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1.
Nat Commun ; 15(1): 3377, 2024 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-38643150

RESUMEN

Zinc-alpha2-glycoprotein (AZGP1) has been implicated in peripheral metabolism; however, its role in regulating energy metabolism in the brain, particularly in POMC neurons, remains unknown. Here, we show that AZGP1 in POMC neurons plays a crucial role in controlling whole-body metabolism. POMC neuron-specific overexpression of Azgp1 under high-fat diet conditions reduces energy intake, raises energy expenditure, elevates peripheral tissue leptin and insulin sensitivity, alleviates liver steatosis, and promotes adipose tissue browning. Conversely, mice with inducible deletion of Azgp1 in POMC neurons exhibit the opposite metabolic phenotypes, showing increased susceptibility to diet-induced obesity. Notably, an increase in AZGP1 signaling in the hypothalamus elevates STAT3 phosphorylation and increases POMC neuron excitability. Mechanistically, AZGP1 enhances leptin-JAK2-STAT3 signaling by interacting with acylglycerol kinase (AGK) to block its ubiquitination degradation. Collectively, these results suggest that AZGP1 plays a crucial role in regulating energy homeostasis and glucose/lipid metabolism by acting on hypothalamic POMC neurons.


Asunto(s)
Leptina , Proopiomelanocortina , Ratones , Animales , Leptina/metabolismo , Fosforilación , Proopiomelanocortina/metabolismo , Hipotálamo/metabolismo , Homeostasis/fisiología , Metabolismo Energético/fisiología , Neuronas/metabolismo
2.
Nat Commun ; 15(1): 3443, 2024 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-38658557

RESUMEN

The hypothalamus contains a remarkable diversity of neurons that orchestrate behavioural and metabolic outputs in a highly plastic manner. Neuronal diversity is key to enabling hypothalamic functions and, according to the neuroscience dogma, it is predetermined during embryonic life. Here, by combining lineage tracing of hypothalamic pro-opiomelanocortin (Pomc) neurons with single-cell profiling approaches in adult male mice, we uncovered subpopulations of 'Ghost' neurons endowed with atypical molecular and functional identity. Compared to 'classical' Pomc neurons, Ghost neurons exhibit negligible Pomc expression and are 'invisible' to available neuroanatomical approaches and promoter-based reporter mice for studying Pomc biology. Ghost neuron numbers augment in diet-induced obese mice, independent of neurogenesis or cell death, but weight loss can reverse this shift. Our work challenges the notion of fixed, developmentally programmed neuronal identities in the mature hypothalamus and highlight the ability of specialised neurons to reversibly adapt their functional identity to adult-onset obesogenic stimuli.


Asunto(s)
Hipotálamo , Neuronas , Obesidad , Proopiomelanocortina , Análisis de la Célula Individual , Animales , Proopiomelanocortina/metabolismo , Proopiomelanocortina/genética , Neuronas/metabolismo , Obesidad/metabolismo , Obesidad/patología , Masculino , Ratones , Hipotálamo/metabolismo , Hipotálamo/citología , Modelos Animales de Enfermedad , Dieta Alta en Grasa , Ratones Endogámicos C57BL , Ratones Transgénicos , Neurogénesis , Ratones Obesos
3.
Mol Autism ; 15(1): 14, 2024 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-38570876

RESUMEN

BACKGROUND: SH3 and multiple ankyrin repeat domains protein 3 (SHANK3) monogenic mutations or deficiency leads to excessive stereotypic behavior and impaired sociability, which frequently occur in autism cases. To date, the underlying mechanisms by which Shank3 mutation or deletion causes autism and the part of the brain in which Shank3 mutation leads to the autistic phenotypes are understudied. The hypothalamus is associated with stereotypic behavior and sociability. p38α, a mediator of inflammatory responses in the brain, has been postulated as a potential gene for certain cases of autism occurrence. However, it is unclear whether hypothalamus and p38α are involved in the development of autism caused by Shank3 mutations or deficiency. METHODS: Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and immunoblotting were used to assess alternated signaling pathways in the hypothalamus of Shank3 knockout (Shank3-/-) mice. Home-Cage real-time monitoring test was performed to record stereotypic behavior and three-chamber test was used to monitor the sociability of mice. Adeno-associated viruses 9 (AAV9) were used to express p38α in the arcuate nucleus (ARC) or agouti-related peptide (AgRP) neurons. D176A and F327S mutations expressed constitutively active p38α. T180A and Y182F mutations expressed inactive p38α. RESULTS: We found that Shank3 controls stereotypic behavior and sociability by regulating p38α activity in AgRP neurons. Phosphorylated p38 level in hypothalamus is significantly enhanced in Shank3-/- mice. Consistently, overexpression of p38α in ARC or AgRP neurons elicits excessive stereotypic behavior and impairs sociability in wild-type (WT) mice. Notably, activated p38α in AgRP neurons increases stereotypic behavior and impairs sociability. Conversely, inactivated p38α in AgRP neurons significantly ameliorates autistic behaviors of Shank3-/- mice. In contrast, activated p38α in pro-opiomelanocortin (POMC) neurons does not affect stereotypic behavior and sociability in mice. LIMITATIONS: We demonstrated that SHANK3 regulates the phosphorylated p38 level in the hypothalamus and inactivated p38α in AgRP neurons significantly ameliorates autistic behaviors of Shank3-/- mice. However, we did not clarify the biochemical mechanism of SHANK3 inhibiting p38α in AgRP neurons. CONCLUSIONS: These results demonstrate that the Shank3 deficiency caused autistic-like behaviors by activating p38α signaling in AgRP neurons, suggesting that p38α signaling in AgRP neurons is a potential therapeutic target for Shank3 mutant-related autism.


