Ovário/crescimento & desenvolvimento , Ovário/metabolismo , Perciformes/metabolismo , Filogenia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Hormônios Tireóideos/administração & dosagem , Hormônios Tireóideos/farmacologia , Distribuição Tecidual , Vitelogênese/efeitos dos fármacos
4.
Artigo em Inglês | MEDLINE | ID: mdl-31887407

RESUMO

In order to evaluate fatty acid (FA) sensing systems based on binding to FAT/CD36 in hypothalamus of Chinese perch (Siniperca chuatsi) and its sensitivity to FAs with the same chain length and different unsaturation levels. The effects of Stearate (SA; C18:0), oleate (OA; C18:1 n-9), linoleic acid (LA; C18:2 n-6), and α-linolenic acid (ALA; C18:3 n-3) on hypothalamic FA sensing were evaluated by intracerebroventricular (ICV) administration. Food intake was assessed after 2, 4, 6, 8 and 12 h. Gene expression associated with FA sensing mechanism such as cd36, pparα and srebp1c, and neuropeptides controlling appetite such as pomca, cart, agrp2 and npy were assessed after 6 h. The ICV treatment of OA, LA and ALA activated FAT/CD36 and PPARα, rather than SA, and modulated gene expression levels of hypothalamic neuropeptides associated with appetite. And then, OA, LA and ALA inhibited food intake, which was consistent with the activation of hypothalamus FA sensing. Our data indicated some mechanisms of the hypothalamic FA sensing systems also existed in Chinese perch. It's worth noting that polyunsaturated fatty acids (PUFA) could also activate hypothalamic FA sensing mechanisms in Chinese perch. The unsaturation of FA appears to be extremely important for FA sensing mechanisms, since no major influences in Chinese perch after SA treatment. Our findings will contribute to the study of long-chain FAs sensing mechanisms in fish hypothalamus and highlight the importance of PUFAs in fish species.


Assuntos
Antígenos CD36/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Ácidos Graxos Insaturados/administração & dosagem , Ácidos Graxos/administração & dosagem , Hipotálamo/efeitos dos fármacos , Neuropeptídeos/metabolismo , Percas/fisiologia , Animais , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Hipotálamo/metabolismo , Infusões Intraventriculares , PPAR alfa/metabolismo
5.
J Agric Food Chem ; 67(49): 13737-13750, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31789024

RESUMO

Genistein is abundant in animal feed. In this study, the side effects of high-dose genistein on intestinal health and hypothalamic RNA profile were evaluated. Chicks exposed to high-dose genistein by intraperitoneal injection (416 ± 21, 34.5 ± 2.5) and feed supplementation (308 ± 19, 27.2 ± 2.1) both showed a reduced body weight gain and feed intake in comparison with the control group (261 ± 16, 22.7 ± 1.6, P < 0.01). In comparison with the control (22.4 ± 0.5, 33.3 ± 2.4), serum levels of albumin and total protein were decreased after high-dose genistein injection (21.6 ± 0.5, 31.8 ± 1.6) and diet supplementation (20.6 ± 0.9, 29.9 ± 2.5, P < 0.001). Interestingly, the genistein diet presented the chick hypothalamus with downregulated expression of bitter receptors (TAS1R3, P < 0.05). Meanwhile, it upregulated the expressions of TAS2R1 (P < 0.05) and downstream genes (PLCB2 and IP3R3) in the ileum (P < 0.05). Accordingly, high-dose dietary genistein reduced villus height and the abundance of Lactobacillus, along with the increased abundance of pathogenic bacteria in the ileum (P < 0.05). Furthermore, transcriptomic analysis identified 348 differently expressed genes (168 upregulated and 224 downregulated) in the high-dose dietary genistein treated group in comparison with the control (P < 0.05, |log2FoldChange| > 0.585). Therefore, high-dose dietary genistein altered the hypothalamic RNA profile and signal processing. Cluster analysis further revealed that high-dose dietary genistein significantly influenced apoptosis, the immune process, and the whole synthesis of steroid hormones in the hypothalamus (P < 0.05). In conclusion, high-dose dietary genistein altered the hypothalamic RNA profile and intestinal health of female chicks.


