Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo
Abstract
The transcription factor, signal transducer and activator of transcription-3 (STAT-3) contributes to various physiological processes. Here we show that mice with liver-specific deficiency in STAT-3, achieved using the Cre-loxP system, show insulin resistance associated with increased hepatic expression of gluconeogenic genes. Restoration of hepatic STAT-3 expression in these mice, using adenovirus-mediated gene transfer, corrected the metabolic abnormalities and the alterations in hepatic expression of gluconeogenic genes. Overexpression of STAT-3 in cultured hepatocytes inhibited gluconeogenic gene expression independently of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha), an upstream regulator of gluconeogenic genes. Liver-specific expression of a constitutively active form of STAT-3, achieved by infection with an adenovirus vector, markedly reduced blood glucose, plasma insulin concentrations and hepatic gluconeogenic gene expression in diabetic mice. Hepatic STAT-3 signaling is thus essential for normal glucose homeostasis and may provide new therapeutic targets for diabetes mellitus.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Hepatocyte-specific STAT3 knockout causes insulin resistance and impaired liver regeneration.
“Insulin resistance; impaired liver regeneration”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Inoue et al., 2004
STAT3 in hepatocytes regulates glucose homeostasis by transcriptionally suppressing expression of gluconeogenic genes, e.g., glucose-6-phosphatase and phosphoenolpyruvate carboxykinase.
“which in turn regulates glucose homeostasis by transcriptionally suppressing (Ramadoss et al., 2009) expression of gluconeogenic genes, e.g., glucose-6-phosphatase and phosphoenolpyruvate carboxykinase (Inoue et al., 2004).”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Inoue et al., 2004
Cites
SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
Horton, J. D., Goldstein, J. L., & Brown, M. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215593 · Cited by 4,092 · see citing works
Vgontzas, A. N., Papanicolaou, D. A., Bixler, E. O., Kales, A., Tyson, K., & Chrousos, G. P. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.5.3950 · Cited by 974 · see citing works
Takeda, K., Kaisho, T., Yoshida, N., Takeda, J., Kishimoto, T., & Akira, S. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.9.4652 · Cited by 584 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Interleukin-6 induces hepcidin expression through STAT3
Wrighting, D. M., & Andrews, N. C. (2006) · Blood · doi:10.1182/blood-2006-06-027631 · Cited by 983 · see citing works
IL-6 pathway in the liver: From physiopathology to therapy
Schmidt-Arras, D., & Rose-John, S. (2016) · Journal of Hepatology · doi:10.1016/j.jhep.2016.02.004 · Cited by 881 · see citing works
A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo
Bai, L., Zhou, H., Xu, R., Zhao, Y., Chinnaswamy, K., McEachern, D., Chen, J., Yang, C.-Y., Liu, Z., Wang, M., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.10.002 · Cited by 652 · see citing works
Hormonal regulation of hepatic glucose production in health and disease
Lin, H. V., & Accili, D. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.06.003 · Cited by 429 · see citing works
Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance
Netea, M. G., Joosten, L. A. B., Lewis, E., Jensen, D. R., Voshol, P. J., Kullberg, B. J., Tack, C. J., van Krieken, H., Kim, S.-H., Stalenhoef, A. F., et al. (2006) · Nature Medicine · doi:10.1038/nm1415 · Cited by 424 · see citing works
Self-citationBharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
