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The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic

Abstract

Fibroblast growth factor 21 (FGF21) is a stress-inducible hormone that has important roles in regulating energy balance and glucose and lipid homeostasis through a heterodimeric receptor complex comprising FGF receptor 1 (FGFR1) and β-klotho. Administration of FGF21 to rodents or non-human primates causes considerable pharmacological benefits on a cluster of obesity-related metabolic complications, including a reduction in fat mass and alleviation of hyperglycaemia, insulin resistance, dyslipidaemia, cardiovascular disorders and non-alcoholic steatohepatitis (NASH). However, native FGF21 is unsuitable for clinical use owing to poor pharmacokinetic and biophysical properties. A large number of long-acting FGF21 analogues and agonistic monoclonal antibodies for the FGFR1–β-klotho receptor complexes have been developed. Several FGF21 analogues and mimetics have progressed to early phases of clinical trials in patients with obesity, type 2 diabetes mellitus and NASH. In these trials, the primary end points of glycaemic control have not been met, whereas substantial improvements were observed in dyslipidaemia, hepatic fat fractions and serum markers of liver fibrosis in patients with NASH. The complexity and divergence in pharmacology and pathophysiology of FGF21, interspecies variations in FGF21 biology, the possible existence of obesity-related FGF21 resistance and endogenous FGF21 inactivation enzymes represent major obstacles to clinical implementation of FGF21-based pharmacotherapies for metabolic diseases.

Key points

  • The discovery of fibroblast growth factor 21 (FGF21) as a potent agent for treatment of obesity and type 2 diabetes mellitus in animals has inspired the development of engineered FGF21 analogues and mimetics with improved potency and pharmacokinetic profiles.

  • The multiple metabolic effects of FGF21 are mediated by both its central and peripheral actions, and by its fine-tuning of inter-organ metabolic crosstalk.

  • In individuals with obesity and type 2 diabetes mellitus, FGF21 analogues alleviate dyslipidaemia and increase adiponectin levels, but have minimal effects on glycaemic control, thereby highlighting interspecies differences in the actions of FGF21.

  • In patients with non-alcoholic steatohepatitis, FGF21 analogues ameliorate hepatic steatosis, liver stiffness and biomarkers of liver fibrosis, whereas the long-term effects on histopathology and clinical outcomes of non-alcoholic steatohepatitis remain unknown.

  • In obesity, systemic and/or adipose depot-selective FGF21 resistance might exist and underpin insulin resistance, thus potentially compromising the therapeutic effects of FGF21 analogues.

  • Target-specific delivery of FGF21 analogues, as well as the development of tissue-selective FGF21 receptor agonists and FGF21 sensitizers, might help to improve the therapeutic efficacy and safety of FGF21-based pharmacotherapies.

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Fig. 1: FGF21 exerts its pharmacological effects by coordinating inter-organ communications.
Fig. 2: A summary of engineered hFGF21 analogues and FGF21 receptor agonists.

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Acknowledgements

The authors acknowledge the support of the Hong Kong Research Grants Council/Area of Excellence (AoE/M/707-18), the Collaborative Research Fund (C7037-17W), the General Research Fund (17125317 and 17127518) and the Science and Technology Major Project of Hunan Province (2017SK1020).

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A.X. and L.G. researched data for the article, made substantial contributions to discussions of the content and wrote the article. A.X., L.G. and K.S.L.L. carried out a review and editing of the manuscript before submission.

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Correspondence to Aimin Xu.

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Nature Reviews Endocrinology thanks D. Mangelsdorf, E. Maratos-Flier and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Type 2 immune responses

Type 2 T helper cell immune responses are characterized by the recruitment and activation of mast cells, basophils and eosinophils, and goblet cell hyperplasia to produce IL-4, IL-5 and IL-13 in tissues.

Fragment antigen-binding region

(Fab). A region on an antibody that binds to antigens that is composed of one constant and one variable domain of each of the heavy and the light chain.

Fragment crystallizable region

(Fc). The tail region of an antibody that interacts with cell surface receptors called Fc receptors and some proteins of the complement system.

Avimer

A type of artificial antibody mimetic specifically binding to certain antigens via multiple binding sites.

Phage display

A laboratory technique for the study of protein–protein, protein–peptide and protein–DNA interactions that uses bacteriophages (viruses that infect bacteria) to connect proteins with the genetic information that encodes them, which enables antibody maturation in vitro and revolutionizes antibody drug discovery.

XenoMouse

A genetically engineered strain of mice that produce fully humanized antibodies for therapeutic applications.

Knobs-into-holes

Originally proposed as a model for the packing of amino acid side chains between adjacent α-helices, this technology is now being used as an effective design strategy for engineering antibody heavy chain homodimers for heterodimerization.

Biparatopic molecule

A bispecific molecule that recognizes two different epitopes on the same antigen.

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Geng, L., Lam, K.S.L. & Xu, A. The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic. Nat Rev Endocrinol 16, 654–667 (2020). https://doi.org/10.1038/s41574-020-0386-0

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