Heterogeneity of hypothalamic Pro-opiomelanocortin-expressing neurons revealed by single-cell RNA sequencing
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE92707 | GEO | 2017/03/08
SECONDARY ACCESSION(S): PRJNA358404
REPOSITORIES: GEO
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Project description:Over recent decades, research has established the hypothalamus, particularly the arcuate nucleus, as a central hub for the homeostatic control of energy balance. The hypothalamic arcuate nucleus is a pivotal regulator of energy balance, containing anorexic proopiomelanocortin (POMC) neurons and orexigenic agouti-related peptide (AgRP) neurons, which exert opposing effects on energy homeostasis. However, the molecular identity of “non-AgRP, non-POMC” neurons remains unclear. We identified a distinct neuronal subtype characterized by the absence of Agrp and Pomc expressions, while exhibiting robust Crabp1 expression.
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Project description:Neurons in the hypothalamic arcuate nucleus (ARC) are fundamental regulators of energy homeostasis, growth and reproduction. Spatially overlapping subpopulations of ARC neurons produce specific neuropeptides including melanocortins, opioids, neuropeptide Y, growth hormone releasing hormone and kisspeptin. However, the developmental pathways controlling ARC neuron specification, differentiation and maturation remain poorly understood relative to more structurally ordered brain regions. Here, we analyzed the transcriptomes of individual mouse ARC neurons sorted for expression of a Proopiomelanocortin-Td-dsRed transgene at four embryonic (E11.5, E13.5, E15.5 and E17.5) and two postnatal (P5 and P12) ages. There was an unanticipated complexity of neurochemical subpopulations in the developing ARC characterized by low, medium or high levels of Pomc transcripts and distinct temporal patterns of transcription factor expression. Moreover, sizeable fractions of Pomc-positive neural progenitors differentiated into non-POMC neurons by P12. We conclude that ARC neuronal development is highly dynamic with plasticity that may be susceptible to environmental programming.
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Project description:<p>The central nervous system has been implicated in the age-induced reduction in adipose tissue lipolysis. SLC7A14 is a lysosomal membrane protein highly expressed in the brain. Herein, we investigated the possible role of hypothalamic SLC7A14 in the age-induced lipolysis reduction. In this study, we demonstrated the expression of SLC7A14 was reduced in proopiomelanocortin (POMC) neurons of aged mice. Overexpression of SLC7A14 in POMC neurons alleviated the age-induced reduction in white adipose tissue (WAT) lipolysis, whereas SLC7A14 deletion mimicked the age-induced lipolysis impairment. Moreover, POMC SLC7A14 regulated WAT lipolysis independently of sympathetic nerves in WAT. Metabolomics analysis revealed that POMC SLC7A14 increased the primary bile acid taurochenodeoxycholic acid (TCDCA) content, which mediated the SLC7A14 knockout- or age-induced WAT lipolysis impairment. Furthermore, SLC7A14-increased TCDCA content is dependent on intestinal apical sodium-dependent bile acid transporter (ASBT), which is regulated by intestinal sympathetic afferent nerves. Finally, SLC7A14 regulated the intestinal sympathetic afferent nerves by inhibiting mTORC1 signaling through inhibiting TSC1 phosphorylation. Collectively, our study suggests the function for central SLC7A14 and an upstream mechanism for the mTORC1 signaling pathway. Moreover, our data provides insights into the brain-gut-adipose tissue crosstalk in age-induced lipolysis impairment.</p>
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Project description:The relationship between loss of hypothalamic function and onset of diabetes mellitus remains elusive. Therefore, we generated a targeted oxidative-stress murine model utilizing conditional knockout of selenocysteine-tRNA (Trsp) using rat insulin promoter-driven-Cre (RIP-Cre). These Trsp-knockout (TrspRIPKO) mice exhibit deletion of Trsp in both hypothalamic cells and pancreatic β-cells leading to increased hypothalamic oxidative stress and severe insulin resistance. Leptin signals were suppressed and numbers of proopiomelanocortin-positive neurons in the hypothalamus were decreased. In contrast, a Trsp-knockout mouse (TrspIns1KO) expressing Cre specifically in pancreatic β-cells, but not in the hypothalamus, did not display insulin and leptin resistance, demonstrating a critical role of the hypothalamus in the onset of diabetes mellitus. Nrf2 (NF-E2-related-factor-2) regulates antioxidant gene expression. Gene-driven increase in Nrf2 signaling suppressed hypothalamic oxidative stress and improved insulin and leptin resistance in TrspRIPKO mice. Thus, Nrf2 harbors the potential to prevent the onset of diabetic mellitus by reducing hypothalamic oxidative damage.
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Project description:The relationship between loss of hypothalamic function and onset of diabetes mellitus remains elusive. Therefore, we generated a targeted oxidative-stress murine model utilizing conditional knockout of selenocysteine-tRNA (Trsp) using rat insulin promoter-driven-Cre (RIP-Cre). These Trsp-knockout (TrspRIPKO) mice exhibit deletion of Trsp in both hypothalamic cells and pancreatic β-cells leading to increased hypothalamic oxidative stress and severe insulin resistance. Leptin signals were suppressed and numbers of proopiomelanocortin-positive neurons in the hypothalamus were decreased. In contrast, a Trsp-knockout mouse (TrspIns1KO) expressing Cre specifically in pancreatic β-cells, but not in the hypothalamus, did not display insulin and leptin resistance, demonstrating a critical role of the hypothalamus in the onset of diabetes mellitus. Nrf2 (NF-E2-related-factor-2) regulates antioxidant gene expression. Gene-driven increase in Nrf2 signaling suppressed hypothalamic oxidative stress and improved insulin and leptin resistance in TrspRIPKO mice. Thus, Nrf2 harbors the potential to prevent the onset of diabetic mellitus by reducing hypothalamic oxidative damage.
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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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