Asunto(s)
Trastorno Autístico , Animales , Ratones , Proteína Relacionada con Agouti/genética , Proteína Relacionada con Agouti/metabolismo , Núcleo Arqueado del Hipotálamo/metabolismo , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Hipotálamo/metabolismo , Proteínas de Microfilamentos/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Proteína Quinasa 14 Activada por Mitógenos/metabolismo
4.
J Ethnopharmacol ; 330: 118205, 2024 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-38641079

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Ginseng is a valuable herb in traditional Chinese medicine. Modern research has shown that it has various benefits, including tonifying vital energy, nourishing and strengthening the body, calming the mind, improving cognitive function, regulating fluids, and returning blood pressure, etc. Rg1 is a primary active component of ginseng. It protects hippocampal neurons, improves synaptic plasticity, enhances cognitive function, and boosts immunity. Furthermore, it exhibits anti-aging and anti-fatigue properties and holds great potential for preventing and managing neurodegenerative diseases (NDDs). AIM OF THE STUDY: The objective of this study was to examine the role of Rg1 in treating chronic inflammatory NDDs and its molecular mechanisms. MATERIALS AND METHODS: In vivo, we investigated the protective effects of Rg1 against chronic neuroinflammation and cognitive deficits in mice induced by 200 µg/kg lipopolysaccharide (LPS) for 21 days using behavioral tests, pathological sections, Western blot, qPCR and immunostaining. In vitro experiments involved the stimulation of HT22 cells with 10 µg/ml of LPS, verification of the therapeutic effect of Rg1, and elucidation of its potential mechanism of action using H2DCFDA staining, BODIPY™ 581/591 C11, JC-1 staining, Western blot, and immunostaining. RESULTS: Firstly, it was found that Rg1 significantly improved chronic LPS-induced behavioral and cognitive dysfunction in mice. Further studies showed that Rg1 significantly attenuated LPS-induced neuronal damage by reducing levels of IL-6, IL-1ß and ROS, and inhibiting AIM2 inflammasome. Furthermore, chronic LPS exposure induced the onset of neuronal ferroptosis by increasing the lipid peroxidation product MDA and regulating the ferroptosis-associated proteins Gpx4, xCT, FSP1, DMT1 and TfR, which were reversed by Rg1 treatment. Additionally, Rg1 was found to activate Nrf2 and its downstream antioxidant enzymes, such as HO1 and NQO1, both in vivo and in vitro. In vitro studies also showed that the Nrf2 inhibitor ML385 could inhibit the anti-inflammatory, antioxidant, and anti-ferroptosis effects of Rg1. CONCLUSIONS: This study demonstrated that Rg1 administration ameliorated chronic LPS-induced cognitive deficits and neuronal ferroptosis in mice by inhibiting neuroinflammation and oxidative stress. The underlying mechanisms may be related to the inhibition of AIM2 inflammasome and activation of Nrf2 signaling. These findings provide valuable insights into the treatment of chronic neuroinflammation and associated NDDs.


Asunto(s)
Disfunción Cognitiva , Ferroptosis , Ginsenósidos , Neuronas , Transducción de Señal , Animales , Masculino , Ratones , Antiinflamatorios/farmacología , Línea Celular , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Proteínas de Unión al ADN , Ferroptosis/efectos de los fármacos , Ginsenósidos/farmacología , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Lipopolisacáridos/toxicidad , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal/efectos de los fármacos
5.
Acta Biomater ; 179: 325-339, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38561074