Assuntos
Galinhas/metabolismo , Suplementos Nutricionais/efeitos adversos , Genisteína/efeitos adversos , Hipotálamo/metabolismo , RNA/genética , Ração Animal/efeitos adversos , Ração Animal/análise , Animais , Peso Corporal/efeitos dos fármacos , Galinhas/genética , Galinhas/crescimento & desenvolvimento , Galinhas/imunologia , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Genisteína/análise , Hipotálamo/efeitos dos fármacos , Íleo/efeitos dos fármacos , Íleo/metabolismo , RNA/metabolismo , Esteroides/metabolismo
6.
Artigo em Russo | MEDLINE | ID: mdl-31851173

RESUMO

AIM: To study an effect of cabergoline on dopamine and noradrenaline concentration and BDNF mRNA level in the rat midbrain and hypothalamus. MATERIAL AND METHODS: Twenty adult male Wistar rats were used in a single treatment paradigm: animals of the treatment group (n=10) received cabergoline (i.p., 0.5 mg/kg) and the control group (n=10) received an equivalent volume of the solvent. Quantitative analysis for the dopamine (DA) and noradrenaline (NA) was carried out using high-performance liquid chromatography (HPLC) coupled with electrochemical detection. BDNF mRNA levels were studied using quantitative RT-PCR. RESULTS AND CONCLUSION: Cabergoline significantly increases NA concentration in the midbrain 24 hours after injection: 639.2±64.5 ng/g in the treatment group versus 398.0±66.0 ng/g in the control group (p<0.05), while mean content of DA is not significantly changed (211.4±16.3 ng/g vs 169.7±54.6 ng/g, respectively). Cabergoline does not affect hypothalamic DA and NA levels. The drug increases BDNF mRNA levels by 2-times in the midbrain, but not in the hypothalamus, 24 hours after injection.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Cabergolina , Catecolaminas , Receptores de Dopamina D2 , Animais , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cabergolina/farmacologia , Catecolaminas/metabolismo , Ergolinas , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , RNA Mensageiro , Ratos , Ratos Wistar , Receptores de Dopamina D2/agonistas
7.
PLoS Genet ; 15(11): e1008478, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31693685

RESUMO

Circadian rhythms allow animals to coordinate behavioral and physiological processes with respect to one another and to synchronize these processes to external environmental cycles. In most animals, circadian rhythms are produced by core clock neurons in the brain that generate and transmit time-of-day signals to downstream tissues, driving overt rhythms. The neuronal pathways controlling clock outputs, however, are not well understood. Furthermore, it is unclear how the central clock modulates multiple distinct circadian outputs. Identifying the cellular components and neuronal circuitry underlying circadian regulation is increasingly recognized as a critical step in the effort to address health pathologies linked to circadian disruption, including heart disease and metabolic disorders. Here, building on the conserved components of circadian and metabolic systems in mammals and Drosophila melanogaster, we used a recently developed feeding monitor to characterize the contribution to circadian feeding rhythms of two key neuronal populations in the Drosophila pars intercerebralis (PI), which is functionally homologous to the mammalian hypothalamus. We demonstrate that thermogenetic manipulations of PI neurons expressing the neuropeptide SIFamide (SIFa) as well as mutations of the SIFa gene degrade feeding:fasting rhythms. In contrast, manipulations of a nearby population of PI neurons that express the Drosophila insulin-like peptides (DILPs) affect total food consumption but leave feeding rhythms intact. The distinct contribution of these two PI cell populations to feeding is accompanied by vastly different neuronal connectivity as determined by trans-Tango synaptic mapping. These results for the first time identify a non-clock cell neuronal population in Drosophila that regulates feeding rhythms and furthermore demonstrate dissociable control of circadian and homeostatic aspects of feeding regulation by molecularly-defined neurons in a putative circadian output hub.


