ArticleThe Journal of biological chemistry2017
Glucagon and Insulin Cooperatively Stimulate Fibroblast Growth Factor 21 Gene Transcription by Increasing the Expression of Activating Transcription Factor 4.
Article in The Journal of biological chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
19 citing papers in PubMed, 33 citations in OpenAlex.
- Meal sugar-protein balance determines postprandial FGF21 response in humans.American journal of physiology. Endocrinology and metabolism · 2023Trial
- Alterations in 3-Hydroxyisobutyrate and FGF21 Metabolism Are Associated With Protein Ingestion-Induced Insulin Resistance.Diabetes · 2017Trial
- FGF-based drug discovery: advances and challenges.Nature reviews. Drug discovery · 2025Review
- The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk.Nature communications · 2024Article
- LINC00894 Regulates Cerebral Ischemia/Reperfusion Injury by Stabilizing EIF5 and Facilitating ATF4-Mediated Induction of FGF21 and ACOD1 Expression.Neurochemical research · 2024Article
- FGF21 attenuates high uric acid‑induced endoplasmic reticulum stress, inflammation and vascular endothelial cell dysfunction by activating Sirt1.Molecular medicine reports · 2022Article
- Hepatic FGF21: Its Emerging Role in Inter-Organ Crosstalk and Cancers.International journal of biological sciences · 2022Review
- β-Hydroxybutyrate upregulates FGF21 expression through inhibition of histone deacetylases in hepatocytes.Open life sciences · 2022Article
- Hormonal regulation of glycine decarboxylase and its relationship to oxidative stress.Physiological reports · 2021Article
- OPA1 deletion in brown adipose tissue improves thermoregulation and systemic metabolism via FGF21.eLife · 2021Article
- FGF21 facilitates autophagy in prostate cancer cells by inhibiting the PI3K-Akt-mTOR signaling pathway.Cell death & disease · 2021Article
- Nutritional Regulation of Hepatic FGF21 by Dietary Restriction of Methionine.Frontiers in endocrinology · 2021Review
- Fibroblast Growth Factor 21 and the Adaptive Response to Nutritional Challenges.International journal of molecular sciences · 2019Review
- Intestinal serine protease inhibition increases FGF21 and improves metabolism in obese mice.American journal of physiology. Gastrointestinal and liver physiology · 2019Article
- Regulation of metabolic health by essential dietary amino acids.Mechanisms of ageing and development · 2019Review
- Hepatic Glucagon Receptor Signaling Enhances Insulin-Stimulated Glucose Disposal in Rodents.Diabetes · 2018Article
- Fibroblast growth factor 21 inhibits atherosclerosis in apoE-/- mice by ameliorating Fas-mediated apoptosis.Lipids in health and disease · 2018Article
- Article
- Diabetes and dyslipidemia: characterizing lipoprotein metabolism.Diabetes, metabolic syndrome and obesity : targets and therapy · 2017Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Previous studies have shown that glucagon cooperatively interacts with insulin to stimulate hepatic FGF21 gene expression. Here we investigated the mechanism by which glucagon and insulin increased FGF21 gene transcription in primary hepatocyte cultures. Transfection analyses demonstrated that glucagon plus insulin induction of FGF21 transcription was conferred by two activating transcription factor 4 (ATF4) binding sites in the FGF21 gene. Glucagon plus insulin stimulated a 5-fold increase in ATF4 protein abundance, and knockdown of ATF4 expression suppressed the ability of glucagon plus insulin to increase FGF21 expression. In hepatocytes incubated in the presence of insulin, treatment with a PKA-selective agonist mimicked the ability of glucagon to stimulate ATF4 and FGF21 expression. Inhibition of PKA, PI3K, Akt, and mammalian target of rapamycin complex 1 (mTORC1) suppressed the ability of glucagon plus insulin to stimulate ATF4 and FGF21 expression. Additional analyses demonstrated that chenodeoxycholic acid (CDCA) induced a 6-fold increase in ATF4 expression and that knockdown of ATF4 expression suppressed the ability of CDCA to increase FGF21 gene expression. CDCA increased the phosphorylation of eIF2α, and inhibition of eIF2α signaling activity suppressed CDCA regulation of ATF4 and FGF21 expression. These results demonstrate that glucagon plus insulin increases FGF21 transcription by stimulating ATF4 expression and that activation of cAMP/PKA and PI3K/Akt/mTORC1 mediates the effect of glucagon plus insulin on ATF4 expression. These results also demonstrate that CDCA regulation of FGF21 transcription is mediated at least partially by an eIF2α-dependent increase in ATF4 expression.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.