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FGF-21 as a novel metabolic regulator
Open accessAbstract
Diabetes mellitus is a major health concern, affecting more than 5% of the population. Here we describe a potential novel therapeutic agent for this disease, FGF-21, which was discovered to be a potent regulator of glucose uptake in mouse 3T3-L1 and primary human adipocytes. FGF-21-transgenic mice were viable and resistant to diet-induced obesity. Therapeutic administration of FGF-21 reduced plasma glucose and triglycerides to near normal levels in both ob/ob and db/db mice. These effects persisted for at least 24 hours following the cessation of FGF-21 administration. Importantly, FGF-21 did not induce mitogenicity, hypoglycemia, or weight gain at any dose tested in diabetic or healthy animals or when overexpressed in transgenic mice. Thus, we conclude that FGF-21, which we have identified as a novel metabolic factor, exhibits the therapeutic characteristics necessary for an effective treatment of diabetes.
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In the citing paper
“In general, FGF21 stimulates the uptake of glucose by adipocytes and inhibits the production of glucose in the liver.”
From Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases (2018) · cites this paper as Kharitonenkov et al., 2005
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“FGF21 acts in the control of glucose and lipid homeostasis (Kharitonenkov et al., 2005).”
From Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases (2018) · cites this paper as Kharitonenkov et al., 2005
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In the citing paper
“In addition, FGF21 appears to protect pancreatic β cells from cell death induced by glycotoxicity (Kharitonenkov et al., 2005, 2007).”
From Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases (2018) · cites this paper as Kharitonenkov et al., 2005
Experimental — accuracy not yet measuredIn the citing paper
“Interestingly, mice that overexpress FGF-21, a circulating FGF which is induced by a ketogenic diet 106, are lean and have increased brown fat 107, suggesting that the beneficial metabolic effects induced by a ketogenic diet are brought about in part by increases in BAT mass.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [107]
In the citing paper
“FGF21 binding promotes the formation of a dimeric FGFR1c–KLB signalling complex, which activates the intracellular tyrosine kinase domains of FGFR1c and propagates signalling through phosphorylation by the kinase ERK46,53,58,59”
From Metabolic messengers: FGF21 (2021) · cites this paper as [58]
In the citing paper
“prolonged administration of FGF21 or FGF21 analogues has important metabolic effects, including a marked decrease in body weight in rodents and non-human primates, and more modest effects on body weight in humans3,40,58,77,78.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [58]
In the citing paper
“overexpression of FGF21 is highly protective [135].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [135]
In the citing paper
“activation of the FGF21/FGFR1c/KLB receptor complex results in the phosphorylation of ERK1/2 and FRS2α [135].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [135]
In the citing paper
“A myriad of studies ensued demonstrating that administering FGF21 to obese or diabetic rodents and primates markedly reduced body weight and significantly improved carbohydrate and lipid homeostasis (21, 64, 65, 141).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [64]
In the citing paper
“In rodents, pharmacological levels of FGF21 increase energy expenditure (64, 141), which results in increased food intake (54, 64).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [64]
In the citing paper
“Since FGF21 administration increases energy expenditure and the browning of adipose tissues in vivo (21, 64, 141), it was hypothesized that FGF21 regulates adaptive thermogenesis in response to cold.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [64]
In the citing paper
“When administered to diabetic and obese animal models, FGF21 provides multiple metabolic benefits and has been shown to decrease blood glucose levels and body weight, improve insulin and leptin sensitivity, improve plasma lipid profiles, and decrease hepatic steatosis (21, 64, 141, 142).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [64]
In the citing paper
“Importantly, in animal models FGF21 treatment not only prevents (64) but also reverses diabetes and obesity (21, 141).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [64]
In the citing paper
“In addition, FGF21 enhances insulin sensitivity in primary brown adipocytes (86) but not in primary white adipocytes (64, 86).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [64]
In the citing paper
“FGF21’s ability to reduce body weight, glucose levels, and lipid concentrations in models of obesity generated substantial initial interest”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [114]
In the citing paper
“Fibroblast growth factor 21 (FGF21) was first identified as an hepatokine 61 and has been shown to be necessary for the adaptation to fasting 62, 63.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [61]
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Metadata
- Authors
- Kharitonenkov, A., Shiyanova, T. L., Koester, A., Ford, A. M., Micanovic, R., Galbreath, E. J., Sandusky, G. E., Hammond, L. J., Moyers, J. S., Owens, R. A., Gromada, J., Brozinick, J. T., Hawkins, E. D., Wroblewski, V. J., Li, D.-S., Mehrbod, F., Jaskunas, S. R., & Shanafelt, A. B.
- Affiliations
- Eli Lilly (United States) (US)
- Corresponding author
- Kharitonenkov, Alexei
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2005-06-01
- Volume
- 115
- Issue
- 6
- Pages
- 1627-1635
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1088017
- OpenAlex
- W2000665430
- Cited by
- 2,125
- References
- 46
- Citations by year
- 2026: 72 · 2025: 99 · 2024: 111 · 2023: 120 · 2022: 137 · 2021: 138 · 2020: 116 · 2019: 136 · 2018: 147 · 2017: 135 · 2016: 142 · 2015: 155 · 2014: 124 · 2013: 125 · 2012: 115
- FWCI
- 8.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- Hospital for Sick Children
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- FGF21, diabetes mellitus, glucose uptake, adipocytes, diet-induced obesity, transgenic mice, ob/ob mice, db/db mice, plasma glucose, triglycerides, metabolic regulation, diabetes treatment
- MeSH terms
- Animals, Blood Glucose, Cell Division, Cells, Cultured, Diabetes Mellitus, Fibroblast Growth Factors, Humans, Hyperglycemia, Hypoglycemic Agents, Mice, Obese, Mice, Transgenic, Triglycerides, Weight Gain, Adipocytes, Mice
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