FGF21-based pharmacotherapy – potential utility for metabolic disorders

•FGF21 is a secreted protein that reduces glucose levels, decreases body weight, and decreases serum lipids in rodents and non-human primates. •FGF21 signals primarily through the β-Klotho/FGFR1c receptor complex with adipose tissue being a key target for its metabolic actions. •Endogenous FGF21 circulates at variable levels and plays a role in mediating the physiological response to starvation and a variety of other metabolic stresses. •FGF21-based therapies are being developed and a FGF21-based analog has shown promising results in a human proof-of-concept trial. Currently available therapies for diabetes or obesity produce modest efficacy and are usually used in combination with agents targeting cardiovascular risk factors. Fibroblast growth factor 21 (FGF21) is a circulating protein with pleiotropic metabolic actions; pharmacological doses of FGF21 produce anti-diabetic, lipid-lowering, and weight-reducing effects in rodents. Several potential benefits have translated to non-human primates and obese humans with type 2 diabetes (T2D). Accumulating results point to a specific receptor complex and actions in adipose tissue, liver, and brain; several pathways lead to enhanced fatty acid oxidation, increased insulin sensitivity, and augmented energy expenditure. A range of strategies are being explored to derive potent, safe, and convenient therapies which could potentially represent novel approaches to prevent and treat a variety of metabolic disorders. Currently available therapies for diabetes or obesity produce modest efficacy and are usually used in combination with agents targeting cardiovascular risk factors. Fibroblast growth factor 21 (FGF21) is a circulating protein with pleiotropic metabolic actions; pharmacological doses of FGF21 produce anti-diabetic, lipid-lowering, and weight-reducing effects in rodents. Several potential benefits have translated to non-human primates and obese humans with type 2 diabetes (T2D). Accumulating results point to a specific receptor complex and actions in adipose tissue, liver, and brain; several pathways lead to enhanced fatty acid oxidation, increased insulin sensitivity, and augmented energy expenditure. A range of strategies are being explored to derive potent, safe, and convenient therapies which could potentially represent novel approaches to prevent and treat a variety of metabolic disorders.