Fibroblast growth factor 21 (FGF21) belongs to the FGF19 subfamily. It is mainly expressed in the liver and acts on adipose, liver and pancreatic tissues to regulate the metabolism of substances such as glycolipid balance. It is a metabolic hormone.
(Data source: Phuc P , et al. Cells. 2021)
FGF21 is composed of 209 amino acids and is an endocrine extracellular protein. The 1-28 segment is a signal peptide that guides secretion, and the main functional domain is the 29-216 segment. The C-terminus includes a disordered structure and is easily inactivated by FAP hydrolysis.
(Data source: AlphaFold)
(Data source: Uniprot)
Following its discovery in 2000, understanding of FGF21's functions advanced rapidly: FGF21 was initially identified as a regulator of body weight and an insulin-independent regulator of glucose uptake (2005). Subsequent work demonstrated that FGF21 signals through a unique receptor complex (KLB-FGFR) (2007) and has potent insulin-sensitizing effects in obese rodents (2009). Subsequently, physiological roles for FGF21 in regulating fasting (2007) and macronutrient intake (2013 and 2016) were revealed, highlighting its role in energy and nutrient homeostasis. FGF21 is also a key cellular target in the central nervous system (2014) and adipose tissue (2017), mediating diverse metabolic effects. Clinical studies have revealed the therapeutic potential of FGF21 analogs for the treatment of diabetes and obesity (2013) and nonalcoholic steatohepatitis (2019–2020).
(Data source: Flippo KH, et al. Nat Metab. 2021)
In terms of its mechanism of action, FGF21 primarily relies on the specific cofactor receptor β - Klotho (KLB ) to help activate the "c" splice isoform of FGFR1, 2, and 3, thereby activating extracellular signaling. When β - Klotho is deficient, FGF21 cannot directly bind to FGFRs, making β - Klotho a key factor in mediating the biological functions of FGF21.
(Data source: Sonoda J, et al. Horm Mol Biol Clin Investig. 2017)
At the same time, in the body, FGF21 is proteolytically cleaved by the serine proteases fibroblast activation protein (FAP) and dipeptidyl peptidase IV (DPP-IV) (DPP -IV is responsible for cleavage at the amino termini of residues 2 and 4 , while FAP is responsible for cleavage at residue 171).Although cleavage of residues 2 and 4 does not significantly impair the function of FGF21, cleavage of residue 171 will inactivate FGF21 because the ten residues at the C-terminus of FGF21 are critical for its interaction with the receptor β - Klotho , which is also the main reason for the short half-life of FGF21 (approximately 0.5-1.5 hours).
(Data source: Phuc P , et al. Cells. 2021)
Based on the well-documented beneficial metabolic effects of FGF21, the pharmacological effects of recombinant human FGF21 have also been observed in preclinical disease models, showing outstanding therapeutic potential. However, due to issues with the half-life of enzymatic hydrolysis, the natural form of FGF21 is not suitable for commercialization. Therefore, some pharmaceutical companies are focusing on improving various properties of human FGF21 protein to make it suitable for therapeutic development.
(Data source: Geng L, et al. Nat Rev Endocrinol. 2020)
Over the past decade, more than 160 clinical trials have been conducted on various FGF21 analogs and other forms of agonists that directly activate the FGFR1/KLB receptor complex (i.e., FGF21 receptor agonists or FGF21RAs) to improve obesity and obesity-related complications.
(Data source: Clinical trials)
Although great progress has been made in deciphering the underlying mechanisms of FGF21's metabolic effects, the complexity and diversity of FGF21 pharmacology and pathophysiology, interspecies variation in FGF21 biology, obesity-related FGF21 resistance, and the presence of endogenous FGF21-inactivating enzymes are major obstacles to the clinical implementation of FGF21-based drug therapies for metabolic diseases. We sincerely hope that these obstacles can be overcome as soon as possible to benefit patients.
