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Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23

Key Points

  • Endocrine fibroblast growth factors (FGFs) are critical regulators of glucose and lipid metabolism, and gatekeepers of vitamin D and phosphate homeostasis.

  • Endocrine FGFs may serve as both risk factors and biomarkers of chronic metabolic disorders, including obesity, type 2 diabetes, cancer, and kidney and cardiovascular disease.

  • The intestine-derived FGF19 is a critical regulator of both bile acid and glucose metabolism, and its pharmacological modulation has been proposed as a promising approach for the treatment of disorders related to the gut–liver axis, including cholestasis.

  • The liver-derived hormone FGF21 is a master regulator of substrate turnover and orchestrates crosstalk between the liver, white adipose tissue, brain, pancreas and brown adipose tissue. FGF21 is rapidly emerging as an attractive target in the treatment of metabolic syndrome and type 2 diabetes.

  • The bone-derived hormone FGF23 is the physiological regulator of phosphate and vitamin D serum levels and, along with its cofactor α-klotho, it could serve as an effective biomarker for prediction of outcome as well as treatment guidance in chronic kidney disease. A health-promoting activity of FGF23 has also been proposed.

  • Pharmaceutical efforts are in progress to develop FGF analogues or mimetics that are devoid of mitogenic potential and risk of bone loss, and also endowed with a better pharmacokinetic profile.

Abstract

The endocrine fibroblast growth factors (FGFs), FGF19, FGF21 and FGF23, are critical for maintaining whole-body homeostasis, with roles in bile acid, glucose and lipid metabolism, modulation of vitamin D and phosphate homeostasis and metabolic adaptation during fasting. Given these functions, the endocrine FGFs have therapeutic potential in a wide array of chronic human diseases, including obesity, type 2 diabetes, cancer, and kidney and cardiovascular disease. However, the safety and feasibility of chronic endocrine FGF administration has been challenged, and FGF analogues and mimetics are now being investigated. Here, we discuss current knowledge of the complex biology of the endocrine FGFs and assess how this may be harnessed therapeutically.

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Figure 1: Endocrine FGF transcriptional regulation.
Figure 2: Liver-specific FGF19 metabolic actions.
Figure 3: Pleiotropic metabolic actions of FGF21.
Figure 4: FGF23, an endocrine nexus between hormones and mineral ions.

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Acknowledgements

The authors apologize to our distinguished colleagues whose work has not been cited owing to space limitations. The authors are indebted to Dr R. Le Donne for the artwork. The authors received research grants from the European Marie Curie Initial Training Network (NR-NET 606806), the Italian Association for Cancer Research (AIRC, IG 14732), the Italian Ministry of University and Education (Finanziamenti per la Ricerca di Base IDEAS RBID08C9N7; PRIN 2010FHH32M-002), the Italian Ministry of Health (Young Researchers Grant GR-2010-2314703), Intercept Pharmaceuticals (San Diego CA), NGM BioPharmaceuticals (San Francisco CA) and University of Bari Aldo Moro (IDEA GRBA0802SJ-2008).

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Glossary

Heparin or heparan sulphate glycosaminoglycans

(HSGAGs). Long chains of repeated saccharide units that can be variably sulphated or acetylated, allowing for considerable structural diversity. HSGAGs are located in the extracellular matrix of the surface of every cell, where they modulate the activity of a wide range of growth factors and morphogens.

Tumour-induced osteomalacia

(TIO). A rare paraneoplastic syndrome in which patients present with bone pain, fractures and muscle weakness. This uncommon disorder results in increased renal phosphate excretion, hypophosphataemia and osteomalacia.

Cholestasis

A decrease in bile flow owing to impaired secretion by hepatocytes or owing to obstruction of bile flow through intra-or extrahepatic bile ducts. Therefore, the clinical definition of cholestasis is any condition in which substances that are normally excreted into bile are retained.

Promoter

An element of DNA that may bind RNA polymerase and other proteins for the successful initiation of transcription directly upstream of the gene.

Insulin resistance

The inability of a known quantity of exogenous or endogenous insulin to induce a normal increase in glucose uptake and utilization. Insulin resistance occurs as part of a cluster of cardiovascular-metabolic abnormalities commonly referred to as the insulin resistance syndrome or the metabolic syndrome.

Non-alcoholic fatty liver disease

(NAFLD). A condition defined by excessive fat accumulation in the form of triglycerides (steatosis) in the liver. In the majority of patients, NAFLD is associated with metabolic risk factors such as obesity, diabetes mellitus, and dyslipidaemia.

Hypothalamic–pituitary–adrenal axis

(HPA axis). A complex set of direct influences and feedback interactions among three endocrine glands: the hypothalamus, the pituitary gland and the adrenal glands. The HPA axis controls reactions to stress and regulates many body processes, including digestion, the immune system, mood and emotions, sexuality, and energy storage and expenditure.

Sumoylation

A post-translational modification process affecting protein structure and subcellular localization. It is analogous to ubiquitylation in terms of the reaction scheme and enzyme classes used, but rather than conjugation by ubiquitin, sumoylation involves addition of SUMOs (small ubiquitin-like modifiers).

Suprachiasmatic nucleus

(SCN). A tiny region located in the hypothalamus, situated directly above the optic chiasm, responsible for controlling circadian rhythms. The neuronal and hormonal activities it generates regulate many different body functions in a 24-hour cycle, using around 20,000 neurons. The SCN contains several cell types and several different peptides (including vasopressin and vasoactive intestinal peptide) and neurotransmitters.

Dorsal vagal complex

(DVC). The DVC encompasses the nucleus tractus solitarii (NTS), the dorsal motor nucleus of the vagus nerve (DMX) and the area postrema (AP), that altogether provide the major integrative centre for the mammalian autonomic nervous system.

Hyperparathyroidism

A disease characterized by excessive secretion of parathyroid hormone, an 84-amino-acid polypeptide hormone.

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Degirolamo, C., Sabbà, C. & Moschetta, A. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Nat Rev Drug Discov 15, 51–69 (2016). https://doi.org/10.1038/nrd.2015.9

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