Assuntos
Relógios Circadianos/genética , Drosophila melanogaster/genética , Comportamento Alimentar/fisiologia , Proteínas Circadianas Period/genética , Animais , Animais Geneticamente Modificados , Encéfalo/fisiologia , Ritmo Circadiano/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/fisiologia , Jejum , Hipotálamo/metabolismo , Mamíferos/genética , Mamíferos/fisiologia , Neuroglia/fisiologia , Neurônios/metabolismo , Neuropeptídeos/genética , Neuropeptídeos/metabolismo
8.
J Anim Sci ; 97(11): 4488-4495, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31586423

RESUMO

Adenosine monophosphate-activated protein kinase (AMPK) acts as a sensor of cellular energy changes and is involved in the control of food intake. A total of 216 1-d-old broilers were randomly allotted into 3 treatments with 6 replicates per treatment and 12 broilers in each cage. The dietary treatments included 1) high-energy (HE) diet (3,500 kcal/kg), 2) normal-energy (NE) diet (3,200 kcal/kg), and 3) low-energy (LE) diet (2,900 kcal/kg). The present study was conducted to investigate the effects of dietary energy level on appetite and the central AMPK signal pathway. The results showed that a HE diet increased average daily gain (ADG), whereas a LE diet had the opposite effect (P < 0.05, N = 6). The average daily feed intake (ADFI) of the chickens fed the LE diet was significantly higher than that of the control (P < 0.05, N = 6). Overall, the feed conversion rate gradually decreased with increasing dietary energy level (P < 0.05, N = 6). Moreover, the chickens fed the LE and HE diets demonstrated markedly improved urea content compared with the control group (P < 0.0001, N = 8). The triglyceride (TG) content in the LE group was obviously higher than that in the HE group but showed no change compared with the control (P = 0.0678, N = 8). The abdominal fat rate gradually increased with increased dietary energy level (P = 0.0927, N = 8). The HE group showed downregulated gene expression levels of liver kinase B1 (LKB1), neuropeptide Y (NPY), cholecystokinin (CCK), and glucocorticoid receptor (GR) in the hypothalamus compared with the control group (P < 0.05, N = 8). However, LE treatment significantly increased the mRNA level of AMP-activated protein kinase α2 (AMPKα2) compared with other groups (P = 0.0110, N = 8). In conclusion, a HE diet inhibited appetite and central AMPK signaling. In contrast, a LE diet activated central AMPK and appetite. Overall, the central AMPK signal pathway and appetite were modulated in accordance with the energy level in the diet to regulate nutritional status and maintain energy homeostasis in birds.


Assuntos
Ração Animal/análise , Galinhas/fisiologia , Ingestão de Energia , Regulação da Expressão Gênica , Transdução de Sinais , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Gordura Abdominal/metabolismo , Monofosfato de Adenosina/metabolismo , Animais , Apetite , Galinhas/crescimento & desenvolvimento , Dieta/veterinária , Homeostase , Hipotálamo/metabolismo , Masculino , Distribuição Aleatória , Ganho de Peso
9.
Int J Mol Sci ; 20(20)2019 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-31614951

RESUMO

Obesity is closely associated with neuroinflammation in the hypothalamus, which is characterized by over-activated microglia and excessive production of pro-inflammatory cytokines. The present study was aimed at elucidating the effects of (-)-epigallocatechin gallate (EGCG) on palmitic acid-stimulated BV-2 microglia and high-fat-diet-induced obese mice. The results indicated the suppressive effect of EGCG on lipid accumulation, pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß) release, and microglial activation in both cellular and high-fat-diet rodent models. These results were associated with lower phosphorylated levels of the janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) signaling pathway. In conclusion, EGCG can attenuate high-fat-induced hypothalamic inflammation via inhibiting the JAK2/STAT3 signaling pathways in microglia.


Assuntos
Fármacos Antiobesidade/farmacologia , Catequina/análogos & derivados , Microglia/efeitos dos fármacos , Obesidade/tratamento farmacológico , Animais , Fármacos Antiobesidade/uso terapêutico , Catequina/farmacologia , Catequina/uso terapêutico , Linhagem Celular , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Hipotálamo/efeitos dos fármacos , Hipotálamo/imunologia , Hipotálamo/metabolismo , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Janus Quinase 2/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Microglia/metabolismo , Obesidade/metabolismo , Ácido Palmítico/metabolismo , Ácido Palmítico/farmacologia , Polifenóis/farmacologia , Fator de Transcrição STAT3/metabolismo , Chá/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
10.
Int J Mol Sci ; 20(20)2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31615150

