RESUMO
A previous study on ovarian and hypothalami transcriptome analysis in white Muscovy duck revealed that MAP3K8 gene participated in MAPK signaling pathway that influence egg production. Additionally, MAP3K8 was predicted as a target gene of miRNA-509-3p that promotes the secretion of oestradiol which is an important hormone in egg ovulation. This suggested that MAP3K8 might have a functional role in the reproductive performance "egg production" of white Muscovy ducks. Herein, we focused on expression level of MAP3K8 in reproductive and non-reproductive tissues of highest (HP) and lowest (LP) egg producing white Muscovy ducks and identified the polymorphism in MAP3K8 and its association with three egg production traits; Age at first egg (AFE), number of eggs at 300 days (N300D) and 59 weeks (N59W). The results of expression level indicated that mRNA of MAP3K8 was significantly (p < 0.01) expressed in the oviduct than in the ovary and hypothalamus. Seven synonymous SNPs were detected, and association analysis showed that g.148303340 G>A and g.148290065 A>G were significantly (p < 0.05) associated with N300D and N59W. The results of this study might serve as molecular marker for marker-assisted selection of white Muscovy ducks for egg production.
Assuntos
Patos , Perfilação da Expressão Gênica , MAP Quinase Quinase Quinases , Ovário , Polimorfismo de Nucleotídeo Único , Animais , Patos/genética , Feminino , Ovário/metabolismo , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Hipotálamo/metabolismo , Oviductos/metabolismoRESUMO
The major female ovarian hormone, 17ß-estradiol (E2), can alter neuronal excitability within milliseconds to regulate a variety of physiological processes. Estrogen receptor-α (ERα), classically known as a nuclear receptor, exists as a membrane-bound receptor to mediate this rapid action of E2, but the ionic mechanisms remain unclear. Here, we show that a membrane channel protein, chloride intracellular channel protein-1 (Clic1), can physically interact with ERα with a preference to the membrane-bound ERα. Clic1-mediated currents can be enhanced by E2 and reduced by its depletion. In addition, Clic1 currents are required to mediate the E2-induced rapid excitations in multiple brain ERα populations. Further, genetic disruption of Clic1 in hypothalamic ERα neurons blunts the regulations of E2 on female body weight balance. In conclusion, we identified the Clic1 chloride channel as a key mediator for E2-induced rapid neuronal excitation, which may have a broad impact on multiple neurobiological processes regulated by E2.
Assuntos
Canais de Cloreto , Receptor alfa de Estrogênio , Neurônios , Neurônios/metabolismo , Canais de Cloreto/metabolismo , Canais de Cloreto/genética , Receptor alfa de Estrogênio/metabolismo , Receptor alfa de Estrogênio/genética , Animais , Feminino , Humanos , Estradiol/metabolismo , Estradiol/farmacologia , Camundongos , Hipotálamo/metabolismo , Hipotálamo/citologia , Ligação ProteicaRESUMO
Classically, the central actions of thyroid hormones (THs) on metabolism occur within the hypothalamus. A recent article published in Cell by Sabatini and colleagues demonstrates that TH modulates cerebral cortical circuits of male mice, which might integrate exploratory behavior and whole-body metabolism.
Assuntos
Córtex Cerebral , Hormônios Tireóideos , Animais , Hormônios Tireóideos/metabolismo , Camundongos , Masculino , Córtex Cerebral/metabolismo , Hipotálamo/metabolismo , Comportamento Exploratório , HumanosRESUMO
Obesity is a growing public health concern that affects the longevity and lifestyle of all human populations including children and older individuals. Diverse factors drive obesity, making it challenging to understand and treat. While recent studies highlight the importance of GPCR signaling for metabolism and fat accumulation, we lack a molecular description of how obesogenic signals accumulate and propagate in cells, tissues, and organs. In this issue of the JCI, Jiang et al. utilized germline mutagenesis to generate a missense variant of GRP75, encoded by the Thinner allele, which resulted in mice with a lean phenotype. GPR75 accumulated in the cilia of hypothalamic neurons. However, mice with the Thinner allele showed defective ciliary localization with resistance to fat accumulation. Additionally, GPR75 regulation of fat accumulation appeared independent of leptin and ADCY3 signaling. These findings shed light on the role of GPR75 in fat accumulation and highlight the need to identify relevant ligands.