RESUMEN

Subarachnoid hemorrhage (SAH) is primarily attributed to the rupture of intracranial aneurysms and is associated with a high incidence of disability and mortality. SAH disrupts the blood‒brain barrier, leading to the release of iron ions from blood within the subarachnoid space, subsequently inducing neuronal ferroptosis. A recently discovered protein, known as ferroptosis suppressor protein 1 (FSP1), exerts anti-ferroptotic effects by facilitating the conversion of oxidative coenzyme Q 10 (CoQ10) to its reduced form, which effectively scavenges reactive oxygen radicals and mitigates iron-induced ferroptosis. In our investigation, we observed an increase in FSP1 levels following SAH. However, the depletion of CoQ10 caused by SAH hindered the biological function of FSP1. Therefore, we created neuron-targeted liposomal CoQ10 by introducing the neuron-targeting peptide Tet1 onto the surface of liposomal CoQ10. Our objective was to determine whether this formulation could activate the FSP1 system and subsequently inhibit neuronal ferroptosis. Our findings revealed that neuron-targeted liposomal CoQ10 effectively localized to neurons at the lesion site after SAH. Furthermore, it facilitated the upregulation of FSP1, reduced the accumulation of malondialdehyde and reactive oxygen species, inhibited neuronal ferroptosis, and exerted neuroprotective effects both in vitro and in vivo. Our study provides evidence that supplementation with CoQ10 can effectively activate the FSP1 system. Additionally, we developed a neuron-targeted liposomal CoQ10 formulation that can be selectively delivered to neurons at the site of SAH. This innovative approach represents a promising therapeutic strategy for neuronal ferroptosis following SAH. STATEMENT OF SIGNIFICANCE: Subarachnoid hemorrhage (SAH) is primarily attributed to the rupture of intracranial aneurysms and is associated with a high incidence of disability and mortality. Ferroptosis suppressor protein 1 (FSP1), exerts anti-ferroptotic effects by facilitating the conversion of oxidative coenzyme Q 10 (CoQ10) to its reduced form, which effectively scavenges reactive oxygen radicals and mitigates iron-induced ferroptosis. In our investigation, we observed an increase in FSP1 levels following SAH. However, the depletion of CoQ10 caused by SAH hindered the biological function of FSP1. Therefore, we created neuron-targeted liposomal CoQ10. We find that it effectively localized to neurons at the lesion site after SAH and activated the FSP1/CoQ10 system. This innovative approach represents a promising therapeutic strategy for neuronal ferroptosis following SAH and other central nervous system diseases characterized by disruption of the blood-brain barrier.


Asunto(s)
Ferroptosis , Liposomas , Neuronas , Hemorragia Subaracnoidea , Ubiquinona , Ubiquinona/análogos & derivados , Ubiquinona/farmacología , Hemorragia Subaracnoidea/tratamiento farmacológico , Hemorragia Subaracnoidea/metabolismo , Hemorragia Subaracnoidea/patología , Animales , Ferroptosis/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Liposomas/química , Masculino , Ratones , Especies Reactivas de Oxígeno/metabolismo , Ratas Sprague-Dawley , Ratones Endogámicos C57BL
6.
Science ; 384(6694): 438-446, 2024 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-38662831

RESUMEN

Liver mitochondria play a central role in metabolic adaptations to changing nutritional states, yet their dynamic regulation upon anticipated changes in nutrient availability has remained unaddressed. Here, we found that sensory food perception rapidly induced mitochondrial fragmentation in the liver through protein kinase B/AKT (AKT)-dependent phosphorylation of serine 131 of the mitochondrial fission factor (MFFS131). This response was mediated by activation of hypothalamic pro-opiomelanocortin (POMC)-expressing neurons. A nonphosphorylatable MFFS131G knock-in mutation abrogated AKT-induced mitochondrial fragmentation in vitro. In vivo, MFFS131G knock-in mice displayed altered liver mitochondrial dynamics and impaired insulin-stimulated suppression of hepatic glucose production. Thus, rapid activation of a hypothalamus-liver axis can adapt mitochondrial function to anticipated changes of nutritional state in control of hepatic glucose metabolism.


Asunto(s)
Alimentos , Gluconeogénesis , Glucosa , Hígado , Proteínas de la Membrana , Mitocondrias Hepáticas , Dinámicas Mitocondriales , Proteínas Mitocondriales , Percepción , Animales , Masculino , Ratones , Técnicas de Sustitución del Gen , Glucosa/metabolismo , Hipotálamo/metabolismo , Insulina/metabolismo , Hígado/metabolismo , Ratones Endogámicos C57BL , Mitocondrias Hepáticas/metabolismo , Proteínas Mitocondriales/metabolismo , Proteínas Mitocondriales/genética , Neuronas/metabolismo , Fosforilación , Proopiomelanocortina/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Transgénicos
7.
J Ethnopharmacol ; 330: 118223, 2024 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-38642624

