Fibroblast Growth Factor 21 Signaling in Metabolic Regulation

Fibroblast Growth Factor 21 (FGF21) has emerged as a pivotal endocrine regulator of energy balance, glucose homoeostasis and lipid metabolism. Synthesised predominantly by the liver under conditions of metabolic stress—such as fasting, thermogenic activation or high carbohydrate intake—FGF21 circulates to act on distant tissues including adipose depots, skeletal muscle and the central nervous system. Its activity requires binding to fibroblast growth factor receptors (FGFRs) in complex with the obligate coreceptor β-Klotho, thereby initiating downstream cascades such as the PI3K–Akt pathway or modulation of transcriptional programmes. FGF21 promotes fatty acid oxidation and ketogenesis in the liver, enhances insulin sensitivity in adipocytes, stimulates glucose uptake and dampens lipogenesis in peripheral tissues. Moreover, FGF21 intersects with other hormonal axes—such as growth hormone/IGF-1 signalling—to coordinate adaptive responses to nutrient scarcity and overnutrition. Preclinical models have demonstrated that chronic elevation of FGF21 can prevent weight gain, ameliorate hepatic steatosis and extend lifespan, underlining its therapeutic potential for obesity, type 2 diabetes and related cardiometabolic disorders.

Research from Nature Portfolio

Recent investigations have uncovered a novel cardioprotective role for FGF21 beyond classical metabolic targets. In models of myocardial ischaemia–reperfusion, FGF21 is upregulated in the liver and adipose tissue and released into the circulation. Interaction with FGFR1 and β-Klotho on cardiomyocytes activates the PI3K–Akt–BAD signalling axis, reducing caspase-3 activity, cardiomyocyte apoptosis and infarct size while improving cardiac function. This work highlights endocrine communication between metabolic organs and the injured heart, suggesting FGF21 as a mediator of innate myocardial resilience.

Fibroblast Growth Factor 21 Signaling in Metabolic Regulation publication trend

The graph below shows the total number of articles in fibroblast growth factor 21 signaling in metabolic regulation across all publications each year (not limited to Nature Index journals).

Technical terms

FGF21: endocrine hormone of the fibroblast growth factor family involved in regulating glucose, lipid and energy homeostasis.

Fibroblast Growth Factor Receptor (FGFR): cell-surface tyrosine kinase receptors that mediate FGF21 signalling when bound by cofactors.

β-Klotho: transmembrane coreceptor required for FGF21 to activate FGFRs in target tissues.

Homeostatic Model Assessment of Insulin Resistance (HOMA-IR): a calculated index reflecting insulin sensitivity based on fasting glucose and insulin levels.

Carbohydrate Responsive-Element Binding Protein (ChREBP): transcription factor that regulates glycolytic and lipogenic gene expression in response to carbohydrate intake.

Adeno-associated viral vector (AAV): a delivery system for gene therapy that enables sustained expression of target proteins in specific organs.

References

1. The role of fibroblast growth factor 21 in metabolic processes in patients with gastrointestinal diseases. Gastroenterology (2024).
2. FGF21 as Modulator of Metabolism in Health and Disease. Frontiers in Physiology (2019).
3. Thermogenic Activation Induces FGF21 Expression and Release in Brown Adipose Tissue*. Journal of Biological Chemistry (2011).
4. FGF21 Requires βklotho to Act In Vivo. PLOS ONE (2012).
5. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. eLife (2012).
6. Endocrine Protection of Ischemic Myocardium by FGF21 from the Liver and Adipose Tissue. Scientific Reports (2013).
7. FGF21 gene therapy as treatment for obesity and insulin resistance. EMBO Molecular Medicine (2018).
8. A critical role for ChREBP-mediated FGF21 secretion in hepatic fructose metabolism. Molecular Metabolism (2016).