Transcription factor cascades during fasting amplify gluconeogenesis and instigate a secondary wave of ketogenic gene transcription.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE252320 | GEO | 2024/08/18
REPOSITORIES: GEO
Similar Datasets
Project description:During fasting, bodily homeostasis is maintained due to hepatic production of glucose (via gluconeogenesis) and ketone bodies (via ketogenesis). The major hormones governing hepatic fuel production are glucagon and glucocorticoids who initiate a complex transcriptional program aimed at supporting gluconeogenesis and ketogenesis. Here, we found that in addition to the known metabolic genes induced by glucagon and glucocorticoids, these hormones each induce a set of genes encoding transcription factors (TFs) thereby initiating transcriptional cascades. Glucocorticoids activate the glucocorticoid receptor (GR) that induces the genes encoding two TFs - C/EBPβ and PPARα. Transcriptomic analysis combined with gene silencing revealed the role of C/EBPβ as an amplifier of hormone-induced gluconeogenesis. In contrast, the GR-PPARα cascade initiated a secondary transcriptional wave of genes supporting ketogenesis. We show that a dual treatment of glucocorticoids with a PPARα agonist leads to synergistic induction of ketogenic genes and that this induction is dependent on protein synthesis. Genome-wide analysis of enhancer dynamics revealed numerous enhancers activated by the GR-PPARα cascade. These enhancers are proximal to ketogenic genes, are enriched for the PPARα binding motif and show increased PPARα binding as profiled by ChIP-seq. In summary, this study reveals abundant TF cascades occurring during fasting. These cascades serve two separated purposes: the amplification of the primary gluconeogenic transcriptional program and the induction of a secondary gene program aimed at enhancing ketogenesis.
2024-08-18 | GSE252319 | GEO
Project description:During fasting, bodily homeostasis is maintained due to hepatic production of glucose (via gluconeogenesis) and ketone bodies (via ketogenesis). The major hormones governing hepatic fuel production are glucagon and glucocorticoids who initiate a complex transcriptional program aimed at supporting gluconeogenesis and ketogenesis. Here, we found that in addition to the known metabolic genes induced by glucagon and glucocorticoids, these hormones each induce a set of genes encoding transcription factors (TFs) thereby initiating transcriptional cascades. Glucocorticoids activate the glucocorticoid receptor (GR) that induces the genes encoding two TFs - C/EBPβ and PPARα. Transcriptomic analysis combined with gene silencing revealed the role of C/EBPβ as an amplifier of hormone-induced gluconeogenesis. In contrast, the GR-PPARα cascade initiated a secondary transcriptional wave of genes supporting ketogenesis. We show that a dual treatment of glucocorticoids with a PPARα agonist leads to synergistic induction of ketogenic genes and that this induction is dependent on protein synthesis. Genome-wide analysis of enhancer dynamics revealed numerous enhancers activated by the GR-PPARα cascade. These enhancers are proximal to ketogenic genes, are enriched for the PPARα binding motif and show increased PPARα binding as profiled by ChIP-seq. In summary, this study reveals abundant TF cascades occurring during fasting. These cascades serve two separated purposes: the amplification of the primary gluconeogenic transcriptional program and the induction of a secondary gene program aimed at enhancing ketogenesis.
2024-08-18 | GSE252317 | GEO
Project description:During fasting, bodily homeostasis is maintained due to hepatic production of glucose (via gluconeogenesis) and ketone bodies (via ketogenesis). The major hormones governing hepatic fuel production are glucagon and glucocorticoids who initiate a complex transcriptional program aimed at supporting gluconeogenesis and ketogenesis. Here, we found that in addition to the known metabolic genes induced by glucagon and glucocorticoids, these hormones each induce a set of genes encoding transcription factors (TFs) thereby initiating transcriptional cascades. Glucocorticoids activate the glucocorticoid receptor (GR) that induces the genes encoding two TFs - C/EBPβ and PPARα. Transcriptomic analysis combined with gene silencing revealed the role of C/EBPβ as an amplifier of hormone-induced gluconeogenesis. In contrast, the GR-PPARα cascade initiated a secondary transcriptional wave of genes supporting ketogenesis. We show that a dual treatment of glucocorticoids with a PPARα agonist leads to synergistic induction of ketogenic genes and that this induction is dependent on protein synthesis. Genome-wide analysis of enhancer dynamics revealed numerous enhancers activated by the GR-PPARα cascade. These enhancers are proximal to ketogenic genes, are enriched for the PPARα binding motif and show increased PPARα binding as profiled by ChIP-seq. In summary, this study reveals abundant TF cascades occurring during fasting. These cascades serve two separated purposes: the amplification of the primary gluconeogenic transcriptional program and the induction of a secondary gene program aimed at enhancing ketogenesis.
