MECHANISMS IN ENDOCRINOLOGY: Biological role, clinical significance, and therapeutic possibilities of the recently discovered metabolic hormone fibroblastic growth factor 21

Abstract

<jats:p>Fibroblast growth factor 21 (FGF21), a 181 amino acid circulating protein, is a member of the FGF superfamily, with relevant metabolic actions. It acts through the interaction with specific FGF receptors and a cofactor called β-Klotho, whose expression is predominantly detected in metabolically active organs. FGF21 stimulates glucose uptake in adipocytes via the induction of glucose transporter-1. This action is additive and independent of insulin. β-Cell function and survival are preserved, and glucagon secretion is reduced by this protein, thus decreasing hepatic glucose production and improving insulin sensitivity. Lipid profile has been shown to be improved by FGF21 in several animal models. FGF21 increases energy expenditure in rodents and induces weight loss in diabetic nonhuman primates. It also exerts favorable effects on hepatic steatosis and reduces tissue lipid content in rodents. Adaptive metabolic responses to fasting, including stimulation of ketogenesis and fatty acid oxidation, seem to be partially mediated by FGF21. In humans, serum FGF21 concentrations have been found elevated in insulin-resistant states, such as impaired glucose tolerance and type 2 diabetes. FGF21 levels are correlated with hepatic insulin resistance index, fasting blood glucose, HbA1c, and blood glucose after an oral glucose tolerance test. A relationship between FGF21 levels and long-term diabetic complications, such as nephropathy and carotid atheromatosis, has been reported. FGF21 levels decreased in diabetic patients after starting therapy with insulin or oral agents. Increased FGF21 serum levels have also been found to be associated with obesity. In children, it is correlated with BMI and leptin levels, whereas in adults, FGF21 levels are mainly related to several components of the metabolic syndrome. Serum FGF21 levels have been found to be elevated in patients with ischemic heart disease. In patients with renal disease, FGF21 levels exhibited a progressive increase as renal function deteriorates. Circulating FGF21 levels seem to be related to insulin resistance and inflammation in dialysis patients. In summary, FGF21 is a recently identified hormone with antihyperglycemic, antihyperlipidemic, and thermogenic properties. Direct or indirect potentiation of its effects might be a potential therapeutic target in insulin-resistant states.</jats:p>

Additive protection by LDR and FGF21 treatment against diabetic nephropathy in type 2 diabetes model

“…Serum FGF21 levels were increased significantly in humans with both acute and chronic renal dysfunction during early-to end-stage kidney disease, which might be an adaptive response to diabetes to confer protective effects (30). FGF21 suppresses diabetes-induced inflammation, oxidative stress, and fibrosis in multiple organs, which could be attributed to its effects on maintaining glucose and lipid homeostasis and improving insulin resistance (22,27,56). Similarly, renal protective effects of FGF21 were also observed in our recent study performed in an acute lipotoxic model of type 1 diabetes (56).…”

Human brown adipose tissue: regulation and anti-obesity potential [Review]

“…Fibroblast growth factor 21 (FGF21), a liver-derived endocrine factor, has gathered increasing attention because it reduces body fatness and improves glucose tolerance when administrated to rodent models of obesity and type 2 diabetes [54]. FGF21 is potential for inducing the thermogenic program in BAT, and also for driving beige/brite adipocyte recruitment in WAT [55].…”

Serum Level of Fibroblast Growth Factor 21 in Type 2 Diabetic Patients with and without Metabolic Syndrome

“…Production of this factor takes place in the liver, white adipose tissue, skeletal muscle and pancreas. Glucose and lipid metabolism regulation may depend on FGF21 (Iglesias et al, 2012). Some studies have shown that fasting and feeding may regulate FGF21 expression (Uebanso et al, 2011).…”