Since the debut in 2005 (1), fibroblast growth factor 21 (FGF21) has been of growing interest due to its dramatic beneficial effects at pharmacological levels on weight reduction and alleviation of obesity, diabetes, and fatty liver disease (2, 3). These effects include promoting clearance of systemic glucose and lipids (cholesterol, fatty acids, and triacylglycerides) and enhancing insulin sensitivity, adiponectin action, mitochondrial function, thermogenesis, and energy expenditure (1, 2, 4). Unlike most of the FGF family members that require extracellular heparan sulfate proteoglycan and act locally via autocrine and paracrine mechanisms, FGF21 as a member of the endocrine FGF19 subfamily travels through the circulation to sites distal from its origin and acts predominantly as an endocrine hormone (5). Instead of heparan sulfate proteoglycans, the activity of FGF21 is determined by a transmembrane co-receptor betaKlotho (KLB) that is present as a binary complex with FGF receptor tyrosine kinases (FGFR) in several endocrine and metabolic tissues. This allows selective action of circulating FGF21 on the target tissues expressing FGFR1-KLB complex without affecting those expressing FGFR1 alone.