RESUMO

The micronutrients vitamins B9 and B12 act as methyl donors in the one-carbon metabolism involved in transmethylation reactions which critically influence epigenetic mechanisms and gene expression. Both vitamins are essential for proper development, and their deficiency during pregnancy has been associated with a wide range of disorders, including persisting growth retardation. Energy homeostasis and feeding are centrally regulated by the hypothalamus which integrates peripheral signals and acts through several orexigenic and anorexigenic mediators. We studied this regulating system in a rat model of methyl donor deficiency during gestation and lactation. At weaning, a predominance of the anorexigenic pathway was observed in deficient pups, with increased plasma peptide YY and increased hypothalamic pro-opiomelanocortin (POMC) mRNA, in line with abnormal leptin, ghrelin, and insulin secretion and/or signaling during critical periods of fetal and/or postnatal development of the hypothalamus. These results suggest that early methyl donor deficiency can affect the development and function of energy balance circuits, resulting in growth and weight deficits. Maternal administration of folic acid (3 mg/kg/day) during the perinatal period tended to rectify peripheral metabolic signaling and central neuropeptide and receptor expression, leading to reduced growth retardation.


Assuntos
Metabolismo Energético/genética , Grelina/genética , Peptídeo YY/genética , Pró-Opiomelanocortina/genética , Animais , Depressores do Apetite/farmacologia , Metabolismo Energético/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Feminino , Ácido Fólico/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Grelina/sangue , Hipotálamo/metabolismo , Insulina/sangue , Insulina/genética , Lactação , Leptina/sangue , Leptina/genética , Metilação/efeitos dos fármacos , Peptídeo YY/sangue , Gravidez , Pró-Opiomelanocortina/sangue , RNA Mensageiro/genética , Ratos , Vitamina B 12/genética , Vitamina B 12/farmacologia
11.
Biomed Res ; 40(5): 207-214, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31597906

RESUMO

Sensory circumventricular organs contain the subfornical organ, organum vasculosum of the lamina terminalis (OVLT), and area postrema. Here, immunostaining for GLUT3 in the murine brain selectively labeled the sobfornical organ and OVLT. The immunoreactive neural tract of the subfornical organ formed into thin bundles and extended ventro-rostrally over the anterior commissure. After turning over the commissure, the neural tract passed through the median preoptic nucleus (MnPO) and reached the OVLT; thus, a continuous neural tract expressing GLUT3 connected the subfornical organ, MnPO, and OVLT in the lamina terminalis. In the OVLT, GLUT3-immunoreactive fibers gathered in both the dorsal cap and lateral periventricular zone. Electron microscopically, the immunoreactive structures in the subfornical organ corresponded to nerve fibers or nerve terminals containing many small clear vesicles. The area postrema, another sensory organ, was immunonegative for GLUT3. This study not only presented a useful marker tracing the neural tract in the sensory sites of the lamina terminalis but also suggested a unique system for sensing and determining the metabolism of circulating glucose in the circumventricular organs.


Assuntos
Órgãos Circunventriculares/metabolismo , Expressão Gênica , Transportador de Glucose Tipo 3/genética , Hipotálamo/metabolismo , Fibras Nervosas/metabolismo , Animais , Biomarcadores , Modelos Animais de Doenças , Feminino , Imunofluorescência , Imuno-Histoquímica , Masculino , Camundongos
12.
Endocrinology ; 160(12): 2903-2917, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31599926