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Leonurus japonicus Houtt. (Labiatae), commonly known as Chinese motherwort, is a herbaceous flowering plant that is native to Asia. It is widely acknowledged in traditional medicine for its diuretic, hypoglycemic, antiepileptic properties and neuroprotection. Currently, Leonurus japonicus (Leo) is included in the Pharmacopoeia of the People's Republic of China. Traditional Chinese Medicine (TCM) recognizes Leo for its myriad pharmacological attributes, but its efficacy against ICH-induced neuronal apoptosis is unclear. AIMS OF THE STUDY: This study aimed to identify the potential targets and regulatory mechanisms of Leo in alleviating neuronal apoptosis after ICH. MATERIALS AND METHODS: The study employed network pharmacology, UPLC-Q-TOF-MS technique, molecular docking, pharmacodynamic studies, western blotting, and immunofluorescence techniques to explore its potential mechanisms. RESULTS: Leo was found to assist hematoma absorption, thus improving the neurological outlook in an ICH mouse model. Importantly, molecular docking highlighted JAK as Leo's potential therapeutic target in ICH scenarios. Further experimental evidence demonstrated that Leo adjusts JAK1 and STAT1 phosphorylation, curbing Bax while augmenting Bcl-2 expression. CONCLUSION: Leo showcases potential in mitigating neuronal apoptosis post-ICH, predominantly via the JAK/STAT mechanism.


Asunto(s)
Apoptosis , Hemorragia Cerebral , Leonurus , Simulación del Acoplamiento Molecular , Farmacología en Red , Neuronas , Animales , Apoptosis/efectos de los fármacos , Leonurus/química , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratones , Masculino , Hemorragia Cerebral/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/aislamiento & purificación , Extractos Vegetales/farmacología , Extractos Vegetales/química , Janus Quinasa 1/metabolismo , Factor de Transcripción STAT1/metabolismo , Modelos Animales de Enfermedad
8.
Biosystems ; 237: 105175, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38460836

RESUMEN

Proteinoid-neuron networks combine biological neurons with spiking proteinoid microspheres, which are generated by thermal condensation of amino acids. Complex and dynamic spiking patterns in response to varied stimuli make these networks suitable for unconventional computing. This research examines the interaction of proteinoid-neuron networks with function-generator-artificial neural networks (ANN) that may create distinct electrical waveforms. Function-generator- artificial neural network (ANN) stimulates and modulates proteinoid-neuron network spiking activity and synchronisation to encode and decode information. We employ function-generator-ANN to study proteinoid-neuron network nonlinear dynamics and chaos and optimise their performance and energy efficiency. Function-generator-ANN improves proteinoid-neuron networks' computational capacities and robustness and creates unique hybrid systems with electrical devices. We address the benefits as well as the drawbacks of employing proteinoid-neuron networks for unconventional computing with function-generator-ANN.


Asunto(s)
Aminoácidos , Proteínas , Proteínas/metabolismo , Redes Neurales de la Computación , Neuronas/metabolismo
9.
J Cell Mol Med ; 28(7): e18240, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38509741

RESUMEN

Growing evidence supports the analgesic efficacy of electroacupuncture (EA) in managing chronic neuropathic pain (NP) in both patients and NP models induced by peripheral nerve injury. However, the underlying mechanisms remain incompletely understood. Ferroptosis, a novel form of programmed cell death, has been found to be activated during NP development, while EA has shown potential in promoting neurological recovery following acute cerebral injury by targeting ferroptosis. In this study, to investigate the detailed mechanism underlying EA intervention on NP, male Sprague-Dawley rats with chronic constriction injury (CCI)-induced NP model received EA treatment at acupoints ST36 and GV20 for 14 days. Results demonstrated that EA effectively attenuated CCI-induced pain hypersensitivity and mitigated neuron damage and loss in the spinal cord of NP rats. Moreover, EA reversed the oxidative stress-mediated spinal ferroptosis phenotype by upregulating reduced expression of xCT, glutathione peroxidase 4 (GPX4), ferritin heavy chain (FTH1) and superoxide dismutase (SOD) levels, and downregulating increased expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), malondialdehyde levels and iron overload. Furthermore, EA increased the immunofluorescence co-staining of GPX4 in neurons cells of the spinal cord of CCI rats. Mechanistic analysis unveiled that the inhibition of antioxidant pathway of Nrf2 signalling via its specific inhibitor, ML385, significantly countered EA's protective effect against neuronal ferroptosis in NP rats while marginally diminishing its analgesic effect. These findings suggest that EA treatment at acupoints ST36 and GV20 may protect against NP by inhibiting neuronal ferroptosis in the spinal cord, partially through the activation of Nrf2 signalling.


