FGF15/19 Regulates Hepatic Glucose Metabolism by Inhibiting the CREB-PGC-1α Pathway
Open accessAbstract
Regulation of hepatic carbohydrate homeostasis is crucial for maintaining energy balance in the face of fluctuating nutrient availability. Here, we show that the hormone fibroblast growth factor 15/19 (FGF15/19), which is released postprandially from the small intestine, inhibits hepatic gluconeogenesis, like insulin. However, unlike insulin, which peaks in serum 15 min after feeding, FGF15/19 expression peaks approximately 45 min later, when bile acid concentrations increase in the small intestine. FGF15/19 blocks the expression of genes involved in gluconeogenesis through a mechanism involving the dephosphorylation and inactivation of the transcription factor cAMP regulatory element-binding protein (CREB). This in turn blunts expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and other genes involved in hepatic metabolism. Overexpression of PGC-1α blocks the inhibitory effect of FGF15/19 on gluconeogenic gene expression. These results demonstrate that FGF15/19 works subsequent to insulin as a postprandial regulator of hepatic carbohydrate homeostasis.
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Intestine-secreted FGF15 also plays a pivotal role in the regulation of energy metabolism and liver cell regeneration.
“It is recognized that intestine‐secreted FGF15 also plays a pivotal role in the regulation of energy metabolism and liver cell regeneration (Potthoff et al., 2011).”
From <i>Akkermansia muciniphila</i> alleviates <scp>high‐fat‐diet</scp> ‐related metabolic‐associated fatty liver disease by modulating gut microbiota and bile acids (2023) · cites this paper as Potthoff et al., 2011
The Introduction describes FGF15/19 as a hormone induced in the small intestine with effects on energy homeostasis, and the Discussion reports its regulation of hepatic metabolism. The passages found in our copy do not address liver cell regeneration (searched: liver regeneration, hepatocyte proliferation, regenerating liver cells). (LLM, conf=0.88)
Experimental — accuracy not yet measuredFGF19 increases liver protein and glycogen synthesis while repressing hepatic glucose production, independently from insulin.
“FGF19 also increases liver protein and glycogen synthesis while repressing hepatic glucose production 43, 44, in order to ensure proper postprandial energy storage independently from insulin.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [44]
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- Authors
- Potthoff, M. J., Boney-Montoya, J., Choi, M., He, T., Sunny, N. E., Satapati, S., Suino-Powell, K., Xu, H. E., Gerard, R. D., Finck, B. N., Burgess, S. C., Mangelsdorf, D. J., & Kliewer, S. A.
- Affiliations
- Howard Hughes Medical Institute (US)
- The University of Texas Southwestern Medical Center (US)
- Van Andel Institute (US)
- Washington University in St. Louis (US)
- Corresponding author
- Mangelsdorf, David J.
- Kliewer, Steven A.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2011-06
- Volume
- 13
- Issue
- 6
- Pages
- 729-738
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3131185
- OpenAlex
- W2020515276
- Cited by
- 431
- References
- 51
- Citations by year
- 2026: 24 · 2025: 28 · 2024: 34 · 2023: 28 · 2022: 47 · 2021: 39 · 2020: 30 · 2019: 25 · 2018: 22 · 2017: 34 · 2016: 18 · 2015: 28 · 2014: 22 · 2013: 20 · 2012: 24
- FWCI
- 9.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 777 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (DK067158, DK076269, DK078184, DK078187, U19DK62434)
- Howard Hughes Medical Institute
- Welch Foundation (I-1275, I-1588)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- FGF15/19, hepatic gluconeogenesis, CREB, PGC-1α, hepatic glucose metabolism, carbohydrate homeostasis, bile acids, insulin, transcriptional regulation, dephosphorylation
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Citric Acid Cycle, Fatty Acids, Fibroblast Growth Factors, Gluconeogenesis, Glucose, Liver, Luciferases, Male, Mice, Inbred C57BL, Oxidation-Reduction, Transcription Factors, Signal Transduction, Trans-Activators, Gene Expression, Cyclic AMP Response Element-Binding Protein, Genes, Reporter, Mice, Knockout, Gene Expression Profiling, Mice, Metabolic Networks and Pathways
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