RESUMO

Several metabolic and behavioral adaptations that emerge during pregnancy remain present after weaning. Thus, reproductive experience causes long-lasting metabolic programming, particularly in the brain. However, the isolate effects of pregnancy or lactation and the molecular mechanisms involved in these long-term modifications are currently unknown. In the current study, we investigated the role of brain signal transducer and activator of transcription-5 (STAT5), a key transcription factor recruited by hormones highly secreted during gestation or lactation, for the long-term adaptations induced by reproductive experience. In control mice, pregnancy followed by lactation led to increased body adiposity and reduced ambulatory activity later in life. Additionally, pregnancy+lactation induced long-term epigenetic modifications in the brain: we observed upregulation in hypothalamic expression of histone deacetylases and reduced numbers of neurons with histone H3 acetylation in the paraventricular, arcuate, and ventromedial nuclei. Remarkably, brain-specific STAT5 ablation prevented all metabolic and epigenetic changes observed in reproductively experienced control female mice. Nonetheless, brain-specific STAT5 knockout (KO) mice that had the experience of pregnancy but did not lactate showed increased body weight and reduced energy expenditure later in life, whereas pregnancy KO and pregnancy+lactation KO mice exhibited improved insulin sensitivity compared with virgin KO mice. In summary, lactation is necessary for the long-lasting metabolic effects observed in reproductively experienced female mice. In addition, epigenetic mechanisms involving histone acetylation in neuronal populations related to energy balance regulation are possibly associated with these long-term consequences. Finally, our findings highlighted the key role played by brain STAT5 signaling for the chronic metabolic and epigenetic changes induced by pregnancy and lactation.


Assuntos
Hipotálamo/metabolismo , Lactação , Prenhez/metabolismo , Fator de Transcrição STAT5/metabolismo , Adiposidade , Animais , Epigênese Genética , Feminino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora , Gravidez , Distribuição Aleatória
13.
Endocrinology ; 160(12): 2990-3000, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31599937

RESUMO

Recent evidence has implicated neurokinin B (NKB) signaling in the retrochiasmatic area (RCh) of the ewe in the LH surge. To test this hypothesis, we first lesioned NK3R neurons in this area by using a saporin conjugate (NK3-SAP). Three weeks after bilateral injection of NK3-SAP or a blank control (BLK-SAP) into the RCh, an LH surge was induced by using an artificial follicular-phase model in ovariectomized ewes. NK3-SAP lesioned approximately 88% of RCh NK3R-containing neurons and reduced the amplitude of the estrogen-induced LH surge by 58%, an inhibition similar to that seen previously with intracerebroventricular (icv) infusion of a KISS1R antagonist (p271). We next tested the hypothesis that NKB signaling in the RCh acts via kisspeptin by determining whether the combined effects of NK3R-SAP lesions and icv infusion of p271 were additive. Experiment 1 was replicated except that ewes received two sequential artificial follicular phases with infusions of p271 or vehicle using a crossover design. The combination of the two treatments decreased the peak of the LH surge by 59%, which was similar to that seen with NK3-SAP (52%) or p271 (54%) alone. In contrast, p271 infusion delayed the onset and peak of the LH surge in both NK3-SAP- and BLK-SAP-injected ewes. Based on these data, we propose that NKB signaling in the RCh increases kisspeptin levels critical for the full amplitude of the LH surge in the ewe but that kisspeptin release occurs independently of RCh input at the onset of the surge to initiate GnRH secretion.


Assuntos
Hipotálamo/metabolismo , Kisspeptinas/metabolismo , Hormônio Luteinizante/metabolismo , Neurocinina B/metabolismo , Animais , Feminino , Ovinos
14.
Mar Drugs ; 17(10)2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31600939

RESUMO

Leptin resistance in the hypothalamus has an essential role in obesity. Saturated fatty acids such as palmitate bind to Toll-like receptor 4 (TLR4) and lead to endoplasmic reticulum (ER) stress and leptin resistance. In this study, we evaluated whether extracts of Ecklonia cava would attenuate the ER stress induced by palmitate and reduce leptin resistance in hypothalamic neurons and microglia. We added palmitate to these cells to mimic the environment induced by high-fat diet in the hypothalamus and evaluated which of the E. cava phlorotannins-dieckol (DK), 2,7-phloroglucinol-6,6-bieckol (PHB), pyrogallol-phloroglucinol-6,6-bieckol (PPB), or phlorofucofuroeckol-A (PFFA)-had the most potent effect on attenuating leptin resistance. TLR4 and NF-κB expression induced by palmitate was attenuated most effectively by PPB in both hypothalamic neurons and microglia. ER stress markers were increased by palmitate and were attenuated by PPB in both hypothalamic neurons and microglia. Leptin resistance, which was evaluated as an increase in SOCS3 and a decrease in STAT3 with leptin receptor expression, was increased by palmitate and was decreased by PPB in hypothalamic neurons. The culture medium from palmitate-treated microglia increased leptin resistance in hypothalamic neurons and this resistance was attenuated by PPB. In conclusion, PPB attenuated leptin resistance by decreasing ER stress in both hypothalamic neurons and microglia.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Leptina/metabolismo , Neurônios/efeitos dos fármacos , Palmitatos/farmacologia , Feófitas/química , Taninos/farmacologia , Animais , Linhagem Celular , Dieta Hiperlipídica/efeitos adversos , Humanos , Hipotálamo/metabolismo , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , NF-kappa B/metabolismo , Neurônios/metabolismo , Obesidade/metabolismo , Floroglucinol/farmacologia , Receptores para Leptina/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo
15.
Environ Pollut ; 255(Pt 2): 113278, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31574394

