FGF21 (fibroblast growth factor 21; HGNC:3678, NCBI Gene ID 26291) is a human locus mapped to chromosome band 19q13.33 that encodes secreted endocrine non-heparin-binding hepatokine FGF21 (181 mature aa; 19.4 kDa). FGF21 acts in FGFR1c/Beta-Klotho (KLB) adipose lipolysis, UCP1 thermogenesis, hepatic beta-oxidation & hypothalamic sweet/alcohol suppression, together with KL (Alpha-Klotho Longevity Paralog Gene), PPARA (PPAR-Alpha Master Regulator of Fasting FGF21), and UCP1 (Thermogenin Brown Adipose Gene). Encodes the fasting- and stress-induced endocrine hepatokine FGF21 that signals via FGFR1c/beta-Klotho to stimulate fatty acid oxidation, thermogenesis, and liver fibrosis resolution.
Genomic Organization & Cytogenetic Locus: 3-exon gene on chromosome 19q13.33 whose promoter contains canonical response elements for fasting-activated PPARA, ER/mitochondrial stress-activated ATF4, and carbohydrate-activated ChREBP, encoding a 209-residue preprotein (181-residue mature beta-trefoil protein) that lacks the conventional heparin-binding affinity of paracrine FGFs and therefore escapes the extracellular matrix into systemic circulation.
Cellular & Tissue Expression Profile: Synthesized and secreted into plasma predominantly by hepatic hepatocytes during prolonged fasting, ketogenic diets, protein restriction, alcohol or fructose ingestion, and mitochondrial stress, with secondary inducible expression in brown adipocytes, skeletal muscle, and exocrine pancreas.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Requires the single-pass transmembrane co-receptor Beta-Klotho (KLB, paralog of KL) complexed with FGFR1c (and FGFR3c/4) to signal: in white and brown adipose tissue FGF21 induces adiponectin (ADIPOQ) secretion, glucose uptake, PGC-1alpha (PPARGC1A), and UCP1-mediated thermogenesis; in the liver it accelerates fatty acid beta-oxidation and ketogenesis while suppressing de novo lipogenesis; and in the hypothalamic paraventricular nucleus it suppresses sugar and alcohol preference while extending lifespan in transgenic mice by ~30–40%.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Common human coding and non-coding variants at the FGF21 locus (such as rs838133 and rs838145) show strong genome-wide associations with macronutrient intake preference (higher carbohydrate and alcohol intake) and waist-to-hip ratio.
Therapeutic & Clinical Pharmacology: Because native FGF21 has a brief ~1–2 hour half-life due to fibroblast activation protein (FAP) C-terminal cleavage, engineered long-acting glycoPEGylated or Fc-fusion FGF21 analogs (efruxifermin, pegozafermin, zalfermin) are in Phase 3 clinical trials, demonstrating rapid hepatic fat clearance and fibrosis regression in metabolic dysfunction-associated steatohepatitis (MASH) and severe hypertriglyceridemia.