Asunto(s)
Electroacupuntura , Ferroptosis , Neuralgia , Humanos , Ratas , Masculino , Animales , Ratas Sprague-Dawley , Electroacupuntura/métodos , Factor 2 Relacionado con NF-E2/metabolismo , Neuralgia/metabolismo , Neuronas/metabolismo , Médula Espinal/metabolismo , Analgésicos
10.
Nat Commun ; 15(1): 2131, 2024 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-38459068

RESUMEN

AgRP neurons drive hunger, and excessive nutrient intake is the primary driver of obesity and associated metabolic disorders. While many factors impacting central regulation of feeding behavior have been established, the role of microRNAs in this process is poorly understood. Utilizing unique mouse models, we demonstrate that miR-33 plays a critical role in the regulation of AgRP neurons, and that loss of miR-33 leads to increased feeding, obesity, and metabolic dysfunction in mice. These effects include the regulation of multiple miR-33 target genes involved in mitochondrial biogenesis and fatty acid metabolism. Our findings elucidate a key regulatory pathway regulated by a non-coding RNA that impacts hunger by controlling multiple bioenergetic processes associated with the activation of AgRP neurons, providing alternative therapeutic approaches to modulate feeding behavior and associated metabolic diseases.


Asunto(s)
Hambre , MicroARNs , Animales , Ratones , Proteína Relacionada con Agouti/genética , Proteína Relacionada con Agouti/metabolismo , Hambre/fisiología , Hipotálamo/metabolismo , MicroARNs/metabolismo , Neuronas/metabolismo , Obesidad/metabolismo
11.
J Comp Neurol ; 532(3): e25602, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38483002

RESUMEN

The orexinergic/hypocretinergic system, while having several roles, appears to be a key link in the balance between arousal and food intake. In birds, to date, this system has only been examined anatomically in four species, all with brains smaller than 3.5 g and of limited phylogenetic range. Here, using orexin-A immunohistochemistry, we describe the distribution, morphology, and nuclear parcellation of orexinergic neurons within the hypothalami of a Congo gray and a Timneh gray parrot, a pied crow, an emu, and a common ostrich. These birds represent a broad phylogeny, with brains ranging in size from 7.85 to 26.5 g. Within the hypothalami of the species studied, the orexinergic neurons were organized in two clusters, and a densely packed paraventricular hypothalamic nucleus cluster located within the medial hypothalamus (Hyp), but not contacting the ventricle, and a more loosely packed lateral hypothalamic cluster in the lateral Hyp. Stereological analysis revealed a strong correlation, using phylogenetic generalized least squares regression analyses, between brain mass and the total number of orexinergic neurons, as well as soma parameters such as volume and area. Orexinergic axonal terminals evinced two types of boutons, larger and the smaller en passant boutons. Unlike the orexinergic system in mammals, which has several variances in cluster organization, that of the birds studied, in the present and previous studies, currently shows organizational invariance, despite the differences in brain and body mass, phylogenetic relationships, and life-histories of the species studied.


Asunto(s)
Neuropéptidos , Animales , Neuropéptidos/metabolismo , Filogenia , Neuronas/metabolismo , Orexinas , Encéfalo/metabolismo , Hipotálamo/metabolismo , Aves , Mamíferos
12.
Cell Rep ; 43(3): 113900, 2024 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-38460132

RESUMEN

Iron overload is closely associated with metabolic dysfunction. However, the role of iron in the hypothalamus remains unclear. Here, we find that hypothalamic iron levels are increased, particularly in agouti-related peptide (AgRP)-expressing neurons in high-fat-diet-fed mice. Using pharmacological or genetic approaches, we reduce iron overload in AgRP neurons by central deferoxamine administration or transferrin receptor 1 (Tfrc) deletion, ameliorating diet-induced obesity and related metabolic dysfunction. Conversely, Tfrc-mediated iron overload in AgRP neurons leads to overeating and adiposity. Mechanistically, the reduction of iron overload in AgRP neurons inhibits AgRP neuron activity; improves insulin and leptin sensitivity; and inhibits iron-induced oxidative stress, endoplasmic reticulum stress, nuclear factor κB signaling, and suppression of cytokine signaling 3 expression. These results highlight the critical role of hypothalamic iron in obesity development and suggest targets for treating obesity and related metabolic disorders.


Asunto(s)
Sobrecarga de Hierro , Enfermedades Metabólicas , Ratones , Animales , Proteína Relacionada con Agouti/metabolismo , Obesidad/metabolismo , Hipotálamo/metabolismo , Leptina/metabolismo , Neuronas/metabolismo , Dieta Alta en Grasa/efectos adversos , Enfermedades Metabólicas/metabolismo , Hierro/metabolismo , Ratones Endogámicos C57BL
13.
Nature ; 628(8009): 826-834, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38538787