RESUMO

Increasing urbanisation is altering the physiology of wild animals and the mechanisms involved are largely unknown. We hypothesised that altering the physiology of urban organisms is due to the effect of extra light at night on the circadian clock by modulating the expression of pineal machinery and clock genes. Two experiments were performed. In Experiment 1, immediately after being procured from their respective sites (urban and rural sites), birds were released individually in LLdim light conditions. Circadian rhythm period, activity duration, and total activity count were calculated and did not differ between urban and rural birds. In Experiment 2, birds (from urban and rural habitats) were sampled at six time points at regular 4-h intervals, beginning 1 h after sunrise. We measured daily variations in plasma melatonin levels. We also analysed the expression levels of Aanat, Mel1A and Mel1B as an indicator of melatonin biosynthesis and action machinery. Clock and clock-controlled genes (Bmal1, Clock, Per2, Per3, Cry1 and Npas2) were studied in the hypothalamus, the pineal gland, and retina to investigate the effects of urban habitats on the circadian clock. Our results show that there is a lower expression of Aanat in the pineal gland and relatively low plasma melatonin levels in urban birds. Further, clock genes are also differentially expressed in all three central tissues of urban birds. We propose that alterations in the melatonin biosynthesis machinery and the expression of clock genes could result in miscalculations in the internal timing of the organism, with environmental timings leading to altered physiology in urban wild animals.


Assuntos
Ritmo Circadiano/genética , Glândula Pineal , Pardais/fisiologia , Animais , Relógios Circadianos/genética , Expressão Gênica , Hipotálamo/metabolismo , Melatonina/metabolismo , Fotoperíodo , Retina
16.
Endocrinology ; 160(11): 2630-2645, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504391

RESUMO

Common mutations in the human prohormone convertase (PC)1/3 gene (PCKSI) are linked to increased risk of obesity. Previous work has shown that the rs6232 single-nucleotide polymorphism (N221D) results in slightly decreased activity, although whether this decrease underlies obesity risk is not clear. We observed significantly decreased activity of the N221D PC1/3 enzyme at the pH of the trans-Golgi network; at this pH, the mutant enzyme was less stable than wild-type enzyme. Recombinant N221D PC1/3 also showed enhanced susceptibility to heat stress. Enhanced susceptibility to tunicamycin-induced endoplasmic reticulum stress was observed in AtT-20/PC2 cell clones in which murine PC1/3 was replaced by human N221D PC1/3, as compared with wild-type human PC1/3. However, N221D PC1/3-expressing AtT-20/PC2 clones processed proopiomelanocortin to α-MSH similarly to wild-type PC1/3. We also generated a CRISPR-edited mouse line expressing the N221D mutation in the PCKSI gene. When homozygous N221D mice were fed either a standard or a high-fat diet, we found no increase in body weight compared with their wild-type sibling controls. Sexual dimorphism was observed in pituitary ACTH for both genotypes, with females exhibiting lower levels of pituitary ACTH. In contrast, hypothalamic α-MSH content for both genotypes was higher in females compared with males. Hypothalamic corticotropin-like intermediate peptide content was higher in wild-type females compared with wild-type, but not N221D, males. Taken together, these data suggest that the increased obesity risk linked to the N221D allele in humans may be due in part to PC1/3-induced loss of resilience to stressors rather than strictly to decreased enzymatic activity on peptide precursors.


