EphrinB1 Modulates Glutamatergic Inputs into POMC Neurons and Controls Glucose Homeostasis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA605210 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11039820.fastq.gz | Fastqsanger.gz | |||
| SRR11039821.fastq.gz | Fastqsanger.gz | |||
| SRR11039822.fastq.gz | Fastqsanger.gz | |||
| SRR11039823.fastq.gz | Fastqsanger.gz | |||
| SRR11039824.fastq.gz | Fastqsanger.gz |
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Project description:We aim at identifying genes enriched in POMC neurons versus NPY neurons that were involved in glutamatergic synapse formation
2020-02-07 | GSE144887 | GEO
Project description:Proopiomelanocortin (POMC) neurons are major regulators of energy balance and glucose homeostasis. In addition to being regulated by hormones and nutrients, POMC neurons are controlled by glutamatergic input originating from multiple brain regions. However, the factors involved in the formation of glutamatergic inputs and how they contribute to bodily functions remain largely unknown. Here, we show that during the development of glutamatergic inputs, POMC neurons exhibit enriched expression of the Efnb1 (EphrinB1) and Efnb2 (EphrinB2) genes, which are known to control excitatory synapse formation. In vivo loss of Efnb1 in POMC-expressing progenitors decreases the amount of glutamatergic inputs, associated with a reduced number of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor subunits and excitability of these cells. We found that mice lacking Efnb1 in POMC-expressing progenitors display impaired glucose tolerance due to blunted vagus nerve activity and decreased insulin secretion. However, despite reduced excitatory inputs, mice lacking Efnb2 in POMC-expressing progenitors showed no deregulation of insulin secretion and only mild alterations in feeding behavior and gluconeogenesis. Collectively, our data demonstrate the role of ephrins in controlling excitatory input amount into POMC-expressing progenitors and show an isotype-specific role of ephrins on the regulation of glucose homeostasis and feeding.
| S-EPMC7728393 | biostudies-literature
Project description:Agouti-related peptide (AgRP)- and proopiomelanocortin (POMC)-expressing neurons reciprocally regulate food intake. Here, we combined non-interacting recombinases to simultaneously express functionally opposing chemogenetic receptors in AgRP and POMC neurons allowing to compare metabolic responses in mice with simultaneous activation of AgRP and inhibition of POMC neurons with isolated activation of AgRP neurons or isolated inhibition of POMC neurons. These experiments revealed that food intake is regulated by the additive effect of AgRP-neuron activation and POMC-neuron inhibition, while systemic insulin sensitivity and gluconeogenesis are differentially modulated by isolated versus simultaneous regulation of AgRP and POMC neurons. We identified a neurocircuit engaging Npy1R-expressing neurons in the paraventricular nucleus of the hypothalamus (PVH), where activated AgRP- and inhibited POMC neurons synergize to promote food consumption and activate neurons in the nucleus tractus solitarii (NTS). We then performed single-nuclei RNA sequencing to define the molecular nature of Fos+ cells in the posterior NTS/AP area that respond to simultaneous chemogenetic intervention over AgRP and POMC neurons and identified TH+ neurons as candidates for receiving neuronal inputs initiated by the simultaneous and coordinated interplay between AgRP and POMC neurocircuits and relayed to the NTS area by the silenced glutamatergic Npy1R neurons.
2024-02-12 | GSE248391 | GEO
Project description:Long-range glutamatergic inputs from the cortex and thalamus provide important motor and cognitive information to the striatum where they are integrated for learning and action planning. Genetic programs and transcription factors that orchestrate the development of these inputs are relatively unknown. The transcription factor, FOXP1, is crucial for the development of spiny projection neurons (SPNs) in the striatum. We investigated the cell-specific role of Foxp1 in the formation of glutamatergic inputs – including corticostriatal inputs. Embryonic Foxp1 deletion in dopamine receptor 2-expressing SPNs (D2 Foxp1cKO) leads to reduced transmission of corticostriatal excitatory inputs and decreased synaptically driven excitability. Postnatal deletion of Foxp1 also resulted in decreased glutamatergic inputs onto D2 SPNs. Single nuclei RNA sequencing of D2 Foxp1cKO striatum identified downregulated postsynaptic genes, consistent with the synaptic phenotype. Reinstating Foxp1 postnatally rescued electrophysiological deficits and expression of a subset of genes that were altered by embryonic deletion in D2 SPNs. Postnatal Foxp1 reinstatement could also rescue behavioral phenotypes. In summary, we demonstrate that FOXP1 regulates the development of corticostriatal circuitry. Further, changes at multiple levels of brain function resulting from loss of Foxp1 are rescued with postnatal Foxp1 reinstatement, indicating a therapeutic approach for individuals with FOXP1 syndrome.