Awazawa, M., Ueki, K., Inabe, K., Yamauchi, T., Kubota, N., Kaneko, K., Kobayashi, M., Iwane, A., Sasako, T., Okazaki, Y., et al. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.02.010 · Cited by 277 · see citing works
Self-citationCritical role of STAT3 in leptin's metabolic actions
Buettner, C., Pocai, A., Muse, E. D., Etgen, A. M., Myers, M. G., & Rossetti, L. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.04.014 · Cited by 228 · see citing works
Gao, H., Bryzgalova, G., Hedman, E., Khan, A., Efendic, S., Gustafsson, J.-A., & Dahlman-Wright, K. (2006) · Molecular Endocrinology · doi:10.1210/me.2006-0012 · Cited by 179 · see citing works
Moh, A., Iwamoto, Y., Chai, G.-X., Zhang, S. S.-M., Kano, A., Yang, D. D., Zhang, W., Wang, J., Jacoby, J. J., Gao, B., et al. (2007) · Laboratory Investigation · doi:10.1038/labinvest.3700630 · Cited by 147 · see citing works
Kim, J.-H., Yoon, M.-S., & Chen, J. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.051516 · Cited by 92 · see citing works
Kimura, K., Tanida, M., Nagata, N., Inaba, Y., Watanabe, H., Nagashimada, M., Ota, T., Asahara, S.-I., Kido, Y., Matsumoto, M., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.02.032 · Cited by 84 · see citing works
Self-citationKroy, D. C., Beraza, N., Tschaharganeh, D. F., Sander, L. E., Erschfeld, S., Giebeler, A., Liedtke, C., Wasmuth, H. E., Trautwein, C., & Streetz, K. L. (2010) · Hepatology · doi:10.1002/hep.23322 · Cited by 76 · see citing works
NeuCode Proteomics Reveals Bap1 Regulation of Metabolism
Baughman, J. M., Rose, C. M., Kolumam, G., Webster, J. D., Wilkerson, E. M., Merrill, A. E., Rhoads, T. W., Noubade, R., Katavolos, P., Lesch, J., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.05.096 · Cited by 73 · see citing works
Adewale, Q., Khan, A. F., Carbonell, F., Iturria-Medina, Y., & Initiative, A. D. N. (2021) · eLife · doi:10.7554/elife.62589 · Cited by 44 · see citing works
Inaba, Y., Hashiuchi, E., Watanabe, H., Kimura, K., Sato, M., Kobayashi, M., Matsumoto, M., Kitamura, T., Kasuga, M., & Inoue, H. (2019) · Endocrinology · doi:10.1210/en.2019-00422 · Cited by 18 · see citing works
Self-citationCentral Control of Glucose Homeostasis
Puglianiello, A., & Cianfarani, S. (2006) · The Review of Diabetic Studies · doi:10.1900/rds.2006.3.54 · Cited by 14 · see citing works
- Authors
- Inoue, H., Ogawa, W., Ozaki, M., Haga, S., Matsumoto, M., Furukawa, K., Hashimoto, N., Kido, Y., Mori, T., Sakaue, H., Teshigawara, K., Jin, S., Iguchi, H., Hiramatsu, R., LeRoith, D., Takeda, K., Akira, S., & Kasuga, M.
- Affiliations
- Kobe University (JP)
- Okayama University (JP)
- National Research Institute for Child Health and Development (JP)
- National Institutes of Health (US)
- Research Institute for Microbial Diseases, The University of Osaka (JP)
- Corresponding author
- Kasuga, Masato
- ORCID
- Venue
- Nature Medicine
- Published
- 2004-01-11
- Volume
- 10
- Issue
- 2
- Pages
- 168-174
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2066243203
- Cited by
- 384
- References
- 3
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 14 · 2023: 14 · 2022: 11 · 2021: 18 · 2020: 16 · 2019: 16 · 2018: 24 · 2017: 10 · 2016: 18 · 2015: 13 · 2014: 23 · 2013: 16 · 2012: 21
- FWCI
- 10.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- STAT3, hepatic gluconeogenesis, gluconeogenic gene expression, glucose homeostasis, insulin resistance, adenoviral gene transfer, PGC-1α, diabetes mellitus, hepatocytes, blood glucose, plasma insulin
- MeSH terms
- Adenoviridae, Animals, Blood Glucose, Cells, Cultured, Diabetes Mellitus, Dietary Fats, DNA-Binding Proteins, Gluconeogenesis, Insulin, Liver, Male, Receptors, Cell Surface, Transcription Factors, Trans-Activators, Gene Transfer Techniques, Mice, Knockout, Hepatocytes, Carbohydrate Metabolism, STAT3 Transcription Factor, Mice, Receptors, Leptin
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
