Functionally Distinct Pomc-Expressing Neuron Subpopulations in Hypothalamus Revealed by Intersectional Targeting
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PROVIDER: PRJNA643978 | ENA |
REPOSITORIES: ENA
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Project description:Pro-opiomelanocortin (POMC)-expressing neurons in the arcuate nucleus of the hypothalamus represent key regulators of metabolic homeostasis. Electrophysiological and single-cell sequencing experiments have revealed a remarkable degree of heterogeneity of these neurons. However, the exact molecular basis and functional consequences of this heterogeneity have not yet been addressed. Here, we have developed new mouse models in which intersectional Cre/Dre-dependent recombination allowed for successful labeling, translational profiling and functional characterization of distinct POMC neurons expressing the leptin receptor (Lepr) and glucagon like peptide 1 receptor (Glp1r). Our experiments reveal that POMCLepr+ and POMCGlp1r+ neurons represent largely nonoverlapping subpopulations with distinct basic electrophysiological properties. They exhibit a specific anatomical distribution within the arcuate nucleus and differentially express receptors for energy-state communicating hormones and neurotransmitters. Finally, we identify a differential ability of these subpopulations to suppress feeding. Collectively, we reveal a notably distinct functional microarchitecture of critical metabolism-regulatory neurons.
| S-EPMC8249241 | biostudies-literature
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:We report differences in translational profiles between POMCLepr+ and POMCGlp1r+ neurons.
2021-02-26 | GSE153753 | GEO
Project description: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 increase 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, highlighting the ability of specialized neurons to adapt their funcitonal identity to adult-onset obesogenic stimuli
2024-04-29 | GSE261715 | GEO
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:Maternal unbalanced nutritional habits during embryo development and perinatal stages perturb hypothalamic neuronal programming of the offspring, thus increasing “diabesity” risk. Here we report that exposure to high-fat diet during gestation and lactation did not interfere with progeny’s hypothalamic POMC neuron specification, but significantly impaired their spatial distribution and axonal extension to target areas. Importantly, we established POMC neuron-specific translatome signatures accounting for neuronal aberrant development and axonal growth. These anatomical and molecular alterations caused metabolic dysfunction in early-life and adulthood. Our study provides fundamental insights on the molecular mechanisms underlying POMC neuron malprogramming in obesogenic contexts.
2020-02-20 | GSE135639 | GEO
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).
2015-04-16 | GSE56917 | GEO
Project description:The mammalian CNS relies on a constant supply of external glucose for its undisturbed operation. However, neurons can readily switch to using fatty acids and ketones as alternative fuels. Here, we show that oleic acid (OA) excites pro-opiomelanocortin (POMC) neurons by inhibition of ATP-activated potassium (K(ATP)) channels. The involvement of K(ATP) channels is further supported by experiments in SUR1 KO animals. Inhibition of beta-oxidation using carnitine palmitoyltransferase-1 inhibitors blocks OA-induced depolarization. The depolarizing effect of OA is specific because it is not mimicked by octanoic acid. Furthermore, OA does not regulate the excitability of agouti-related peptide neurons. High-fat feeding alters POMC neuron excitability, but not its response to OA. Thus beta-oxidation in POMC neurons may mediate the appetite-suppressing (anorexigenic) effects of OA.
| S-EPMC2681442 | biostudies-literature
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
Project description:Dopamine acts on neurons in the arcuate nucleus of the hypothalamus (ARC) which control homeostatic feeding responses. Here we demonstrate a differential enrichment of Drd1 expression in food intake-promoting AgRP/NPY neurons and a large proportion of Drd2-expressing anorexigenic POMC neurons. This translates into a predominant activation of AgRP/NPY neurons upon dopamine stimulation and a larger proportion of dopamine-inhibited POMC neurons. Employing intersectional targeting of Drd2-expressing POMC neurons, we reveal, that dopamine-mediated POMC neuron inhibition is Drd2-dependent and that POMCDrd2+ neurons exhibit differential expression of neuropeptide signaling mediators, which manifests in enhanced somatostatin responsiveness of these neurons compared to the global POMC neuron population. Retrograde pseudorabies mapping reveals predominant synaptic input onto these cells from within the ARC as well as characterized dopaminergic cell groups within the hypothalamus and subthalamic areas. Finally, selective chemogenetic activation of POMCDrd2+ neurons uncovers their ability to acutely suppress feeding and to preserve body temperature. Collectively, the present study provides the molecular and functional characterization of POMCDrd2+ neurons and aids to our understanding of dopamine-dependent control of homeostatic energy regulatory neurocircuits.
2022-11-08 | GSE210311 | GEO