RESUMEN

Empirical evidence suggests that heat exposure reduces food intake. However, the neurocircuit architecture and the signalling mechanisms that form an associative interface between sensory and metabolic modalities remain unknown, despite primary thermoceptive neurons in the pontine parabrachial nucleus becoming well characterized1. Tanycytes are a specialized cell type along the wall of the third ventricle2 that bidirectionally transport hormones and signalling molecules between the brain's parenchyma and ventricular system3-8. Here we show that tanycytes are activated upon acute thermal challenge and are necessary to reduce food intake afterwards. Virus-mediated gene manipulation and circuit mapping showed that thermosensing glutamatergic neurons of the parabrachial nucleus innervate tanycytes either directly or through second-order hypothalamic neurons. Heat-dependent Fos expression in tanycytes suggested their ability to produce signalling molecules, including vascular endothelial growth factor A (VEGFA). Instead of discharging VEGFA into the cerebrospinal fluid for a systemic effect, VEGFA was released along the parenchymal processes of tanycytes in the arcuate nucleus. VEGFA then increased the spike threshold of Flt1-expressing dopamine and agouti-related peptide (Agrp)-containing neurons, thus priming net anorexigenic output. Indeed, both acute heat and the chemogenetic activation of glutamatergic parabrachial neurons at thermoneutrality reduced food intake for hours, in a manner that is sensitive to both Vegfa loss-of-function and blockage of vesicle-associated membrane protein 2 (VAMP2)-dependent exocytosis from tanycytes. Overall, we define a multimodal neurocircuit in which tanycytes link parabrachial sensory relay to the long-term enforcement of a metabolic code.


Asunto(s)
Tronco Encefálico , Células Ependimogliales , Conducta Alimentaria , Calor , Hipotálamo , Vías Nerviosas , Neuronas , Animales , Femenino , Masculino , Ratones , Proteína Relacionada con Agouti/metabolismo , Núcleo Arqueado del Hipotálamo/metabolismo , Núcleo Arqueado del Hipotálamo/citología , Tronco Encefálico/citología , Tronco Encefálico/fisiología , Dopamina/metabolismo , Ingestión de Alimentos/fisiología , Células Ependimogliales/citología , Células Ependimogliales/fisiología , Conducta Alimentaria/fisiología , Ácido Glutámico/metabolismo , Hipotálamo/citología , Hipotálamo/fisiología , Vías Nerviosas/metabolismo , Neuronas/metabolismo , Núcleos Parabraquiales/citología , Núcleos Parabraquiales/metabolismo , Núcleos Parabraquiales/fisiología , Sensación Térmica/fisiología , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/líquido cefalorraquídeo , Factor A de Crecimiento Endotelial Vascular/metabolismo
15.
Elife ; 132024 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-38334260

RESUMEN

Cellular metabolism plays an essential role in the regrowth and regeneration of a neuron following physical injury. Yet, our knowledge of the specific metabolic pathways that are beneficial to neuron regeneration remains sparse. Previously, we have shown that modulation of O-linked ß-N-acetylglucosamine (O-GlcNAc) signaling, a ubiquitous post-translational modification that acts as a cellular nutrient sensor, can significantly enhance in vivo neuron regeneration. Here, we define the specific metabolic pathway by which O-GlcNAc transferase (ogt-1) loss of function mediates increased regenerative outgrowth. Performing in vivo laser axotomy and measuring subsequent regeneration of individual neurons in C. elegans, we find that glycolysis, serine synthesis pathway (SSP), one-carbon metabolism (OCM), and the downstream transsulfuration metabolic pathway (TSP) are all essential in this process. The regenerative effects of ogt-1 mutation are abrogated by genetic and/or pharmacological disruption of OCM and the SSP linking OCM to glycolysis. Testing downstream branches of this pathway, we find that enhanced regeneration is dependent only on the vitamin B12 independent shunt pathway. These results are further supported by RNA sequencing that reveals dramatic transcriptional changes by the ogt-1 mutation, in the genes involved in glycolysis, OCM, TSP, and ATP metabolism. Strikingly, the beneficial effects of the ogt-1 mutation can be recapitulated by simple metabolic supplementation of the OCM metabolite methionine in wild-type animals. Taken together, these data unearth the metabolic pathways involved in the increased regenerative capacity of a damaged neuron in ogt-1 animals and highlight the therapeutic possibilities of OCM and its related pathways in the treatment of neuronal injury.


Asunto(s)
Caenorhabditis elegans , Transducción de Señal , Animales , Caenorhabditis elegans/fisiología , Neuronas/metabolismo , Procesamiento Proteico-Postraduccional , Carbono/metabolismo , N-Acetilglucosaminiltransferasas/genética , N-Acetilglucosaminiltransferasas/metabolismo , Acetilglucosamina/metabolismo
16.
Sci Adv ; 10(5): eadj3808, 2024 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-38306424

RESUMEN

G protein-coupled receptor 39 (GPR39) senses the change of extracellular divalent zinc ion and signals through multiple G proteins to a broad spectrum of downstream effectors. Here, we found that GPR39 was prevalent at inhibitory synapses of spinal cord somatostatin-positive (SOM+) interneurons, a mechanosensitive subpopulation that is critical for the conveyance of mechanical pain. GPR39 complexed specifically with inhibitory glycine receptors (GlyRs) and helped maintain glycinergic transmission in a manner independent of G protein signalings. Targeted knockdown of GPR39 in SOM+ interneurons reduced the glycinergic inhibition and facilitated the excitatory output from SOM+ interneurons to spinoparabrachial neurons that engaged superspinal neural circuits encoding both the sensory discriminative and affective motivational domains of pain experience. Our data showed that pharmacological activation of GPR39 or augmenting GPR39 interaction with GlyRs at the spinal level effectively alleviated the sensory and affective pain induced by complete Freund's adjuvant and implicated GPR39 as a promising therapeutic target for the treatment of inflammatory mechanical pain.


