The ventromedial hypothalamic nucleus: watchdog of whole-body glucose homeostasis

Tu, Longlong; Fukuda, Makoto; Tong, Qingchun; Xu, Yong

doi:10.1186/s13578-022-00799-2

Cited by 25 publications

(19 citation statements)

References 165 publications

(256 reference statements)

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“…Furthermore, we identified DEGs linked to synaptic organization and transduction (e.g. MYO16 (33), HS3ST4 (34), SORCS3 (35)), metabolism ( GCK (36)), neuronal survival, dendrite branching, axonal growth and neural projection in development (e.g. NSG1 (37), TMEM3C6 (38), TMOD1 (39), PLPPR4 (40), NEBL (41), NRN1 (42) and GFRA2 (43)) and channelopathies (e.g.…”

Section: Resultsmentioning

confidence: 99%

Multi-omics approach reveals dysregulated genes during hESCs neuronal differentiation exposure to paracetamol

Spildrejorde

Samara

Sharma

et al. 2022

Preprint

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Background: Several epidemiological studies have found associations between long-term prenatal exposure to paracetamol and neurodevelopmental outcomes in childhood. Pharmacoepigenetic studies have identified differences in DNA methylation (DNAm) in cord blood between exposed and unexposed neonates. However, the causal implications and impact of prenatal long-term paracetamol exposure on brain development are not known. Methods: We exposed human embryonic stem cells (hESCs) undergoing in vitro neuronal differentiation to daily changes of media containing amount of paracetamol corresponding to human foetal exposure with maternal therapeutic doses. An integrated multi-omics approach was used to investigate epigenetic and transcriptomic effects of paracetamol on the early stages of human brain development. Results: Multi-omics analyses of DNAm, chromatin opening, and gene expression identified dose-dependent effects on cell proliferation and maturation. We found differentially methylated and/or expressed genes involved in signal transduction, neurotransmitter secretion and cell fate determination trajectories. Integration of single-cell RNA-seq and ATAC-seq showed that paracetamol-induced changes in chromatin opening were linked to transcription. For example, EP300 encoding a histone acetyltransferase and H3K27ac were linked to many putative cis regulatory elements and downregulated upon paracetamol exposure. Some of the genes are involved in neuronal injury, response to toxic insults and development-specific pathways, such as KCNE3, overlapped with differentially methylated genes previously identified in cord blood associated with prenatal paracetamol exposure. Conclusion: We identified dose-dependent epigenetic and transcriptional changes in hESCs undergoing neuronal differentiation after paracetamol exposure. The overlap of differentially methylated genes with our previous analysis in cord blood from children exposed to paracetamol during pregnancy could suggest a causal role in impaired neurodevelopment.

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Section: Resultsmentioning

confidence: 99%

Multi-omics approach reveals dysregulated genes during hESCs neuronal differentiation exposure to paracetamol

Spildrejorde

Samara

Sharma

et al. 2022

Preprint

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“…Interestingly, we found a substantial amount of NMU neurons in the vlVMH overlapping with ERα, supporting the hypothesis that NMU plays a modulatory role in reproduction and energy expenditure 2,77,78 . However, NMU neurons were found not only in the vlVMH, but throughout all three subdivisions of the VMH, in contrast with many other neuronal subpopulations identified in this nucleus, such as the aforementioned ERα, leptin receptor, pituitary adenylate cyclase-activating peptide (PACAP) or cholecystokinin receptor B (CCKBR), among others 79,80 . The expression pattern of NMU neurons in the VMH and ARC, the limited colocalization with ERα in both regions, and the absence of colocalization with other welldescribed hypothalamic markers, such as POMC and NPY, suggest that NMU neurons constitute mainly a unique population of hypothalamic cells.…”

Section: Discussionmentioning

confidence: 97%

Neuroanatomical characterization of the Nmu-Cre knock-in mice reveals an interconnected network of unique neuropeptidergic cells

