Fibroblast growth factor 21: a promising therapeutic target in obesity-related diseases

Abstract

Fibroblast growth factor 21 (FGF21) is a peptide hormone secreted by the liver, adipocytes, pancreas and skeletal muscle. It acts locally but is also a circulating hormone. Administration of FGF21 in animals and humans results in a decrease in body weight, blood triglycerides and LDL-cholesterol, with improvement in insulin sensitivity. FGF21 is known to play an important role during fasting and starvation by stimulating gluconeogenesis in the liver and inducing lipolysis in white adipose tissues. FGF21 expression is mediated by the peroxisome proliferator-activated receptor-α, while its biological actions are mediated through binding to a complex formed by its receptors and an essential coreceptor, β-Klotho. Serum FGF21 levels are paradoxically elevated in obesity, suggesting a decreased responsiveness. Recent data showed that serum FGF21 level is elevated in hypertension, atherosclerosis and coronary artery disease, raising the possibility that FGF21 plays a role in the pathophysiology of these diseases.

Keywords::

• fibroblast growth factor 21
• metabolic syndrome
• obesity

Financial & competing interests disclosure

Funding of research into FGF21 is supported by a Collaborative Research Grant (HKU2/CRF/12R) from the Hong Kong Research Grant Council. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• FGF21 regulates lipid and glucose homeostasis via stimulating fatty acid oxidation, gluconeogenesis and glucose uptake. The expressions of β-Klotho and various FGF receptors determine the tissue-specific actions of FGF21.

• Circulating levels of FGF21 are increased in diseases related to obesity, such as metabolic syndrome, diabetes, hypertension and dyslipidemia. Administration of FGF21 in animals with obesity and diabetes decreases body weight and blood triglyceride, and increases insulin sensitivity.

• A first-in-man, proof-of-concept randomized trial showed that LY2405319, an analog of FGF21 injected daily for a month improved the lipid profile in 38 patients with Type 2 diabetes. This exciting discovery paves the way for the search of an oral drug that mimics the actions of FGF21, and also long-term studies of the safety and efficacy of raising FGF21 in man. Such a drug has the potential to lower body fat, body weight, triglyceride and LDL while raising HDL-cholesterol, and treating obesity, dyslipidemia, diabetes and hypertension all at once.