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Single cell tracing of Pomc neurons reveals recruitment of ‘Ghost’ subtypes with atypical identity in a mouse model of obesity

ABSTRACT: 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

ORGANISM(S): Mus musculus

PROVIDER: GSE261715 | GEO | 2024/04/29

REPOSITORIES: GEO

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PC1/3 deficiency impacts POMC processing in human embryonic stem cell-derived hypothalamic neurons

Project description:We developed a technique for generating hypothalamic neurons from human pluripotent stem cells. Here, as proof-of-principle, we examine the use of these cells in modeling of a monogenic form of severe obesity: PCSK1 deficiency. We generated PCSK1 (PC1/3)-deficient human embryonic stem cell (hESC) lines using both shRNA and CRISPR-Cas9, and investigated pro-opiomelanocortin (POMC) processing using hESC-differentiated hypothalamic neurons.

2017-01-31 | GSE89503 | GEO

Identification of the hypothalamic neuronal populations that derive from Pomc-expressing precursors

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.

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Histone lactylation mediated by Fam172a in POMC neurons regulates energy balance [CUT&TAG]

Project description:Glycolysis-derived lactate was identified as substrate for histone lactylation, which has been regarded as a significant role in transcriptional regulation in many tissues. However, the role of histone lactylation in the metabolic center, the hypothalamus, is still unknown. Here, we show that hypothalamic pro-opiomelanocortin (POMC) neuron-specific deletion of family with sequence similarity 172, member A (Fam172a) can increase histone lactylation and protect mice against diet-induced obesity (DIO) and related metabolic disorders. Conversely, overexpression of Fam172a in POMC neurons led to an obesity-like phenotype. Using RNA-seq and CUT&Tag chromatin profiling analyses, we find that knockdown of Fam172a activates the glycolytic process and increases peptidylglycine α-amidating monooxygenase (PAM), which affects the synthesis of α-MSH, via H4K12la (histone lactylation). In addition, pharmacological inhibition of lactate production clearly abrogates the anti-obesity effect of PFKO (POMC-Cre, Fam172aloxP/loxP, POMC neurons Fam172a knockout). These findings highlight the importance of Fam172a and lactate in the development of obesity.

2024-11-06 | GSE280695 | GEO

Histone lactylation mediated by Fam172a in POMC neurons regulates energy balance [RNA-seq]

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Comparative transcriptomic analyses of developing melanocortin neurons reveal new regulators for the anorexigenic neuron identity

Project description:Despite their opposing actions on food intake, POMC and NPY/AgRP neurons in the arcuate nucleus of the hypothalamus (ARH) are derived from the same progenitors that give rise to ARH neurons. However, the mechanism whereby common neuronal precursors subsequently adopt either the anorexigenic (POMC) or the orexigenic (NPY/AgRP) identity remains elusive.We hypothesize that POMC and NPY/AgRP cell fates are specified and maintained by distinct intrinsic factors. In search of them, we profiled the transcriptomes of developing POMC and NPY/AgRP neurons in E15.5 mice embryos. Moreover, cell-type-specific transcriptomic analyses revealed transcription regulators that are selectively enriched in either population, but whose developmental functions are unknown in these neurons.Among them, we found the expression of the PR domain-containing factor 12 (Prdm12) was enriched in POMC neurons but absent in NPY/AgRP neurons. To study the role of Prdm12 in vivo, we developed and characterized a floxed Prdm12 allele. Selective ablation of Prdm12 in embryonic POMC neurons led to significantly reduced Pomc expression as well as early-onset obesity in mice of either sex that recapitulates symptoms of human POMC deficiency. Interestingly, however, specific deletion of Prdm12 in adult POMC neurons showed that it is no longer required for Pomc expression nor energy balance. Collectively, these findings establish a critical role for Prdm12 in the anorexigenic neuron identity and suggest that it acts developmentally to program body weight homeostasis. Finally, the combination of cell-type-specific genomic and genetic analyses provides a means to dissect cellular and functional diversity in the hypothalamus whose neurodevelopment remains poorly studied.