Assuntos
Cílios , Obesidade , Receptores Acoplados a Proteínas G , Animais , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Camundongos , Cílios/metabolismo , Cílios/genética , Obesidade/metabolismo , Obesidade/genética , Obesidade/patologia , Humanos , Mutação de Sentido Incorreto , Transdução de Sinais , Hipotálamo/metabolismo , Neurônios/metabolismo , Tecido Adiposo/metabolismo , Leptina/metabolismo , Leptina/genética , Adenilil CiclasesRESUMO
The central nervous system has been implicated in the age-induced reduction in adipose tissue lipolysis. However, the underlying mechanisms remain unclear. Here, we show the expression of SLC7A14 is reduced in proopiomelanocortin (POMC) neurons of aged mice. Overexpression of SLC7A14 in POMC neurons alleviates the aging-reduced lipolysis, whereas SLC7A14 deletion mimics the age-induced lipolysis impairment. Metabolomics analysis reveals that POMC SLC7A14 increased taurochenodeoxycholic acid (TCDCA) content, which mediates the SLC7A14 knockout- or age-induced WAT lipolysis impairment. Furthermore, SLC7A14-increased TCDCA content is dependent on intestinal apical sodium-dependent bile acid transporter (ASBT), which is regulated by intestinal sympathetic afferent nerves. Finally, SLC7A14 regulates the intestinal sympathetic afferent nerves by inhibiting mTORC1 signaling through inhibiting TSC1 phosphorylation. Collectively, our study suggests the function for central SLC7A14 and an upstream mechanism for the mTORC1 signaling pathway. Moreover, our data provides insights into the brain-gut-adipose tissue crosstalk in age-induced lipolysis impairment.
Assuntos
Tecido Adiposo Branco , Envelhecimento , Sistema y+ de Transporte de Aminoácidos , Hipotálamo , Lipólise , Animais , Masculino , Camundongos , Tecido Adiposo Branco/metabolismo , Envelhecimento/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Hipotálamo/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Pró-Opiomelanocortina/metabolismo , Pró-Opiomelanocortina/genética , Transdução de Sinais , Simportadores/metabolismo , Simportadores/genéticaRESUMO
OBJECTIVE: Glucagon-like peptide-1 (GLP1) and leptin (Lep) are afferent signals that regulate energy metabolism. Lactational hypernutrition results in hyperphagia and adiposity in adult life, and these events can be prevented by exercise. We evaluated the effects of swimming training on hypothalamic (GLP1-R) and Lep receptor (Lep-R) gene expressions in lactational hypernutrition-induced obesity. METHODS: On the 3rd postnatal day, the litter sizes of lactating dams were adjusted to small litters (SL; 3 pups/dams) or normal litters (NL; 9 pups/dams). After weaning (21 days), NL and SL male rats were randomly distributed to sedentary (Sed) and exercised (Exe) groups. Exercised mice swam (30 min/3 times/week) for 68 days. Food intake and body weight gain were registered. At 92 days, intraperitoneal glucose and insulin tolerance tests were performed and rats were euthanized at 93 days; adipose tissue depots were weighed, and blood counts and plasma biochemical analyses performed. Hypothalamus were isolated to evaluate Lep-R and GLP1-R gene expressions. RESULTS: Small litters sedentary rats presented increased body weight gain, adiposity, insulin sensibility and higher fasting values of glucose and triglycerides, besides higher hypothalamic gene expressions of Lep-R and GLP1-R, compared to NLSed animals. SLExe rats did not develop obesity or metabolic abnormalities and Lep-R and GLP1-R hypothalamic gene expressions were normalized. CONCLUSION: Lactational hypernutrition induces obesity and metabolic dysfunction in adult life, in association with higher hypothalamic expressions of the Lep-R and GLP1-R genes. Exercise prevented obesity and improved metabolic state in SL overnourished rats, and normalized their hypothalamic Lep-R and GLP1-R gene expressions.