Asunto(s)
Dolor , Receptores Acoplados a Proteínas G , Humanos , Neuronas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Glicina/metabolismo , Transducción de Señal , Médula Espinal/metabolismo
17.
Nat Commun ; 15(1): 1327, 2024 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-38351088

RESUMEN

Inflammation, caused by accumulation of inflammatory cytokines from immunocytes, is prevalent in a variety of diseases. Electro-stimulation emerges as a promising candidate for inflammatory inhibition. Although electroacupuncture is free from surgical injury, it faces the challenges of imprecise pathways/current spikes, and insufficiently defined mechanisms, while non-optimal pathway or spike would require high current amplitude, which makes electro-stimulation usually accompanied by damage and complications. Here, we propose a neuromorphic electro-stimulation based on atomically thin semiconductor floating-gate memory interdigital circuit. Direct stimulation is achieved by wrapping sympathetic chain with flexible electrodes and floating-gate memory are programmable to fire bionic spikes, thus minimizing nerve damage. A substantial decrease (73.5%) in inflammatory cytokine IL-6 occurred, which also enabled better efficacy than commercial stimulator at record-low currents with damage-free to sympathetic neurons. Additionally, using transgenic mice, the anti-inflammation effect is determined by ß2 adrenergic signaling from myeloid cell lineage (monocytes/macrophages and granulocytes).


Asunto(s)
Citocinas , Inflamación , Ratones , Animales , Inflamación/metabolismo , Citocinas/metabolismo , Adrenérgicos , Ratones Transgénicos , Neuronas/metabolismo
18.
Mol Metab ; 82: 101904, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38395148

RESUMEN

OBJECTIVE: The prevalence of obesity has increased over the past three decades. Proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus (ARC) play a vital role in induction of satiety. Chronic consumption of high-fat diet is known to reduce hypothalamic neuronal sensitivity to hormones like leptin, thus contributing to the development and persistence of obesity. The functional and morphological effects of a high-calorie diet on POMC neurons and how these effects contribute to the development and maintenance of the obese phenotype are not fully understood. For this purpose, POMC-Cre transgenic mice model was exposed to high-fat diet (HFD) and at the end of a 3- and 6-month period, electrophysiological and morphological changes, and the role of POMC neurons in homeostatic nutrition and their response to leptin were thoroughly investigated. METHODS: Effects of HFD on POMC-satiety neurons in transgenic mice models exposed to chronic high-fat diet were investigated using electrophysiological (patch-clamp), chemogenetic and Cre recombinase advanced technological methods. Leptin, glucose and lipid profiles were determined and analyzed. RESULTS: In mice exposed to a high-fat diet for 6 months, no significant changes in POMC dendritic spine number or projection density from POMC neurons to the paraventricular hypothalamus (PVN), lateral hypothalamus (LH), and bed nucleus stria terminalis (BNST) were observed. It was revealed that leptin hormone did not change the electrophysiological activities of POMC neurons in mice fed with HFD for 6 months. In addition, chemogenetic stimulation of POMC neurons increased HFD consumption. In the 3-month HFD-fed group, POMC activation induced an orexigenic response in mice, whereas switching to a standard diet was found to abolish orexigenic behavior in POMC mice. CONCLUSIONS: Chronic high fat consumption disrupts the regulation of POMC neuron activation by leptin. Altered POMC neuron activation abolished the neuron's characteristic behavioral anorexigenic response. Change in nutritional content contributes to the reorganization of developing maladaptations.


Asunto(s)
Dieta Alta en Grasa , Leptina , Ratones , Animales , Dieta Alta en Grasa/efectos adversos , Leptina/metabolismo , Proopiomelanocortina/metabolismo , Hipotálamo/metabolismo , Obesidad , Neuronas/metabolismo , Ratones Transgénicos
19.
Zhen Ci Yan Jiu ; 49(2): 127-134, 2024 Feb 25.
Artículo en Inglés, Chino | MEDLINE | ID: mdl-38413033