Medrano

Allaoui

Bulck

et al. 2023

Preprint

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Neuromedin U (NMU) is an evolutionary conserved neuropeptide that has been implicated in multiple processes, such as circadian regulation, energy homeostasis, reward processing and stress coping. Although central expression of NMU has been addressed previously, the lack of specific and sensitive tools has prevented a comprehensive characterization of NMU-expressing neurons in the brain. We have generated a knock-in mouse model constitutively expressing Cre recombinase under the Nmu promoter. We have validated the model using a multi-level approach based on quantitative reverse-transcription polymerase chain reactions, in situ hybridization, a reporter mouse line and an adenoviral vector driving Cre-dependent expression of a fluorescent protein. Using the Nmu-Cre mouse, we performed a complete mapping of NMU expression in adult mouse brain, unveiling a potential midline NMU modulatory circuit with the ventromedial hypothalamic nucleus (VMH) as a key node. Moreover, immunohistochemical analysis suggested that NMU neurons in the VMH mainly constitute a unique population of hypothalamic cells. Taken together, our results suggest that Cre expression in the Nmu-Cre mouse model largely reflects NMU expression in the adult mouse brain, without altering endogenous NMU expression. Thus, the Nmu-Cre mouse model is a powerful and sensitive tool to explore the role of NMU neurons in mice.

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“…Hence, hyperglycemia in trappc9 KO mice is unlikely to stem from insulin resistance or dysregulated insulin secretion. The brain contains a distinct set of neurons that sense and respond to changes of the blood glucose level and plays a key role in re-setting the range of blood glucose (85)(86)(87). Glucose-sensing neurons are enriched in the hypothalamic areas and also present in other brain regions including the striatum and the hippocampus (85)(86)(87)(88), which are altered in trappc9 KO mice (40).…”

Section: Discussionmentioning

confidence: 99%

Chronic pharmacologic manipulation of dopamine transmission ameliorates metabolic disturbance in syndrome caused by mutated trappc9

Li,

Usman,

Sapp

et al. 2024

Preprint

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Loss-of-function mutations of the gene encoding the trafficking protein particle complex subunit 9 (trappc9) cause intellectual disability and obesity by unknown mechanisms. Genome-wide analysis links trappc9 to non-alcoholic fatty liver disease (NAFLD). Trappc9-deficient mice gain body weight normally in early developmental periods but become overweight shortly after being weaned. Here, we report that trappc9 deficiency in mice disrupts systemic glucose homeostasis and triggers the onset of obesity and NAFLD. Chronic treatment combining drugs suppressing dopamine receptor D1 (DRD1) and stimulating DRD2 restores systemic glucose homeostasis and counteracts abnormal body weight gain and lipid accumulation in adipose and liver tissues in trappc9-deficient mice. Additional pharmacological studies imply that the disruption of systemic glucose homeostasis in trappc9-deficient mice originates from deficient stimulation of DRD2 in the brain. Transcriptomic and proteomic analyses reveal signs of impairments in dopamine secretion in trappc9-deficient mice. Brain examinations indicate that trappc9-deficient mice synthesize dopamine normally, but their dopamine-secreting neurons have a lower abundance of structures for releasing dopamine. Our study suggests that trappc9 loss-of-function causes obesity and NAFLD by constraining dopamine neurotransmission.

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The ventromedial hypothalamic nucleus: watchdog of whole-body glucose homeostasis

Cited by 25 publications

References 165 publications

Multi-omics approach reveals dysregulated genes during hESCs neuronal differentiation exposure to paracetamol

Multi-omics approach reveals dysregulated genes during hESCs neuronal differentiation exposure to paracetamol

Neuroanatomical characterization of the Nmu-Cre knock-in mice reveals an interconnected network of unique neuropeptidergic cells

Chronic pharmacologic manipulation of dopamine transmission ameliorates metabolic disturbance in syndrome caused by mutated trappc9

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