Assuntos
Hipotálamo , Obesidade , Condicionamento Físico Animal , Ratos Wistar , Receptores para Leptina , Natação , Animais , Hipotálamo/metabolismo , Obesidade/metabolismo , Obesidade/genética , Obesidade/prevenção & controle , Condicionamento Físico Animal/fisiologia , Condicionamento Físico Animal/métodos , Masculino , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Feminino , Natação/fisiologia , Tamanho da Ninhada de Vivíparos , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Ratos , Lactação/metabolismo , Lactação/fisiologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Leptina/sangue , Leptina/metabolismo , Distribuição Aleatória , Expressão Gênica , Ingestão de Alimentos/fisiologia , Adiposidade/fisiologiaRESUMO
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
Microglia, as the resident macrophages of the brain, are essential for maintaining brain homeostasis. They shape neuronal circuits during development, survey their environment for debris or dead cells, as well as respond to infection and injury in the brain, among many other functions. However, their important role in neurodevelopment and synaptic plasticity and pathophysiology has not been fully defined, highlighting the need for further investigation. To gain a more comprehensive understanding of the role of microglia in these processes, we need to isolate microglia and characterize them genetically, metabolically, and functionally. However, the isolation of microglia from adult mice, especially from small brain structures, is challenging as they represent a small percentage of the total brain cells, and the yield of isolated microglia is often too low. Here, the magnetic isolation of microglia using CD11b+ microbeads allows us to sort microglial cells from the hypothalamus of a freshly perfused adult mouse brain. The current method allows us to achieve relatively high purity and yield in a short period while maintaining cell viability.
Assuntos
Hipotálamo , Microglia , Animais , Microglia/citologia , Camundongos , Hipotálamo/citologia , Antígeno CD11b/metabolismo , Separação Imunomagnética/métodosRESUMO
OBJECTIVE: Obesity is a chronic disease that affects more than 400 million adults with severe comorbidities. The search for new treatments to reduce its negative consequences is necessary. Orexins are hypothalamic neuropeptides involved in various physiological processes related to obesity. The aim of this study was to investigate the consequences of chronic orexin-A treatment in mouse models. METHODS: Female wild-type C57BL/6 mice that were obesity-prone or obesity-resistant and mice that were deficient for orexin receptors were fed with a high-fat diet. Glucose tolerance, indirect calorimetry, expression of brain neuropeptides and receptors, microglial activation, and microbiota were determined to evaluate the role of orexins on metabolic flexibility. RESULTS: Orexin-A reduces weight gain in obesity-prone mice. This reduction is associated with a decrease in body fat, food intake, steatosis, and insulin resistance, as well as alterations of intestinal microbiota composition. A decreased expression of orexin receptors and neuropeptides involved in food intake was also observed in the hypothalamus. CONCLUSIONS: Our data support the notion that orexin receptor signaling is involved in different aspects of energy metabolism and can mitigate several dysfunctions associated with obesity, suggesting that orexin receptors can represent new targets for obesity treatment.
Assuntos
Dieta Hiperlipídica , Metabolismo Energético , Microbioma Gastrointestinal , Hipotálamo , Resistência à Insulina , Camundongos Endogâmicos C57BL , Obesidade , Receptores de Orexina , Orexinas , Animais , Orexinas/metabolismo , Obesidade/metabolismo , Camundongos , Feminino , Hipotálamo/metabolismo , Receptores de Orexina/metabolismo , Aumento de Peso , Tecido Adiposo/metabolismo , Ingestão de Alimentos/fisiologia , Transdução de Sinais , Camundongos Knockout , Modelos Animais de DoençasRESUMO
One of the main underlying etiologies of type 2 diabetes (T2DM) is insulin resistance, which is most frequently caused by obesity. Notably, the deregulation of adipokine secretion from visceral adiposity has been identified as a crucial characteristic of type 2 diabetes and obesity. Spexin is an adipokine that is released by many different tissues, including white adipocytes and the glandular stomach, and is negatively connected with the state of energy storage. This peptide acts through GALR2/3 receptors to control a wide range of metabolic processes, including inflammation, browning, lipolysis, energy expenditure, and eating behavior. Specifically, spexin can enter the hypothalamus and regulate the hypothalamic melanocortin system, which in turn balances energy expenditure and food intake. This review examines recent advances and the underlying mechanisms of spexin in obesity and T2DM. In particular, we address a range of topics from basic research to clinical findings, such as an analysis of the possible function of spexin in the hypothalamic melanocortin response, which involves reducing energy intake and increasing energy expenditure while also enhancing insulin sensitivity and glucose tolerance. Gaining more insight into the mechanisms that underlie the spexin system's control over energy metabolism and homeostasis may facilitate the development of innovative treatment approaches that focus on combating obesity and diabetes.