RESUMEN

OBJECTIVES: To investigate the neuroprotective effect of electroacupuncture (EA) at "Quchi"(LI11) and "Zusanli"(ST36) in the rats with cerebral ischemia reperfusion injury and its influence on programmed necrosis of cerebral cortical neurons. METHODS: Sixty male SD rats were randomly divided into sham-operation group, model group, EA group and inhibitor group, with 15 rats in each group. Left middle cerebral artery occlusion model was established using the modified thread embolism method. In the sham-operation group, the carotid artery was exposed and dissociated in each rat. EA was applied to "Quchi"(LI11) and "Zusanli"(ST36) on the right side for 30 min each time, once daily for 7 days in the rats of the EA group. The rats in the inhibitor group were intraperitoneally injected with norstatin-1 (0.6 mg/kg) for consecutive 7 days. The neurological deficit score of rats in each group was observed. HE staining was adopted to detect the degree of pathological damage of the cerebral cortex in the infarction area. Using TUNEL staining, the apoptosis of cortical neurons in the infarction area was determined;the contents of tumor necrosis factor α (TNF-α), interleukin (IL)-1ß and IL-6 were detected by ELISA;the mRNA and protein expression of the receptor interacting protein-1 (RIP1), the receptor interacting protein-3 (RIP3) and the substrate mixed lineage kinase like protein (MLKL) were detected by fluorescence quantitative PCR and Western blot, respectively. RESULTS: In comparison with the sham-operation group, the neurological deficit score in the model group was higher(P<0.01);HE staining showed that there was the pathological damage in the infarction area;the neuron apoptosis rate, the contents of TNF-α, IL-1ß and IL-6, and the mRNA and protein expressions of RIP1, RIP3 and MLKL increased(P<0.01) in the model group. In the EA group, the neurological deficit score was reduced(P<0.01);HE staining showed that the pathological damage was ameliorated in the infarction area;the neuron apoptosis rate, the contents of TNF-α, IL-1ß and IL-6, and the mRNA and protein expressions of RIP1, RIP3, MLKL decreased(P<0.05, P<0.01) when compared with those in the model group. CONCLUSIONS: EA can attenuate cerebral ischemia reperfusion injury and display its neuroprotective effect probably through inhibiting programmed necrosis of cerebral cortical neurons in the rats.


Asunto(s)
Isquemia Encefálica , Electroacupuntura , Fármacos Neuroprotectores , Daño por Reperfusión , Ratas , Masculino , Animales , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/genética , Isquemia Encefálica/genética , Isquemia Encefálica/terapia , Interleucina-6 , Daño por Reperfusión/genética , Daño por Reperfusión/terapia , Neuronas/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Necrosis , Apoptosis , Infarto , ARN Mensajero , Proteínas Quinasas
20.
J Integr Neurosci ; 23(2): 34, 2024 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-38419443

RESUMEN

BACKGROUND: Ischemic stroke is the most common form of stroke and the second most common cause of death and incapacity worldwide. Its pathogenesis and treatment have been the focus of considerable research. In traditional Chinese medicine, the root of Mongolian astragalus has been important in the treatment of stroke since ancient times. Astragalus polysaccharide (APS) is a key active ingredient of astragalus and offers therapeutic potential for conditions affecting the neurological system, the heart, cancer, and other disorders. However, it is not yet known how APS works to protect against ischemic stroke. METHODS: Rats were subjected to middle cerebral artery occlusion (MCAO) to imitate localized cerebral ischemia. Each of four experimental groups (normal, sham, MCAO, and MCAO+APS) contained 12 adult male Sprague-Dawley (SD) rats selected randomly from a total of 48 rats. Following successful establishment of the model, rats in the MCAO+APS group received intraperitoneal injection of APS (50 mg/kg) once daily for 14 days, whereas all other groups received no APS. The Bederson nerve function score and the forelimb placement test were used to detect motor and sensory function defects, while Nissl staining was used to investigate pathological defects in the ventroposterior thalamic nucleus (VPN). Immunohistochemical staining and Western blot were used to evaluate the expression of Neurogenic locus notch homolog protein 1 (Notch1), hairy and enhancer of split 1 (Hes1), phospho-nuclear factor-κB p65 (p-NFκB p65), and nuclear factor-κB p65 (NFκB p65) proteins in the VPN on the ischemic side of MCAO rats. RESULTS: APS promoted the recovery of sensory and motor function, enhanced neuronal morphology, increased the number of neurons, and inhibited the expression of Notch1/NFκB signaling pathway proteins in the VPN of rats with cerebral ischemia. CONCLUSION: After cerebral ischemia, APS can alleviate symptoms of secondary damage to the VPN, which may be attributed to the suppression of the Notch1/NFκB pathway.


Asunto(s)
Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Ratas , Masculino , Animales , Ratas Sprague-Dawley , FN-kappa B/metabolismo , Isquemia Encefálica/metabolismo , Neuronas/metabolismo , Transducción de Señal , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular Isquémico/complicaciones , Receptor Notch1/metabolismo , Receptor Notch1/uso terapéutico
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