TOX3 drives hepatic gluconeogenesis and hyperglycemia by targeting FoxO1 [RNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE228790 | GEO | 2024/01/22
REPOSITORIES: GEO
Similar Datasets
Project description:Purpose: The goals of this study are to explore role of Tox3 in glucose homeostasis Methods: Tox3-activation was generated by adenovirus from Genechem.Successful activation of Tox3 was determined by mRNA and protein expression.
2024-01-22 | GSE228791 | GEO
Project description:TOX3 drives hepatic gluconeogenesis and hyperglycemia by targeting FoxO1
| PRJNA951639 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-01-22 | GSE228792 | GEO
Project description:TOX3 drives hepatic gluconeogenesis and hyperglycemia by targeting FoxO1 [ChIP-seq]
| PRJNA951644 | ENA
Project description:TOX3 drives hepatic gluconeogenesis and hyperglycemia by targeting FoxO1 [RNA-seq]
| PRJNA951645 | ENA
Project description:Organ development relies on precise transcriptional control, yet how lineage-defining factors like Atoh1/Math1 drive robust gene expression despite weak intrinsic transactivation activity remains unclear. Here, we present a comprehensive atlas profiling 1,904 transcription regulators across organs, uncovering TOX3 as a potential co-activator of Atoh1 in cerebellar granule neuron progenitors. Tox3-deficient mice display severe ataxia and cerebellar hypoplasia, driven by depletion of granule neuron progenitors, diminished Atoh1 expression, and impaired primary cilia. Single-nucleus RNA-seq analyses reveals compromised maintenance of the progenitor pool. TOX3 is also highly expressed in subsets of medulloblastoma, and its deletion reduces cerebellar neoplasia and prolongs survival in a mouse model. Mechanistically, Tox3 and Atoh1 co-occupy and synergistically activate E-boxes in shared target genes by up to 120-fold, including an ultra-conserved E-box downstream of Atoh1. These findings establish Tox3 as a critical Atoh1 co-activator in cerebellar development, tumorigenesis and evolution, and provides a resource for exploring novel transcriptional regulators in progenitor maintenance and organogenesis.
2026-03-19 | GSE312741 | GEO
Project description:Dual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B), a member of the CMGC group of kinase, is associated with metabolic syndrome. However, the molecular mechanisms involved remain elusive. In this study, we demonstrate that Dyrk1b expression is induced in liver by fasting and in diabetic mice. Using both in vivo and in vitro studies, we show that DYRK1B promotes hepatic gluconeogenesis and glucose intolerance. Liver-specific Dyrk1b conditional knockout mice were protected from diet-induced hyperglycemia. Mechanistically, DYRK1B interacts with and phosphorylates FOXO1, primarily at Thr467/Ser468, which is essential for its nuclear localization. Additionally, DYRK1B inhibits AKT mediated FOXO1 phosphorylation at Thr24 and Ser256, thereby enhancing its nuclear retention. DYRK1B mediated phosphorylation enhances the expression of gluconeogenic genes and promotes gluconeogenesis. Further, a pharmacological inhibitor of DYRK1B significantly reduced blood glucose levels in diabetic mice. Collectively, these findings offer new insights into DYRK1B’s role in the glucose metabolism and identify it as a new therapeutic target for treating diabetes.
2025-05-07 | PXD052214 | Pride
Project description:Patients with diabetes suffer disproportionately from impaired lipid metabolism and cardiovascular disease, but the relevant roles of insulin resistance and hyperglycemia in these processes are unclear. Transcription factor FoxO1 is regulated dually by insulin and nutrients. In this study, we addressed the hypothesis that, in addition to its established role to regulate hepatic glucose production, FoxO1 controls aspects of lipid metabolism in the diabetic liver. Mice with a liver-specific deletion of FoxO1 (L-FoxO1) and their control littermates were rendered hyperglycemic by streptozotocin administration. Subsequently, we monitored serum lipids, liver VLDL secretion, and hepatic expression of genes related to lipid metabolism. Hepatic FoxO1 ablation resulted in increased VLDL secretion, increased cholesterol, and increased plasma free fatty acids, three hallmarks of the diabetic state. l-FoxO1 mice expressed increased levels of SREBP-2 and FGF21 without affecting lipogenic genes. We propose that FoxO1 fine tunes lipolysis through its actions on FGF21 and that hepatic FoxO1 ablation increases availability of substrates for hepatic triglyceride and cholesterol synthesis and VLDL secretion. The implications of these findings are that FoxO1 protects against excessive hepatic lipid production during hyperglycemia and that its inhibition by intensive insulin treatment may exacerbate paradoxically the lipid abnormalities of diabetes.
| S-EPMC2930685 | biostudies-literature
Project description:Obesity and its associated metabolic disorders, including type 2 diabetes and fatty liver disease, represent a growing global health burden. Although the hypothalamus is well-established as the central regulator of energy homeostasis through specialized neuronal circuits, the molecular mechanisms governing these pathways remain incompletely elucidated. In this study, we identify thymocyte selection-associated high mobility group box 3 (TOX3) as a critical metabolic regulator in pro-opiomelanocortin (POMC) neurons of the arcuate nucleus. By employing cell-type-specific genetic manipulation in murine models, we establish that conditional TOX3 ablation in POMC neurons exacerbates diet-induced obesity and metabolic dysfunction, while its overexpression in these neurons confers robust metabolic benefits. Mechanistically, TOX3 enhances POMC neuronal function via a novel post-translational regulatory mechanism involving PTEN proteasomal degradation, leading to potentiated AKT signaling. This central modulation drives sympathetic activation of adipose tissues, resulting in enhanced lipid mobilization and energy expenditure. Notably, TOX3 exhibits striking neuronal specificity, as both loss- and gain-of-function manipulation in agouti-related peptide (AgRP) neurons produce negligible metabolic consequences. Our work identifies previously unrecognized physiological roles of TOX3 in POMC neurons that are essential for maintaining energy homeostasis, thereby revealing novel therapeutic opportunities for metabolic disorders.
2026-03-03 | GSE308694 | GEO
Project description:Organ development relies on precise transcriptional control, yet how lineage-defining factors like Atoh1/Math1 drive robust gene expression despite weak intrinsic transactivation activity remains unclear. Here, we present a comprehensive atlas profiling 1,904 transcription regulators across organs, uncovering TOX3 as a potential co-activator of Atoh1 in cerebellar granule neuron progenitors. Tox3-deficient mice display severe ataxia and cerebellar hypoplasia, driven by depletion of granule neuron progenitors, diminished Atoh1 expression, and impaired primary cilia. Single-nucleus RNA-seq analyses reveals compromised maintenance of the progenitor pool. TOX3 is also highly expressed in subsets of medulloblastoma, and its deletion reduces cerebellar neoplasia and prolongs survival in a mouse model. Mechanistically, Tox3 and Atoh1 co-occupy and synergistically activate E-boxes in shared target genes by up to 120-fold, including an ultra-conserved E-box downstream of Atoh1. These findings establish Tox3 as a critical Atoh1 co-activator in cerebellar development, tumorigenesis and evolution, and provides a resource for exploring novel transcriptional regulators in progenitor maintenance and organogenesis.
2026-03-19 | GSE312655 | GEO