Non-cell autonomous control of liver autophagy via nutrient sensing AgRP neurons
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE188472 | GEO | 2023/05/17
REPOSITORIES: GEO
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Project description:Autophagy represents a key regulator of aging and metabolism upon cell autonomous sensing of energy deprivation. We find that fasting in mice activates autophagy in liver paralleled by activation of hypothalamic AgRP neurons. Optogenetic and chemogenetic activation of AgRP neurons induces autophagy, alters phosphorylation of autophagy regulators and promotes ß-oxidation in the liver. AgRP neuron dependent induction of liver autophagy relies on NPY expression in these neurons. AgRP neuron projections in the paraventricular nucleus of the hypothalamus (PVH) and the lateral hypothalamus (LHA) mediate AgRP neuron-dependent control of liver autophagy. Conversely, inhibiting AgRP neurons during energy deprivation abrogates induction of hepatic autophagy and re-wiring of metabolism. Finally, AgRP neuron activation increases circulating corticosterone concentrations, and reduction of hepatic glucocorticoid receptor expression attenuates AgRP neuron-dependent activation of hepatic autophagy. Collectively, our study reveals a fundamental regulatory principle of non-cell autonomous control of liver autophagy in control of metabolic adaptation during nutrient deprivation.
2023-04-18 | PXD029247 | Pride
Project description:Hypothalamic neurons expressing Agouti-related peptide (AgRP) are critical for initiating food intake, but druggable biochemical pathways that control this response remain elusive. Thus, genetic ablation of insulin or leptin signaling in AgRP neurons is predicted to reduce satiety but fails to do so. FoxO1 is a shared mediator of both pathways, and its inhibition is required to induce satiety. Accordingly, FoxO1 ablation in AgRP neurons of mice results in reduced food intake, leanness, improved glucose homeostasis, and increased sensitivity to insulin and leptin. Expression profiling of flow-sorted FoxO1-deficient AgRP neurons identifies G-protein-coupled receptor Gpr17 as a FoxO1 target whose expression is regulated by nutritional status. Intracerebroventricular injection of Gpr17 agonists induces food intake, whereas Gpr17 antagonist cangrelor curtails it. These effects are absent in Agrp-Foxo1 knockouts, suggesting that pharmacological modulation of this pathway has therapeutic potential to treat obesity. We used microarrays to detail the change of gene expression in AgRP neurons after knocking out FoxO1. AgRP neurons from control and KO mice were collected by FACS. Gene expression was analyzed by microarray.
2013-04-09 | E-GEOD-45858 | biostudies-arrayexpress
Project description:Translation initiation factors have complex functions in cells which are not yet understood. We show that depletion of initiation factor eIF4GI only modestly reduces overall protein synthesis in cells, but phenocopies nutrient-starvation or inhibition of protein kinase mTOR, a key nutrient sensor. eIF4GI depletion impairs cell proliferation, bioenergetics and mitochondrial activity, thereby promoting autophagy. Translation of mRNAs involved in cell growth, proliferation and bioenergetics were selectively inhibited by reduction of eIF4GI, whereas mRNAs encoding proliferation inhibitors and catabolic pathway factors were increased. Depletion or over-expression of other eIF4G family members did not recapitulate these results. The majority of mRNAs that were translationally impaired with eIF4GI depletion were excluded from polyribosomes due to the presence of multiple upstream open reading frames and low mRNA abundance. These results suggest that the high levels of eIF4GI observed in many breast cancers might act to specifically increase proliferation, prevent autophagy and release tumor cells from control by nutrient sensing. Global regulation of transcription and polysomal association in eIF4GI-silenced cells. Keywords: Gene Silencing
2008-04-01 | GSE11011 | GEO
Project description:We have found that acute activation of AgRP-neurons lead to inhibition of insulin-stimulated glucose uptake into BAT. Based on this finding, we asked whether this effect was accompanied by acute changes in gene expression, which could point to the mechanism(s) underlying the impaired insulin sensitivity. In summary, our data suggest that activation of AgRP-neurons actuely reprograms gene expression in BAT towards a myogenic profile. The arcuate nucleus of 4 mice expressing channelrhodopsin 2 in AgRP-neurons through Cre-mediated recombination (ChR2-AgRP) and 4 Cre-negative controls (ChR2-fl/WT, Ctrl), were stimulated with blue laser light for one hour, total RNA from BAT was isolated and subjected to a microarray-based gene expression analysis.
2016-02-10 | E-GEOD-77766 | biostudies-arrayexpress
Project description:Hypothalamic neurons expressing Agouti-related peptide (AgRP) are critical for initiating food intake, but druggable biochemical pathways that control this response remain elusive. Thus, genetic ablation of insulin or leptin signaling in AgRP neurons is predicted to reduce satiety but fails to do so. FoxO1 is a shared mediator of both pathways, and its inhibition is required to induce satiety. Accordingly, FoxO1 ablation in AgRP neurons of mice results in reduced food intake, leanness, improved glucose homeostasis, and increased sensitivity to insulin and leptin. Expression profiling of flow-sorted FoxO1-deficient AgRP neurons identifies G-protein-coupled receptor Gpr17 as a FoxO1 target whose expression is regulated by nutritional status. Intracerebroventricular injection of Gpr17 agonists induces food intake, whereas Gpr17 antagonist cangrelor curtails it. These effects are absent in Agrp-Foxo1 knockouts, suggesting that pharmacological modulation of this pathway has therapeutic potential to treat obesity. We used microarrays to detail the change of gene expression in AgRP neurons after knocking out FoxO1.