2024-02-20 | GSE243662 | GEO
Project description:Mitofusin 1 (Mfn1) is a transmembrane GTPase protein implicated in mitochondrial fusion. To investigate the potential role of Mfn1 in energy balance and metabolism control we generated mice lacking Mfn1 specifically in hypothalamic POMC neurons (POMCMfn1KO). We used microarrays to determine gene expression changes resulting from deletion of Mfn1 in POMC neurons under fed and fasting conditions
2017-06-27 | GSE81993 | GEO
Project description:From the arcuate nucleus of mice, we have dissociated neurons that express Proopiomelanocortin(POMC) and captured them on the Fluidigm C1 platform. These neuronsplay important roles in the regulation of appetite and sexual behavior. Here we propose tosequence RNA from 96 single POMC-expressing neurons to understand the variance in theirtranscriptomes.This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/
2015-04-28 | E-ERAD-357 | biostudies-arrayexpress
Project description:Hypothalamic neuronal populations are central regulators of energy homeostasis and reproductive function. However, the ontogeny of these critical hypothalamic neuronal populations is largely unknown. Here, we reveal novel cellular fates of the hypothalamic Pomc-expressing precursors by combining mouse genetics with a conditional viral ribosome-tagging approach to phenotype neurons. Our results show that the Pomc-expressing precursors differentiate into discrete neuronal subpopulations that mediate not only energy balance (POMC and AgRP) but also reproductive physiology (Kisspeptin). Punches containing the mediobasal hypothalamus of Pomc-Cre:RiboTag mice and Pomc-Cre mice injected with the RiboTag viral vector (AAV-DIO-RiboTag) were homogenized and incubated with anti-hemagglutin (HA) antibodies and protein A/G magnetic beads to isolate the polysome-associated mRNAS in the Pomc-derived lineage and in adult POMC neurons, respectively. To identify differentially expressed transcripts, RNA from the immunoprecipitates was extracted, amplified, labelled and hybridized to MouseRef-8 v2 expression beadchips.
2015-04-16 | E-GEOD-56917 | biostudies-arrayexpress
Project description:In this study, we aimed at uncovering the molecular mechanisms underlying POMC neuron sensory activation and the mediated behavioral and metabolic processes. Unexpectedly, we found that glycogen metabolism is rapidly engaged in POMC neurons upon sensory food perception. Genetic deletion of glycogen synthase, the sole enzyme able to make glycogen in vivo, in POMC neurons impedes food-related sensory activation while causing impairments in food awareness, short-term food intake and insulin release. These perturbations associate with whole-body metabolic defects, including overweight and insulin resistance, that are exacerbated by high-dense diets or ageing. Collectively, our study identifies glycogen metabolism as an unanticipated mechanistic driver of POMC neuron sensory activation and provides paradigm-shift evidences of the importance of neuronal glycogen for physiology.
2024-01-31 | GSE224274 | GEO
Project description:Paradoxically, glucose, the primary driver of satiety, activates a small population of anorexigenic POMC neurons. Here we show that lactate levels in the circulation and in the cerebrospinal fluid are elevated in fed state and addition of lactate to glucose activates the majority of POMC neurons while increasing cytosolic NADH generation, mitochondrial respiration and extracellular pyruvate levels. Inhibition of lactate dehydrogenases diminishes mitochondrial respiration, NADH production, and POMC neuronal activity. However, inhibition of the mitochondrial pyruvate carrier has no effect. POMC-specific downregulation of Ucp2 (Ucp2PomcKO), a molecule regulated by fatty acid metabolism and shown to play a role as transporter in the malate-aspartate shuttle, abolishes lactate- and glucose-sensing of POMC neurons. Ucp2PomcKO mice have impaired glucose metabolism and are prone to obesity on a high fat diet. Altogether, our data show that lactate through redox signaling and blocking mitochondrial glucose utilization activates POMC neurons to regulate feeding and glucose metabolism.
2022-11-28 | ST002361 | MetabolomicsWorkbench
Project description:Liver mitochondria play a central role in metabolic adaptations to changing nutritional states, yet their dynamic regulation upon anticipated changes in energy state has remained unaddressed. Here, we show that sensory food perception rapidly induces mitochondrial fission in the liver via protein kinase B/AKT-dependent phosphorylation of serine 131 of the Mitochondrial fission factor (MFFS131), and this response is mediated via activation of hypothalamic Pro-opiomelanocortin (POMC)-expressing neurons. A non-phosphorylatable MFFS131G knock-in mutation abrogates AKT-induced mitochondrial fragmentation in vitro. In vivo, MFFS131G knock-in mice display altered liver mitochondrial dynamics upon food perception and refeeding and impaired insulin stimulated suppression of gluconeogenesis. Collectively, we reveal a critical role for rapid activation of a hypothalamic/liver axis to adapt mitochondrial function to anticipated changes of nutritional state in control of hepatic glucose metabolism. The repository contains two LC-MS/MS datasets aiming for the detection of phosphorylated peptides. a) POMC neuron activation and b) time course experiment of fasted, refed and caged food. We assumed that due to the short time (30 min max) that the total protein level remain unchanged.
2024-03-28 | PXD044227 | Pride