Assuntos
Diabetes Mellitus Tipo 2 , Metabolismo Energético , Hipotálamo , Obesidade , Hormônios Peptídicos , Humanos , Hipotálamo/metabolismo , Animais , Hormônios Peptídicos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Obesidade/metabolismo , Melanocortinas/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
Endoplasmic reticulum (ER) homeostasis in the hypothalamus has been implicated in the pathogenesis of diet-induced obesity (DIO) and type 2 diabetes; however, the underlying molecular mechanism remain vague and debatable. Here we report that SEL1L-HRD1 protein complex of the highly conserved ER-associated protein degradation (ERAD) machinery in POMC-expressing neurons ameliorates diet-induced obesity and its associated complications, partly by regulating the turnover of the long isoform of Leptin receptors (LepRb). Loss of SEL1L in POMC-expressing neurons attenuates leptin signaling and predisposes mice to HFD-associated pathologies including fatty liver, glucose intolerance, insulin and leptin resistance. Mechanistically, nascent LepRb, both wildtype and disease-associated Cys604Ser variant, are misfolding prone and bona fide substrates of SEL1L-HRD1 ERAD. In the absence of SEL1L-HRD1 ERAD, LepRb are largely retained in the ER, in an ER stress-independent manner. This study uncovers an important role of SEL1L-HRD1 ERAD in the pathogenesis of central leptin resistance and leptin signaling.
Assuntos
Dieta Hiperlipídica , Degradação Associada com o Retículo Endoplasmático , Retículo Endoplasmático , Leptina , Neurônios , Obesidade , Pró-Opiomelanocortina , Receptores para Leptina , Transdução de Sinais , Ubiquitina-Proteína Ligases , Animais , Obesidade/metabolismo , Obesidade/genética , Obesidade/etiologia , Obesidade/patologia , Neurônios/metabolismo , Leptina/metabolismo , Receptores para Leptina/metabolismo , Receptores para Leptina/genética , Camundongos , Pró-Opiomelanocortina/metabolismo , Pró-Opiomelanocortina/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Dieta Hiperlipídica/efeitos adversos , Masculino , Retículo Endoplasmático/metabolismo , Hipotálamo/metabolismo , Estresse do Retículo Endoplasmático , Camundongos Endogâmicos C57BL , Proteínas/metabolismo , Proteínas/genética , Camundongos Knockout , Humanos , Peptídeos e Proteínas de Sinalização IntracelularRESUMO
Context Understanding of central nervous system mechanisms related to age-related infertility remains limited. Fibril α-synuclein, distinct from its monomer form, is implicated in age-related diseases and propagates among neurons akin to prions. Aims We compared α-synuclein expression in gonadotropin-releasing hormone-expressing neurons (GnRH neurons) in the pre-optic area, arcuate nucleus, and median eminence of healthy heifers and aged cows to determine its role in age-related infertility. Methods We analysed mRNA and protein expression, along with fluorescent immunohistochemistry for GnRH and α-synuclein, followed by Congo red staining to detect amyloid deposits, and confocal microscopy. Key results Both mRNA and protein expressions of α-synuclein were confirmed by reverse transcription-polymerase chain reaction (RT-PCR) and western blots in bovine cortex, hippocampus, and anterior and posterior hypothalamus tissues. Significant differences in α-synuclein mRNA expression were observed in the cortex and hippocampus between young and old cows. Western blots showed five bands of α-synuclein, probably reflecting monomer, dimer, and oligomers, in the cortex, hippocampus, hypothalamus tissues, and there were significant differences in some bands between young and old cows. Bright-field and polarised light microscopy did not detect obvious amyloid deposition in aged hypothalami; however, higher-sensitive confocal microscopy unveiled strong positive signal of Congo red and α-synuclein in GnRH neurons in aged hypothalami. Additionally, α-synuclein expression was detected in immortalised GnRH neurons, GT1-7 cells. Conclusion Alpha-synuclein was expressed in GnRH neurons, and some differences were observed between young and old hypothalami. Implications Alpha-synuclein may play an important role in aging-related infertility.
