Description
Human FGF-21 Fibroblast growth factor 21 (FGF-21) is a member of the FGF gene family, which currently contains 22 human members. Based on its structure, it is further classified as an FGF19 subfamily member. This subfamily includes FGF-19, -21, and -23. Like all other FGF subfamilies, FGF-19 subfamily members contain a 120 amino acid (aa) core FGF domain that exhibits a b-trefoil structure (1, 2). Unlike other FGF subfamilies, FGF-19 subfamily members apparently exhibit poor binding to ECM, resulting in highly diffusible molecules (3). The c-DNA for FGF-21 predicts a 209 aa polypeptide that contains a 28 aa signal sequence and a 181 aa mature region (4). Notably, FGF-21, as well as FGF-19 shows limited binding to heparin (4). One potential alternate splice form has been reported. It shows a 43 aa substitution for the C-terminal 12 aa of the standard form (5). Mature human FGF-21 shows 81% aa identity to mouse FGF-21, and is known to be active on mouse cells (4, 6). The FGF-19 subfamily is considered endocrine in nature. All three subfamily members impact some aspect of metabolism, all three are induced by a nuclear receptor heterodimer that includes RXR, and all three utilize Klotho family members for signal transduction (7, 8, 9). FGF-21 is produced by hepatocytes in response to free fatty acid (FFA) stimulation of a PPARa/RXR dimeric complex (3, 7, 10, 11). This situation occurs clinically during starvation, or following the ingestion of a high-fat/low-carbohydrate diet. Upon FGF-21 secretion, white adipose tissue is induced to release FFAs from triglyceride stores. Once FFAs reach hepatocytes, they are oxidized and reduced to acetyl-CoA. The acetyl-CoA is recombined into 4-carbon ketone bodies (acetoacetate and b-hydroxybutyrate), released, and transported to peripheral tissues for TCA processing and energy generation (11, 12)