Assuntos
Obesidade/genética , Pró-Proteína Convertase 1/metabolismo , Animais , Estresse do Retículo Endoplasmático , Estabilidade Enzimática , Feminino , Intolerância à Glucose , Humanos , Concentração de Íons de Hidrogênio , Hipotálamo/metabolismo , Masculino , Camundongos , Neuropeptídeo Y/metabolismo , Hipófise/metabolismo , Polimorfismo de Nucleotídeo Único , Pró-Opiomelanocortina/metabolismo , Pró-Proteína Convertase 1/genética , Caracteres Sexuais , alfa-MSH/metabolismo
17.
Ecotoxicol Environ Saf ; 185: 109710, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31563750

RESUMO

The purpose of this research was to discuss the effects of copper (Cu)-induced toxicity on oxidative stress and autophagy in hypothalamus of broilers. In this study, 240 one-day-old broilers were randomly divided into 4 groups and the contents of dietary Cu in 4 groups were 11 mg/kg (control group), 110 mg/kg (group I), 220 mg/kg (group II), and 330 mg/kg (group III). The experiment lasted for 49 days and the hypothalamus tissues were collected for histological observation and detection of Cu content. Additionally, the indicators related to oxidative stress in hypothalamus were determined. Moreover, the mRNA expression levels of autophagy-related genes and the protein expression levels of Beclin1, LC3-II/LC3-I, and p62 in hypothalamus were measured. Results showed that the treated groups were observed vacuolar degeneration in hypothalamus compared to control group, and the Cu content in hypothalamus was increased with the increase of dietary Cu. Furthermore, the activities of SOD, CAT, T-AOC were increased in group I and group II and then decreased in group III, and the content of MDA and the mRNA levels of Nrf2, HO-1, SOD-1, CAT, GCLC, GCLM, and GST in treated groups were elevated compared to control group. Moreover, the mRNA expression levels of Beclin1, Atg5, LC3-I, LC3-II and the protein expression levels of Beclin1 and LC3-II/LC3-I up-regulated significantly with the increasing levels of Cu. However, the mRNA expression levels of p62 and mTOR and the protein expression level of p62 down-regulated remarkably. Taken together, our present study evidenced that excessive intake of Cu could induce oxidative stress and autophagy in hypothalamus of broilers.


Assuntos
Autofagia/efeitos dos fármacos , Galinhas , Cobre/toxicidade , Poluentes Ambientais/toxicidade , Hipotálamo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Galinhas/metabolismo , Cobre/metabolismo , Dieta , Exposição Dietética/análise , Relação Dose-Resposta a Droga , Poluentes Ambientais/metabolismo , Hipotálamo/metabolismo , Hipotálamo/patologia , Distribuição Aleatória
18.
BMC Genomics ; 20(1): 699, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31506062

RESUMO

BACKGROUND: Successful social behavior requires real-time integration of information about the environment, internal physiology, and past experience. The molecular substrates of this integration are poorly understood, but likely modulate neural plasticity and gene regulation. In the cichlid fish species Astatotilapia burtoni, male social status can shift rapidly depending on the environment, causing fast behavioral modifications and a cascade of changes in gene transcription, the brain, and the reproductive system. These changes can be permanent but are also reversible, implying the involvement of a robust but flexible mechanism that regulates plasticity based on internal and external conditions. One candidate mechanism is DNA methylation, which has been linked to social behavior in many species, including A. burtoni. But, the extent of its effects after A. burtoni social change were previously unknown. RESULTS: We performed the first genome-wide search for DNA methylation patterns associated with social status in the brains of male A. burtoni, identifying hundreds of Differentially Methylated genomic Regions (DMRs) in dominant versus non-dominant fish. Most DMRs were inside genes supporting neural development, synapse function, and other processes relevant to neural plasticity, and DMRs could affect gene expression in multiple ways. DMR genes were more likely to be transcription factors, have a duplicate elsewhere in the genome, have an anti-sense lncRNA, and have more splice variants than other genes. Dozens of genes had multiple DMRs that were often seemingly positioned to regulate specific splice variants. CONCLUSIONS: Our results revealed genome-wide effects of A. burtoni social status on DNA methylation in the brain and strongly suggest a role for methylation in modulating plasticity across multiple biological levels. They also suggest many novel hypotheses to address in mechanistic follow-up studies, and will be a rich resource for identifying the relationships between behavioral, neural, and transcriptional plasticity in the context of social status.