Assuntos
Envelhecimento , Hormônio Liberador de Gonadotropina , Hipotálamo , Neurônios , alfa-Sinucleína , Animais , Hormônio Liberador de Gonadotropina/metabolismo , Hormônio Liberador de Gonadotropina/genética , Bovinos , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Neurônios/metabolismo , Hipotálamo/metabolismo , Feminino , Envelhecimento/metabolismo , RNA Mensageiro/metabolismoRESUMO
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
Systemic inflammation elicits sickness behaviors and fever by engaging a complex neuronal circuitry that begins in the preoptic area of the hypothalamus. Ectotherms such as teleost fish display sickness behaviors in response to infection or inflammation, seeking warmer temperatures to enhance survival via behavioral fever responses. To date, the hypothalamus is the only brain region implicated in sickness behaviors and behavioral fever in teleosts. Yet, the complexity of neurobehavioral manifestations underlying sickness responses in teleosts suggests engagement of higher processing areas of the brain. Using in vivo models of systemic inflammation in rainbow trout, we find canonical pyrogenic cytokine responses in the hypothalamus whereas in the telencephalon and the optic tectum il-1b and tnfa expression is decoupled from il-6 expression. Polyamine metabolism changes, characterized by accumulation of putrescine and decreases in spermine and spermidine, are recorded in the telencephalon but not hypothalamus upon systemic injection of bacteria. While systemic inflammation causes canonical behavioral fever in trout, blockade of bacterial polyamine metabolism prior to injection abrogates behavioral fever, polyamine responses, and telencephalic but not hypothalamic cytokine responses. Combined, our work identifies the telencephalon as a neuronal substrate for brain responses to systemic inflammation in teleosts and uncovers the role of polyamines as critical chemical mediators in sickness behaviors.
Assuntos
Inflamação , Oncorhynchus mykiss , Poliaminas , Telencéfalo , Animais , Telencéfalo/metabolismo , Poliaminas/metabolismo , Inflamação/metabolismo , Oncorhynchus mykiss/metabolismo , Oncorhynchus mykiss/imunologia , Neurônios/metabolismo , Hipotálamo/metabolismo , Espermina/metabolismo , Putrescina/metabolismo , Comportamento de Doença/fisiologia , Espermidina/metabolismoRESUMO
Sexual maturation in goats is a dynamic process regulated precisely by the hypothalamic-pituitary-gonadal axis and is essential for reproduction. The hypothalamus plays a crucial role in this process and is the control center of the reproductive activity. It is significant to study the molecular mechanisms in the hypothalamus regulating sexual maturation in goats. We analyzed the serum hormone profiles and hypothalamic mRNA expression profiles of female goats during sexual development (1 day old (neonatal, D1, n = 5), 2 months old (prepuberty, M2, n = 5), 4 months old (sexual maturity, M4, n = 5), and 6 months old (breeding period, M6, n = 5)). The results indicated that from D1 to M6, serum hormone levels, including FSH, LH, progesterone, estradiol, IGF1, and leptin, exhibited an initial increase followed by a decline, peaking at M4. Furthermore, we identified a total of 508 differentially expressed genes in the hypothalamus, with a total of four distinct expression patterns. Nuclear receptor subfamily 1, group D, member 1 (NR1D1), glucagon-like peptide 1 receptor (GLP1R), and gonadotropin-releasing hormone 1 (GnRH-1) may contribute to hormone secretion, energy metabolism, and signal transduction during goat sexual maturation via circadian rhythm regulation, ECM receptor interactions, neuroactive ligand-receptor interactions, and Wnt signaling pathways. This investigation offers novel insights into the molecular mechanisms governing the hypothalamic regulation of goat sexual maturation.
Assuntos
Cabras , Hipotálamo , Maturidade Sexual , Transcriptoma , Animais , Cabras/genética , Cabras/crescimento & desenvolvimento , Hipotálamo/metabolismo , Maturidade Sexual/genética , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Hormônio Liberador de Gonadotropina/genética , Perfilação da Expressão Gênica , Hormônio Luteinizante/sangue , Hormônio Luteinizante/metabolismoRESUMO
Metabolic diseases such as obesity and type 2 diabetes are marked by insulin resistance1,2. Cells within the arcuate nucleus of the hypothalamus (ARC), which are crucial for regulating metabolism, become insulin resistant during the progression of metabolic disease3-8, but these mechanisms are not fully understood. Here we investigated the role of a specialized chondroitin sulfate proteoglycan extracellular matrix, termed a perineuronal net, which surrounds ARC neurons. In metabolic disease, the perineuronal net of the ARC becomes augmented and remodelled, driving insulin resistance and metabolic dysfunction. Disruption of the perineuronal net in obese mice, either enzymatically or with small molecules, improves insulin access to the brain, reversing neuronal insulin resistance and enhancing metabolic health. Our findings identify ARC extracellular matrix remodelling as a fundamental mechanism driving metabolic diseases.