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2024-03-28 | PXD044227 | Pride

Reduced a-MSH underlies hypothalamic endoplasmic reticulum stress-induced hepatic gluconeogenesis

Project description:Alterations in endoplasmic reticulum (ER) homeostasis have been implicated in the pathophysiology of obesity and type-2 diabetes (T2D). Acute ER stress induction in the hypothalamus produces glucose metabolism perturbations. However, the neurobiological basis linking hypothalamic ER stress with abnormal glucose metabolism remains unknown. Here we report that genetic and induced models of hypothalamic ER stress are associated with alterations in systemic glucose homeostasis due to increased gluconeogenesis (GNG) independent of body weight changes. Defective alpha melanocyte-stimulating hormone (a-MSH) production underlies this metabolic phenotype, as pharmacological strategies aimed at rescuing hypothalamic a-MSH content reversed this phenotype at metabolic and molecular level. Collectively, our results posit defective a-MSH processing as a fundamental mediator of enhanced GNG in the context of hypothalamic ER stress, and establish a-MSH deficiency in proopiomelanocortin (POMC) neurons as a potential contributor to the pathophysiology of T2D. Total RNA was extracted from whole-liver of 6-week old control (3 biological replicates) and POMCMfn2KO mice (5 biological replicates)

2015-06-18 | E-GEOD-62263 | biostudies-arrayexpress

Identification of the hypothalamic neuronal populations that derive from Pomc-expressing precursors

2015-04-16 | GSE56917 | GEO

A neural basis for melanocortin-4 receptor-regulated appetite.

Project description:Pro-opiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons of the arcuate nucleus of the hypothalamus (ARC) are oppositely regulated by caloric depletion and coordinately stimulate and inhibit homeostatic satiety, respectively. This bimodality is principally underscored by the antagonistic actions of these ligands at downstream melanocortin-4 receptors (MC4R) in the paraventricular nucleus of the hypothalamus (PVH). Although this population is critical to energy balance, the underlying neural circuitry remains unknown. Using mice expressing Cre recombinase in MC4R neurons, we demonstrate bidirectional control of feeding following real-time activation and inhibition of PVH(MC4R) neurons and further identify these cells as a functional exponent of ARC(AgRP) neuron-driven hunger. Moreover, we reveal this function to be mediated by a PVH(MC4R)→lateral parabrachial nucleus (LPBN) pathway. Activation of this circuit encodes positive valence, but only in calorically depleted mice. Thus, the satiating and appetitive nature of PVH(MC4R)→LPBN neurons supports the principles of drive reduction and highlights this circuit as a promising target for antiobesity drug development.

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Decoding the origin of neuronal diversity in hypothalamus by single-cell RNA-seq

Project description:The hypothalamus is one of the most complex brain structures whose development involves a plastic process of neuronal fate specification. Progress has been made to decipher the gene regulatory programs that are responsible for hypothalamus development; however, the molecular developmetal trajectory of hyothalamus is largely unknown. To understand how pre- and postmitotic transcriptional programs interact and coordinate to endow neuronal cell subtypes with their characteristic properties during hypothalamic development, we performed single-cell RNA sequencing (scRNA-seq) on single cells derived from Rax+ hypothalamic neuroepithelium at four critical developmental points during hypothalamic development. Our single-cell analysis provides a developmental landscape of mouse hypothalamus. We show that while the fate of radial glial cells (RGCs) is predetermined before differentiation but lack spatial code to distinguish from each other, different clusters of intermediate progenitors (IPCs) emerge to display diversifying fates and subdivide hypothalamic primordium into distinct spatially-restricted progenitor domains. We further characterize the maturation dynamics of hypothalamic neurons and suggest that immature neurons could evolve into multiple peptidergic neuronal subtypes. Finally, we identify sets of transcription factors (TFs) serving as regulons to determine the fate of diverse GABAergic and Glutamatergic neurons in hypothalamus. Together, our study offers a single-cell transcriptional framework for the hypothalamus developmental trajectory and propose a cascade diversifying model to deconstruct the origin of neuronal diversity in hypothalamus.

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