2024-08-18 | GSE252318 | GEO
Project description:Transcription factor cascades during fasting amplify gluconeogenesis and instigate a secondary wave of ketogenic gene transcription.
| PRJNA1059634 | ENA
Project description:Transcription factor cascades during fasting amplify gluconeogenesis and instigate a secondary wave of ketogenic gene transcription. [ChIP-Seq]
| PRJNA1059637 | ENA
Project description:Transcription factor cascades during fasting amplify gluconeogenesis and instigate a secondary wave of ketogenic gene transcription. [RNA-Seq 1]
| PRJNA1059636 | ENA
Project description:Transcription factor cascades during fasting amplify gluconeogenesis and instigate a secondary wave of ketogenic gene transcription. [RNA-Seq 2]
| PRJNA1059635 | ENA
Project description:Krüppel-like factor 14 (KLF14) is a member of the Cys2/His2 zinc-finger DNA-binding proteins. Despite strong evidence showing that a polymorphism in the Klf14 gene is closely linked to the development of type 2 diabetes, the physiological and metabolic functions of KLF14 still remain unclear. In the present study, we investigated the role of KLF14 in the regulation of hepatic gluconeogenesis. Adenoviruses expressing KLF14 (Ad-Klf14) or KLF14-specific shRNAs (Ad-shKlf14) were injected into normal C57BL/6J, db/db diabetic, or high-fat diet-induced obese (DIO) mice. Gene expression, hepatic glucose production, glucose tolerance, and insulin resistance were tested in C57BL/6J, db/db, and DIO mice and primary hepatocytes. Our results demonstrate that KLF14 expression is induced in the livers of normal C57BL/6J mice upon fasting and significantly up-regulated in the livers of db/db mice, suggesting a physiological link between KLF14 and gluconeogenesis. Adenovirus-mediated overexpression of KLF14 in primary hepatocytes increased both the mRNA and protein levels of peroxisome proliferator-activated receptor-γ coactivator 1α (Pgc-1α, also known as Ppargc1a), thereby stimulating cellular glucose production. Conversely, knockdown of KLF14 expression led to a reduction in PGC-1α, subsequently inhibiting glucose output in primary hepatocytes. Finally, forced expression of KLF14 in the livers of normal mice increased the plasma glucose levels and impaired glucose tolerance; in contrast, KLF14 knockdown in diabetic mouse livers improved glucose tolerance. Taken together, our data strongly indicate that KLF14 modulates hepatic gluconeogenesis.
| S-EPMC5766972 | biostudies-literature
Project description:Hepatic gluconeogenesis is essential to maintain blood glucose levels, and its abnormal activation leads to hyperglycemia and type 2 diabetes. However, the molecular mechanisms in the regulation of hepatic gluconeogenesis remain to be fully defined. In this study, using murine hepatocytes and a liver-specific knockout mouse model, we explored the physiological role of nuclear factor Y (NF-Y) in regulating hepatic glucose metabolism and the underlying mechanism. We found that NF-Y targets the gluconeogenesis pathway in the liver. Hepatic NF-Y expression was effectively induced by cAMP, glucagon, and fasting in vivo Lentivirus-mediated NF-Y overexpression in Hepa1-6 hepatocytes markedly raised the gluconeogenic gene expression and cellular glucose production compared with empty vector control cells. Conversely, CRISPR/Cas9-mediated knockdown of NF-Y subunit A (NF-YA) attenuated gluconeogenic gene expression and glucose production. We also provide evidence indicating that CRE-loxP-mediated, liver-specific NF-YA knockout compromises hepatic glucose production. Mechanistically, luciferase reporter gene assays and ChIP analysis indicated that NF-Y activates transcription of the gluconeogenic genes Pck1 and G6pc, by encoding phosphoenolpyruvate carboxykinase (PEPCK) and the glucose-6-phosphatase catalytic subunit (G6Pase), respectively, via directly binding to the CCAAT regulatory sequence motif in their promoters. Of note, NF-Y enhanced gluconeogenesis by interacting with cAMP-responsive element-binding protein (CREB). Overall, our results reveal a previously unrecognized physiological function of NF-Y in controlling glucose metabolism by up-regulating the gluconeogenic genes Pck1 and G6pc Modulation of hepatic NF-Y expression may therefore offer an attractive therapeutic approach to manage type 2 diabetes.
| S-EPMC5961052 | biostudies-literature
Project description:Calorie restriction can be anticonvulsant in animal models. The ketogenic diet was designed to mimic calorie restriction and has been assumed to work by the same mechanisms. We challenged this assumption by profiling the effects of these dietary regimens in mice subjected to a battery of acute seizure tests.Juvenile male NIH Swiss mice received ketogenic diet or a normal diet fed in restricted quantities (continuously or intermittently) for ?12 days, starting at 3-4 weeks of age. Seizures were induced by the 6 Hz test, kainic acid, maximal electroshock, or pentylenetetrazol.The ketogenic and calorie-restricted diets often had opposite effects depending on the seizure test. The ketogenic diet protected from 6 Hz-induced seizures, whereas calorie restriction (daily and intermittent) increased seizure activity. Conversely, calorie restriction protected juvenile mice against seizures induced by kainic acid, whereas the ketogenic diet failed to protect. Intermittent caloric restriction worsened seizures induced by maximal electroshock but had no effect on those induced by pentylenetetrazol.In contrast to a longstanding hypothesis, calorie restriction and the ketogenic diet differ in their acute seizure test profiles, suggesting that they have different underlying anticonvulsant mechanisms. These findings highlight the importance of the 6 Hz test and its ability to reflect the benefits of ketosis and fat consumption.
| S-EPMC2999843 | biostudies-literature