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Fibroblast Growth Factor 21-Deficient Mice Demonstrate Impaired Adaptation to Ketosis
Open accessAbstract
Fibroblast growth factor 21 (FGF21) is a key metabolic regulator. Expressed primarily in liver and adipose tissue, FGF21 is induced via peroxisome proliferator-activated receptor (PPAR) pathways during states requiring increased fatty acid oxidation including fasting and consumption of a ketogenic diet. To test the hypothesis that FGF21 is a physiological regulator that plays a role in lipid oxidation, we generated mice with targeted disruption of the Fgf21 locus (FGF21 knockout). Mice lacking FGF21 had mild weight gain and slightly impaired glucose homeostasis, indicating a role in long-term energy homeostasis. Furthermore, FGF21KO mice tolerated a 24-h fast, indicating that FGF21 is not essential in the early stages of starvation. In contrast to wild-type animals in which feeding KD leads to dramatic weight loss, FGF21KO mice fed KD gained weight, developed hepatosteatosis, and showed marked impairments in ketogenesis and glucose control. This confirms the physiological importance of FGF21 in the adaptation to KD feeding. At a molecular level, these effects were accompanied by lower levels of expression of PGC1alpha and PGC1beta in FGF21KO mice, strongly implicating these key transcriptional regulators in the action of FGF21. Furthermore, within the liver, the maturation of the lipogenic transcription factor sterol regulatory element-binding protein-1c was increased in FGF21KO mice, implicating posttranscriptional events in the maladaptation of FGF21KO mice to KD. These data reinforce the role of FGF21 is a critical regulator of long-term energy balance and metabolism. Mice lacking FGF21 cannot respond appropriately to a ketogenic diet, resulting in an impaired ability to mobilize and utilize lipids.
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“Consistent with these data, Fgf21 total knockout mice fed a ketogenic diet developed hepatosteatosis and exhibited impaired ketogenesis and glucose control (6).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [6]
In the citing paper
“FGF21 is markedly induced by ketogenic diets in rodents and has been proposed to be a key mediator of hepatic lipid metabolism during ketotic states (6, 7).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [6]
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FGF-21 as a novel metabolic regulator
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Fibroblast Growth Factor 21 Corrects Obesity in Mice
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Identification of a novel FGF, FGF-21, preferentially expressed in the liver
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Mitochondria: In Sickness and in Health
Nunnari, J., & Suomalainen, A. (2012) · Cell · doi:10.1016/j.cell.2012.02.035 · Cited by 3,479
The Fibroblast Growth Factor signaling pathway
Ornitz, D. M., & Itoh, N. (2015) · WIREs Developmental Biology · doi:10.1002/wdev.176 · Cited by 2,050
FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis
Fisher, F. M., Kleiner, S., Douris, N., Fox, E. C., Mepani, R. J., Verdeguer, F., Wu, J., Kharitonenkov, A., Flier, J. S., Maratos-Flier, E., et al. (2012) · Genes & Development · doi:10.1101/gad.177857.111 · Cited by 1,478
Self-citationKetone bodies as signaling metabolites
Newman, J. C., & Verdin, E. (2014) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2013.09.002 · Cited by 966
Understanding the Physiology of FGF21
Fisher, F. M., & Maratos-Flier, E. (2016) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021115-105339 · Cited by 912
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Metadata
- Authors
- Badman, M. K., Koester, A., Flier, J. S., Kharitonenkov, A., & Maratos-Flier, E.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- BioTechnology Discovery Research (A.Ko., A.Kh.), Lilly Research Laboratories, Indianapolis, Indiana 46285
- Eli Lilly (United States) (US)
- Division of Endocrinology, Diabetes, and Metabolism (M.K.B., J.S.F., E.M.-F.), Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215;
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2009-10-09
- Volume
- 150
- Issue
- 11
- Pages
- 4931-4940
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC2775979
- OpenAlex
- W2020958481
- Cited by
- 362
- References
- 27
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 19 · 2023: 15 · 2022: 13 · 2021: 24 · 2020: 24 · 2019: 25 · 2018: 22 · 2017: 26 · 2016: 27 · 2015: 30 · 2014: 20 · 2013: 25 · 2012: 36
- FWCI
- 9.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- National Institutes of Health (5r01dk069983-05)
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK056116, P30DK046200, R01-DK-069983, R37DK028082)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Physiology (medical) › Dietary Effects on Health
- Health Sciences › Medicine › Physiology (medical) › Diet and metabolism studies
- Keywords
- FGF21, FGF21 knockout mice, ketogenic diet, ketogenesis, fasting tolerance, energy homeostasis, PGC-1α, PGC-1β, SREBP-1c, hepatic steatosis, lipid oxidation, glucose homeostasis, weight gain
- MeSH terms
- Animals, Disease Models, Animal, Energy Metabolism, Fatty Liver, Female, Fibroblast Growth Factors, Glucose, Humans, Ketosis, Male, Mice, Inbred C57BL, Mice, Knockout, Gene Silencing, Lipid Metabolism, Mice, Diet, Ketogenic
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