Assuntos
Encéfalo/metabolismo , Ciclídeos/genética , Metilação de DNA , Genômica , Animais , Comportamento Animal , Encéfalo/citologia , Neurônios GABAérgicos/metabolismo , Perfilação da Expressão Gênica , Hipotálamo/citologia , Hipotálamo/metabolismo , Oligodendroglia/metabolismo , Transdução de Sinais/genética , Meio Social
19.
Int J Mol Sci ; 20(18)2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31533319

RESUMO

Induced by a bacterial infection, an immune/inflammatory challenge is a potent negative regulator of the reproduction process in females. The reduction of the synthesis of pro-inflammatory cytokine is considered as an effective strategy in the treatment of inflammatory induced neuroendocrine disorders. Therefore, the effect of direct administration of acetylcholinesterase inhibitor-neostigmine-into the third ventricle of the brain on the gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) secretions under basal and immune stress conditions was evaluated in this study. In the study, 24 adult, 2-years-old Blackhead ewes during the follicular phase of their estrous cycle were used. Immune stress was induced by the intravenous injection of LPS Escherichia coli in a dose of 400 ng/kg. Animals received an intracerebroventricular injection of neostigmine (1 mg/animal) 0.5 h before LPS/saline treatment. It was shown that central administration of neostigmine might prevent the inflammatory-dependent decrease of GnRH/LH secretion in ewes and it had a stimulatory effect on LH release. This central action of neostigmine is connected with its inhibitory action on local pro-inflammatory cytokines, such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)α synthesis in the hypothalamus, which indicates the importance of this mediator in the inhibition of GnRH secretion during acute inflammation.


Assuntos
Inibidores da Colinesterase/administração & dosagem , Endotoxinas/efeitos adversos , Ciclo Estral/efeitos dos fármacos , Ciclo Estral/metabolismo , Hormônio Liberador de Gonadotropina/biossíntese , Hormônio Luteinizante/biossíntese , Neostigmina/administração & dosagem , Fase Folicular/efeitos dos fármacos , Fase Folicular/metabolismo , Hidrocortisona/biossíntese , Hipotálamo/metabolismo , Lipopolissacarídeos/efeitos adversos , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
20.
Endocrinology ; 160(11): 2719-2736, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31513269

RESUMO

The increasing occurrence of obesity has become a significant public health concern. Individuals with obesity have higher prevalence of heart disease, stroke, osteoarthritis, diabetes, and reproductive disorders. Reproductive problems include menstrual irregularities, pregnancy complications, and infertility due to anovulation, in women, and lower testosterone and diminished sperm count, in men. In particular, women with obesity have reduced levels of both gonadotropin hormones, and, in obese men, lower testosterone is accompanied by diminished LH. Taken together, these findings indicate central dysregulation of the hypothalamic-pituitary-gonadal axis, specifically at the level of the GnRH neuron function, which is the final brain output for the regulation of reproduction. Obesity is a state of hyperinsulinemia, hyperlipidemia, hyperleptinemia, and chronic inflammation. Herein, we review recent advances in our understanding of how these metabolic and immune changes affect hypothalamic function and regulation of GnRH neurons. In the latter part, we focus on neuroinflammation as a major consequence of obesity and discuss findings that reveal that GnRH neurons are uniquely positioned to respond to inflammatory changes.


Assuntos
Infertilidade Feminina/etiologia , Infertilidade Masculina/etiologia , Obesidade/complicações , Animais , Feminino , Humanos , Hipotálamo/metabolismo , Infertilidade Feminina/metabolismo , Infertilidade Masculina/metabolismo , Inflamação/etiologia , Masculino , Sistemas Neurossecretores/metabolismo , Obesidade/metabolismo , Reprodução
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