Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models—association with liver and adipose tissue effects
Abstract
Recombinant fibroblast growth factor (FGF)21 has antihyperglycemic, antihyperlipidemic, and antiobesity effects in diabetic rodent and monkey models. Previous studies were confined to measuring steady-state effects of FGF21 following subchronic or chronic administration. The present study focuses on the kinetics of biological actions of FGF21 following a single injection and on the associated physiological and cellular mechanisms underlying FGF21 actions. We show that FGF21 resulted in rapid decline of blood glucose levels and immediate improvement of glucose tolerance and insulin sensitivity in two animal models of insulin resistance ( ob/ob and DIO mice). In ob/ob mice, FGF21 led to a 40–60% decrease in blood glucose, insulin, and amylin levels within 1 h after injection, and the maximal effects were sustained for more than 6 h despite the 1- to 2-h half-life of FGF21. In DIO mice, FGF21 reduced fasting blood glucose and insulin levels and improved glucose tolerance and insulin sensitivity within 3 h of treatment. The acute improvement of glucose metabolism was associated with a 30% reduction of hepatic glucose production and an increase in peripheral glucose turnover. FGF21 appeared to have no direct effect on ex vivo pancreatic islet insulin or glucagon secretion. However, it rapidly induced typical FGF signaling in liver and adipose tissues and in several hepatoma-derived cell lines and differentiated adipocytes. FGF21 was able to inhibit glucose release from H4IIE hepatoma cells and stimulate glucose uptake in 3T3-L1 adipocytes. We conclude that the acute glucose-lowering and insulin-sensitizing effects of FGF21 are potentially associated with its metabolic actions in liver and adipose tissues.
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FGF21 has a short half-life of approximately 0.5-1.5 hours.
“Once secreted, FGF21 has a short half-life of approximately 0.5–1.5 hours (refs. 40,41).”
From Metabolic messengers: FGF21 (2021) · cites this paper as [41]
The decrease in plasma glucose occurs primarily through increased peripheral glucose disposal, although decreases in hepatic glucose production have also been observed.
“This decrease in plasma glucose levels occurs primarily through increased peripheral glucose disposal41,56,65, although decreases in hepatic glucose production have also been observed66.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [41]
A single injection of FGF21 can decrease plasma glucose levels by more than 50% in animal models with genetically induced and diet-induced obesity.
“A single injection of FGF21 can decrease plasma glucose levels by more than 50% in animal models with genetically induced and diet-induced obesity41,65.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [41]
KLB expression is primarily restricted to specific metabolic tissues (liver, pancreas, adipose) and lower in brain; KLB is not expressed in muscle.
“KLB expression is primarily restricted to specific metabolic tissues (for example, the liver, pancreas and adipose tissue)5, and lower expression is observed in the brain22,48–50. Despite some reports to the contrary51,52, KLB is not expressed in muscle5,41.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [41]
FGF21 signalling to adipose tissues promotes the disposal of excess carbohydrates.
“FGF21 signalling to adipose tissues promotes the disposal of excess carbohydrates41,65.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [41]
Pharmacological administration of FGF21 improves insulin and leptin sensitivity in mice.
“Pharmacological administration of FGF21 decreases plasma glucose and lipid levels, improves insulin and leptin sensitivity, decreases hepatic steatosis, increases energy expenditure [[131], [132], [133], [134], [135], [136]], and decreases sugar and alcohol intake in mice [[137], [138], [139], [140], [141], [142]].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [132]
Pharmacological administration of FGF21 increases energy expenditure in mice.
“Pharmacological administration of FGF21 decreases plasma glucose and lipid levels, improves insulin and leptin sensitivity, decreases hepatic steatosis, increases energy expenditure [[131], [132], [133], [134], [135], [136]], and decreases sugar and alcohol intake in mice [[137], [138], [139], [140], [141], [142]].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [132]
Pharmacological administration of FGF21 decreases hepatic steatosis in mice.
“Pharmacological administration of FGF21 decreases plasma glucose and lipid levels, improves insulin and leptin sensitivity, decreases hepatic steatosis, increases energy expenditure [[131], [132], [133], [134], [135], [136]], and decreases sugar and alcohol intake in mice [[137], [138], [139], [140], [141], [142]].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [132]
Pharmacological administration of FGF21 decreases plasma glucose and lipid levels in mice.
“Pharmacological administration of FGF21 decreases plasma glucose and lipid levels, improves insulin and leptin sensitivity, decreases hepatic steatosis, increases energy expenditure [[131], [132], [133], [134], [135], [136]], and decreases sugar and alcohol intake in mice [[137], [138], [139], [140], [141], [142]].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [132]
Acute pharmacological administration of FGF21 increases insulin sensitivity and lowers plasma glucose levels, primarily by stimulating peripheral glucose disposal, while also slightly reducing hepatic glucose production.
“The acute pharmacological administration of FGF21 increases insulin sensitivity and lowers plasma glucose levels, primarily by stimulating peripheral glucose disposal, while also slightly reducing hepatic glucose production (27, 142).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [142]
A single injection of FGF21 to diabetic and obese animal models is sufficient to decrease plasma glucose levels by more than 50%.
“A single injection of FGF21 to diabetic and obese animal models is sufficient to decrease plasma glucose levels by more than 50% (142).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [142]
The half-life of FGF21 is approximately 0.4-2 hours, depending on the species and method of delivery.
“The half-life of FGF21 is approximately 0.4–2 hours, depending on the species and method of delivery (51, 65, 142).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [142]
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Self-citation
- Authors
- Xu, J., Stanislaus, S., Chinookoswong, N., Lau, Y. Y., Hager, T., Patel, J., Ge, H., Weiszmann, J., Lu, S.-C., Graham, M., Busby, J., Hecht, R., Li, Y.-S., Li, Y., Lindberg, R., & Véniant, M. M.
- Affiliations
- Departments of1 Metabolic Disorders,
- Pharmacokinetics and Drug Metabolism, and
- Amgen (United States) (US)
- Protein Sciences, Amgen Inc., Thousand Oaks; and
- Corresponding author
- Xu, Jing
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2009-11
- Volume
- 297
- Issue
- 5
- Pages
- E1105-E1114
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2061333499
- Cited by
- 340
- References
- 28
- Citations by year
- 2026: 14 · 2025: 17 · 2024: 17 · 2023: 21 · 2022: 30 · 2021: 22 · 2020: 22 · 2019: 28 · 2018: 22 · 2017: 29 · 2016: 23 · 2015: 14 · 2014: 23 · 2013: 16 · 2012: 19
- FWCI
- 5.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Amgen
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- FGF21, insulin resistance, glucose tolerance, insulin sensitivity, hepatic glucose production, adipose tissue, FGF signaling, ob/ob mice, diet-induced obesity, amylin, glucagon, hepatoma cells, adipocytes, glucose uptake
- MeSH terms
- Adipose Tissue, Animals, Cell Differentiation, Diet, Dose-Response Relationship, Drug, Enzyme-Linked Immunosorbent Assay, Fibroblast Growth Factors, Humans, Hypoglycemic Agents, Insulin Resistance, Islets of Langerhans, Liver, Liver Neoplasms, Experimental, Male, Mice, Inbred C57BL, Mice, Obese, Obesity, Recombinant Proteins, Blotting, Western, Glucose Clamp Technique, Adipocytes, Area Under Curve, 3T3-L1 Cells, Cell Line, Tumor, Mice, Islet Amyloid Polypeptide
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