Assuntos
Núcleo Arqueado do Hipotálamo , Matriz Extracelular , Resistência à Insulina , Neurônios , Obesidade , Animais , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Camundongos , Masculino , Núcleo Arqueado do Hipotálamo/metabolismo , Núcleo Arqueado do Hipotálamo/patologia , Neurônios/metabolismo , Neurônios/patologia , Obesidade/metabolismo , Obesidade/patologia , Insulina/metabolismo , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Feminino , Camundongos Obesos , Camundongos Endogâmicos C57BL , Hipotálamo/metabolismo , Hipotálamo/patologia , Proteoglicanas de Sulfatos de Condroitina/metabolismo , HumanosRESUMO
Migration is one of the most extreme and energy demanding life history strategies to have evolved in the animal kingdom. In birds, champions of long-distance migrations, the seasonal emergence of the migratory phenotype is characterised by rapid physiological and metabolic remodelling, including substantial accumulation of fat stores and increases in nocturnality. The molecular underpinnings and brain adaptations to seasonal migrations remain poorly understood. Here, we exposed Common quails (Coturnix coturnix) to controlled changes in day length to simulate southward autumn migration, and then blocked the photoperiod until birds entered the non-migratory wintering phase. We first performed de novo RNA-Sequencing from selected brain samples (hypothalamus) collected from birds at a standardised time at night, either in a migratory state (when restlessness was highest and at their body mass peak), or in a non-migratory state and conducted differential gene expression and functional pathways analyses. We found that the migratory state was associated with up-regulation of a few, yet functionally well defined, gene expression networks implicated in fat trafficking, protein and carbohydrate metabolism. Further analyses that focused on candidate genes (apolipoprotein H or APOH, lysosomal associated membrane protein-2 or LAMP2) from samples collected during the day or night across the entire study population suggested differences in the expression of these genes depending on the time of the day with the largest expression levels being found in the migratory birds sampled at night. We also found that expression of APOH was positively associated with levels of nocturnal activity in the migratory birds; such an association was absent within the non-migratory birds. Our results provide novel experimental evidence revealing that hypothalamic changes in expression of apolipoprotein pathways, which regulate the circulatory transport of lipids, are likely key regulatory activators of nocturnal migratory movements. Our study paves the way for performing deeper functional investigations on seasonal molecular remodelling underlying the development of the migratory phenotype.
Assuntos
Migração Animal , Encéfalo , Animais , Migração Animal/fisiologia , Encéfalo/metabolismo , Encéfalo/fisiologia , Fotoperíodo , Coturnix/genética , Coturnix/metabolismo , Coturnix/fisiologia , Estações do Ano , Regulação da Expressão Gênica , Redes Reguladoras de Genes , 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
The hypothalamus lies at the intersection of brain and hormonal mechanisms governing essential bodily functions, including metabolic/body weight homeostasis and reproduction. While metabolism and fertility are precisely regulated by independent neuroendocrine axes, these are tightly connected, as reflection of the bidirectional interplay between the energy status of the organisms and their capacity to reproduce; a connection with important pathophysiological implications in disorders affecting these two crucial systems. Beyond the well-characterized roles of key hormones (e.g., leptin, insulin, ghrelin) and neuropeptides (e.g., melanocortins, kisspeptins) in the integral control of metabolism and reproduction, mounting evidence has pointed out a relevant function of cell energy sensors and lipid sensing mechanisms in the hypothalamic control of metabolism, with prominent roles also for metabolic sensors, such as mTOR, AMPK and SIRT1, in the nutritional regulation of key aspects of reproduction, such as pubertal maturation. We provide herein a synoptic overview of these novel regulatory pathways, with a particular focus on their putative function in the metabolic control of puberty, and delineate new avenues for further exploration of the intricate mechanisms whereby metabolism and reproduction are tightly connected.