2013-04-09 | GSE45858 | GEO
Project description:Objective: The central melanocortin system is essential for the regulation of food intake and body weight. Agouti-related protein (AgRP) is the sole orexigenic component of the central melanocortin system and is conserved across mammalian species. AgRP is currently known to be expressed exclusively in the mediobasal hypothalamus, and hypothalamic AgRP-expressing neurons are essential for feeding. Here we characterized a previously unknown population of AgRP cells in the mouse hindbrain. Methods: Expression of AgRP in the hindbrain was investigated using gene expression analysis, single-cell RNA sequencing, immunofluorescent analysis and multiple transgenic mice with reporter expressions. Activation of AgRP neurons was achieved by Designer Receptors Exclusively Activated by Designer Drugs (DREADD) and by transcranial focal photo-stimulation using a step-function opsin with ultra-high light sensitivity (SOUL). Results: AgRP expressing cells were present in the area postrema (AP) and the adjacent subpostrema area (SubP) and commissural nucleus of the solitary tract (cNTS) of the mouse hindbrain (termed AgRPHind herein). AgRPHind cells consisted of locally projecting neurons as well as tanycyte-like cells. Food deprivation stimulated hindbrain Agrp expression as well as neuronal activity of subsets of AgRPHind cells. In adult mice that lacked hypothalamic AgRP neurons, chemogenetic activation of AgRP neurons resulted in hyperphagia and weight gain. In addition, transcranial focal photo-stimulation of hindbrain AgRP cells increased food intake in adult mice with or without hypothalamic AgRP neurons. Conclusions: Our study indicates that the central melanocortin system in the hindbrain possesses an orexigenic component, and that AgRPHind neurons stimulate feeding independently of hypothalamic AgRP neurons.
2024-01-23 | GSE204865 | GEO
Project description:Macroautophagy (hereafter autophagy) is the major pathway by which macromolecules and organelles are degraded. Autophagy is regulated by the mTOR signaling pathway, which is the focal point for integration of metabolic information, with mTORC1 playing a central role in balancing biosynthesis and catabolism. Of the various inputs to mTORC1, the amino acid sensing pathway is among the most potent. Based upon transcriptome analysis of neurons subjected to nutrient deprivation, we identified let-7 as a microRNA capable of promoting neuronal autophagy. We found that let-7 activates autophagy by coordinately down-regulating the amino acid sensing pathway to prevent mTORC1 activation. Let-7 induced autophagy in the brain and greatly reduced protein aggregates in a lentivirus model of polyglutamine disease, establishing the physiological relevance of let-7 for in vivo autophagy modulation. Moreover, peripheral delivery of let-7 anti-miR repressed autophagy in muscle and white fat, suggesting that let-7 autophagy regulation extends beyond the CNS. Hence, let-7 plays a central role in nutrient homeostasis and proteostasis regulation in higher organisms. Using sets of wild-type C57BL/6J mice, we established primary cortical neuron cultures from P0 littermates, and cultured these neurons (n = 3 / set) in CM or NLM for 4 hrs.
2015-08-03 | E-GEOD-60452 | biostudies-arrayexpress
Project description:Translation initiation factors have complex functions in cells which are not yet understood. We show that depletion of initiation factor eIF4GI only modestly reduces overall protein synthesis in cells, but phenocopies nutrient-starvation or inhibition of protein kinase mTOR, a key nutrient sensor. eIF4GI depletion impairs cell proliferation, bioenergetics and mitochondrial activity, thereby promoting autophagy. Translation of mRNAs involved in cell growth, proliferation and bioenergetics were selectively inhibited by reduction of eIF4GI, whereas mRNAs encoding proliferation inhibitors and catabolic pathway factors were increased. Depletion or over-expression of other eIF4G family members did not recapitulate these results. The majority of mRNAs that were translationally impaired with eIF4GI depletion were excluded from polyribosomes due to the presence of multiple upstream open reading frames and low mRNA abundance. These results suggest that the high levels of eIF4GI observed in many breast cancers might act to specifically increase proliferation, prevent autophagy and release tumor cells from control by nutrient sensing. Global regulation of transcription and polysomal association in eIF4GI-silenced cells. Experiment Overall Design: Two sets of experiments are presented. First, overall transcriptome changes were determined for control or eIF4GI silenced cells. Next, mRNAs associated with polysomes were compared between control and eIF4GI silenced cells.
2008-06-11 | E-GEOD-11011 | biostudies-arrayexpress
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:Dietary habits and obesity in fathers imprint upon progeny through epigenetic signals carried by sperm RNA. By activating hypothalamic AgRP neurons in mice to mimic obesity's effects, we observed significant alterations in sperm tsRNAs, miRNAs, and rsRNAs. These changes, particularly in tsRNAs, mirror those seen with short-term high-fat diets, suggesting a shared upstream regulatory mechanism involving AgRP neurons that influence metabolic epigenetic inheritance.
2024-10-22 | GSE277621 | GEO